new research on cholesterol and heart disease

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• Published: 02 August 2022

Regulation of cholesterol homeostasis in health and diseases: from mechanisms to targeted therapeutics

• Yajun Duan 1 , 2 ,
• Ke Gong 2 ,
• Suowen Xu 1 ,
• Feng Zhang 2 ,
• Xianshe Meng 2 &
• Jihong Han 2 , 3  

Signal Transduction and Targeted Therapy volume  7 , Article number:  265 ( 2022 ) Cite this article

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• Cardiovascular diseases
• Molecular medicine

Disturbed cholesterol homeostasis plays critical roles in the development of multiple diseases, such as cardiovascular diseases (CVD), neurodegenerative diseases and cancers, particularly the CVD in which the accumulation of lipids (mainly the cholesteryl esters) within macrophage/foam cells underneath the endothelial layer drives the formation of atherosclerotic lesions eventually. More and more studies have shown that lowering cholesterol level, especially low-density lipoprotein cholesterol level, protects cardiovascular system and prevents cardiovascular events effectively. Maintaining cholesterol homeostasis is determined by cholesterol biosynthesis, uptake, efflux, transport, storage, utilization, and/or excretion. All the processes should be precisely controlled by the multiple regulatory pathways. Based on the regulation of cholesterol homeostasis, many interventions have been developed to lower cholesterol by inhibiting cholesterol biosynthesis and uptake or enhancing cholesterol utilization and excretion. Herein, we summarize the historical review and research events, the current understandings of the molecular pathways playing key roles in regulating cholesterol homeostasis, and the cholesterol-lowering interventions in clinics or in preclinical studies as well as new cholesterol-lowering targets and their clinical advances. More importantly, we review and discuss the benefits of those interventions for the treatment of multiple diseases including atherosclerotic cardiovascular diseases, obesity, diabetes, nonalcoholic fatty liver disease, cancer, neurodegenerative diseases, osteoporosis and virus infection.

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Introduction.

Cholesterol is a waxy and fat-like substance with pivotal pathophysiological relevance in humans. More than two centuries ago, Michel Eugène Chevreul, a French chemist, found that cholesterol is one of the components in human gallstones. 1 Following this event, many scientists input a lot efforts to elucidate cholesterol structure. In 1927, Heinrich Otto Wieland from Germany won the Nobel Prize in Chemistry for his work on clarifying the structure of cholesterol and bile acids. A year later, Adolf Windaus also from Germany was awarded the Nobel Prize in Chemistry for his work on sterols and the related vitamins, such as vitamin D which is derived from cholesterol. 2 However, it was until 1932, the correct cholesterol structure was finally formulated. 1

Cholesterol can be synthesized in our body and the biosynthesis of this complex molecule starts from acetyl coenzyme A (acetyl-CoA) with involvement of nearly 30 enzymatic reactions. Among these reactions, the step for reduction of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonate catalyzed by HMG-CoA reductase (HMGCR) is rate-limiting, indicating regulation of HMGCR expression/activity is critical for cholesterol biosynthesis. In 1964, Konrad Emil Bloch and Feodor Lynen won the Nobel Prize in the Medicine and Physiology for discovering the major intermediate reactions in the pathway for cholesterol biosynthesis. 3

The cholesterol biosynthesis is an intensely regulated process biologically. 4 The first demonstration of feedback inhibitory loop by the end product in biosynthetic pathways is that cholesterol inhibits its own synthesis intracellularly. In 1933, Rudolph Schoenheimer demonstrated that animals can also synthesize cholesterol, more importantly, he observed that the cholesterol synthesis in animal body was inhibited by cholesterol supplied in the diet. This finding laid the groundwork for discovering sterol regulatory element binding protein (SREBP) pathway. 5 SREBP binds to the sterol regulatory element (SRE) in the proximal region of the promoter of HMGCR . The binding of SREBP triggers transcription of HMGCR to speed up cholesterol biosynthesis. 6 SREBP is also able to bind to the SRE in the promoter of low-density lipoprotein receptor ( LDLR ), the molecule responsible for the LDL cholesterol (LDL-C) clearance in the liver. 6 As a transcription factor, SREBP needs to be chaperoned by SREBP cleavage activating protein (SCAP) from endoplasmic reticulum (ER) to Golgi, where SREBP is cleaved into mature and functional form by sphingosine-1-phosphate (S1P) and S2P proteases. Cholesterol can interact with unmatured SREBP on the ER. 6 , 7 Thus, when the cellular cholesterol level is reduced, the mature SREBP is increased and consequently to activate HMGCR expression. Reciprocally, increased cellular cholesterol level inhibits HMGCR expression. 8

Mounting evidence has established the intricate link between cholesterol levels and atherosclerotic cardiovascular disease (ASCVD). In fact, atherosclerosis is a disease with a long research history. The role of cholesterol in atherosclerosis was initially reported in 1910. 9 Adolf Windaus found that cholesterol content in atherosclerotic plaques of human diseased aorta was 25 times higher than that of normal aortas. 8 Three years later, the first experimental recapitulation of atherosclerosis was completed by Nikolaj Anitschkow. He fed rabbits pure cholesterol contained in diet, and observed severe atherosclerosis in aortas of the animals. 10 In history, Robert Wissler and coworkers set up the first mouse model for atherosclerosis in 1960s. 11 Now, the mice with genetic manipulation, such as ApoE or LDLR deficient mice, is the most frequently-used animal model for investigation on atherosclerosis based on the time and cost issues.

Accumulation of cholesterol in atherosclerotic plaques may lead to formation of cholesterol crystals, a hallmark of advanced atherosclerotic plaques. 12 , 13 , 14 Cholesterol crystals can stimulate the generation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome to promote inflammation and accelerate atherogenesis. 15 , 16 It also induces arterial inflammation and involves in destabilizing atherosclerotic plaques. 17 Currently, the critical role of inflammation in mediating all stages of atherosclerosis has been well defined, and targeting inflammatory pathways may provide a new notion for atherosclerosis prevention and/or treatment. 18 , 19

Cholesterol is a hydrophobic molecule which travels through the bloodstream on proteins called “lipoproteins”. Ultracentrifuge was used to separate lipoproteins in plasma by John Gofman. He also demonstrated that heart attacks were associated with increased blood cholesterol levels, especially LDL-C. In contrast, when blood high-density lipoprotein (HDL) levels rise, the heart attack frequency was reduced. 20 , 21 , 22 Moreover, the beneficial effects of HDL cholesterol (HDL-C) and the negative effects of LDL-C on heart diseases were further confirmed by the Framingham Heart Study, one of the most important epidemiological studies in cardiovascular arena. 23

It was first time that Carl Müller discovered the genetic link between cholesterol and heart attacks. He demonstrated that families with high plasma cholesterol levels and early-onset heart disease are autosomal dominant traits. 24 This kind of disease is called familial hypercholesterolemia (FH). Avedis Khachadurian described two different clinical forms of FH in inbred families. Homozygous patients showed severe hypercholesterolemia at birth (the plasma cholesterol level in this kind of patients is about 800 mg/dl), and they can have heart attack as early as 5 years old, while the heterozygous patients showed cholesterol levels of 300–400 mg/dl and early-onset heart attack usually between 35-60 years old. 25 In 1970s, Joseph Goldstein and Michael Brown discovered the essence of LDLR functional defect in FH, which led them to be awarded the Nobel Prize in 1985. 26 The cellular uptake of LDL requires LDLR and most LDL-C is cleared from circulation by LDLR expressed in the liver. In the absence of LDLR, LDL-C reaches high level in the circulation, eventually deposits in the artery to drive the formation of atherosclerotic plaques. 27 The seminal work by Goldstein and Brown strongly supports the importance of lipid hypothesis in onset of cardiovascular diseases (CVD). In addition to HMGCR, SREBP also regulates LDLR expression in response to cellular cholesterol levels to fine-tune the cholesterol level in cell membranes constant. 6 , 7 , 8

Based on the evidence from epidemiological studies and randomized clinical trials, a cholesterol hypothesis was suggested which indicates the high circulating cholesterol level as a major risk factor for ASCVD while cholesterol-lowering strategies can reduce ASCVD risk. 28 In 1976, Akira Endo discovered the first HMGCR inhibitor, thus inaugurating a category of cholesterol-lowering drugs called statins, which is a therapeutic milestone for CVD treatment. 29 Statins deprive hepatocytes of endogenous synthesis as a source of cholesterol, which can alleviate the feedback inhibition of LDLR, and thus the increased LDLR expression will further reduce plasma LDL-C levels. 30 In 1987, lovastatin (Mevacor) developed by Merck was approved as the first statin for human use to lower plasma LDL-C. Currently, statins are used as the first-line therapy to reduce LDL-C and prevent ASCVD. 31

However, the doubled dose of a statin only leads to about 6% increase in LDL-C lowering efficacy, which may cause statin resistance/intolerance. 32 Thus, there is a need to develop novel lipid-lowering approaches beyond statins. In 2002, ezetimibe was introduced as an intestinal cholesterol absorption inhibitor to decrease total cholesterol (TC) and LDL-C levels. In 2003, Nabil Seidah and co-workers discovered proprotein convertase subtilisin/kexin type 9 (PCSK9). 33 PCSK9 is synthesized in the liver and then secreted into plasma. The circulating PCSK9 can bind hepatic LDLR and disrupt the recycle in which LDLR returns to the cell surface after internalization and release of the bound LDL-C. 34 , 35 The decrease of cell surface LDLR results in impaired LDL-C clearance and elevated LDL-C level. In 2015, alirocumab and evolocumab, the fully human anti-PCSK9 antibodies, were approved by US FDA to treat patients with hypercholesterolemia. 36 Likewise, a long-acting synthetic siRNA targeting PCSK9 mRNA called inclisiran was developed by Novartis and used to treat hypercholesterolemia. In 2020, inclisiran was approved by EU. 37 ATP citrate lyase (ACLY) is a cytoplasmic enzyme catalyzing acetyl-CoA generation, with which cholesterol biosynthesis begins. 38 Thus, inhibition of ACLY can also reduce cholesterol synthesis. Indeed, among ACLY inhibitors, bempedoic acid was approved by US FDA in 2020 for hypercholesterolemia treatment. 39 Notably, bempedoic acid only acts locally in the liver, thereby avoiding the muscle-related toxicities associated with statin use. 40

Taken together, when reviewing the milestones of cholesterol research, we realize that the findings in regulation of cholesterol homeostasis determined the progress on the development of therapeutic strategies, and the feedback from clinical observations may further advance the investigation on cholesterol homeostasis, thereby promoting clinical progress. “HMGCR-statin-LDLR-rule of 6%-PCSK9” should be a typical example. To lower cholesterol synthesis in the liver, statins were initially developed to inhibit HMGCR. Later on, Brown and Goldstein proved that statins increased LDLR on hepatocyte surfaces to soak up excess blood LDL-C, thereby reducing heart attack. Associated with wide use of statins in clinics, the “rule of 6%” was observed, which was mysterious until the discovery of PCSK9. SREBP-2 activates LDLR and PCSK9 expression simultaneously and activated PCSK9 binds to LDLR toward lysosomal degradation, which clearly antagonizes the efficacy of statin-induced LDL-C clearance. Therefore, PCSK9 has become a valuable therapeutic target for cholesterol-lowering therapy and PCSK9 inhibitors have been developed rapidly.

Nowadays, the cholesterol homeostasis is involved in development of various diseases and determined by processes of biosynthesis, uptake, efflux, transport, storage, utilization, and/or excretion. Therefore, in this article, we will summarize the key regulations in cholesterol homeostasis and cholesterol-lowering interventions. Furthermore, we will discuss the benefits of the pharmaceutical interventions targeting cholesterol homeostasis on the multiple related diseases, such as ASCVD, obesity, diabetes and more.

The references used in this review were acquired using the PubMed search engine with a time range from January 1930 to April 2022 by four researchers (Y. D., K. G., F. Z. and X. M.) independently. A list of relevant literature that met the inclusion criteria was manually searched. The following search strategy was applied by using the keywords of “cholesterol history”, “cholesterol development”, “cholesterol metabolism”, “cholesterol homeostasis”, “cholesterol synthesis”, “cholesterol transport”, “ASCVD cholesterol”, “ASCVD cholesterol ester”, “ASCVD foam cells”, “ASCVD statins”, “ASCVD ezetimibe”, “ASCVD PCSK9 inhibitor”, “ASCVD bempedoic acid”, “ASCVD bile acid sequestrants”, “ASCVD lomitapide”, “ASCVD evinacumab”, “ASCVD fibrates”, “ASCVD lipoprotein apheresis”, “ASCVD APOC3”, “ASCVD lipoprotein (a)”, “ASCVD LXRs”, “ASCVD LOX-1”, “ASCVD SR-BI”, “ASCVD LCAT”, “ASCVD MiR-33”, “ASCVD MiR-122”, “ASCVD prekallikrein”, “cholesterol homeostasis NAFLD”, “cholesterol homeostasis obesity”, “cholesterol homeostasis diabetes”, “cholesterol homeostasis Alzheimer’s disease”, “cholesterol homeostasis Parkinson’s disease”, “cholesterol homeostasis Huntington’s disease”, “cholesterol homeostasis cancer”, “cholesterol homeostasis osteoporosis”, or “cholesterol virus infection”. No additional restrictions were placed on the type of research model (in vivo / in vitro), article type (e.g., research article, review, editorial, letter, etc.), or publication language. References cited in articles associated with the literature search were also analyzed for additional information. The studies were excluded from the content retrieved if they are irrelevant or of limited relevance to the main topic.

Regulatory mechanisms of cholesterol homeostasis

Disturbed cholesterol homeostasis is not only the pathological basis of cardiovascular and cerebrovascular diseases, but also participates in the progression of other kinds of diseases including neurodegenerative diseases and cancers. Maintaining cholesterol homeostasis plays a crucial role physiologically. Normally, the cholesterol homeostasis can be well maintained by a dynamic balance among the intake, biosynthesis, transport, cellular uptake and efflux, and/or esterification. Thus, we will review the state-of-the-art research on the molecular mechanisms that regulate cholesterol homeostasis, and provide future research directions.

Sources of cholesterol: intake or biosynthesis

Dietary cholesterol.

Two main sources of cholesterol are present in our body, one is through dietary intake, known as exogenous cholesterol or dietary cholesterol; and another one is through the de novo biosynthesis, known as endogenous cholesterol. 41 A variety of daily foods, such as eggs, animal offal and seafood, contain cholesterol, of which eggs are the main source of dietary cholesterol. 42 The solubility of cholesterol in an aqueous environment is extremely low, so before absorption, it must be dissolved into bile salt micelles, which can be transported to the brush edge of intestinal cells. Then the net cholesterol is absorbed, the process is regulated by Niemann-Pick C1 (NPC1) like 1 (NPC1L1) protein. Inhibition of NPC1L1 by ezetimibe can reduce cholesterol absorption, thereby improving coronary artery disease. 43 After a series of processes, the absorbed cholesterol is esterified and then secreted into circulation as chylomicrons and eventually being taken up by the liver. 44 , 45 In addition, phytosterols/phytostanols can be added into the foods to replace cholesterol in micelles, leading to less cholesterol is absorbed by enterocytes and enters the liver. 46

To maintain hepatic cholesterol pool, the liver enhances LDL-C uptake from plasma by increasing LDLR expression and decreases cholesterol efflux, thereby reducing plasma TC and LDL-C levels. 47 NPC1L1 promoter also contains a SRE, the sterol-sensing structural domain, therefore, NPC1L1 expression is repressed by a high-cholesterol contained diet and increased by cholesterol-depleted food. 48 In addition, endogenous cholesterol synthesis is negatively regulated by the exogenous cholesterol. Hepatic cholesterol biosynthesis accounts for approximately three-quarters of the total endogenous cholesterol production at the low cholesterol intake situation. However, hepatic cholesterol biosynthesis is completely inhibited when 800–1000 mg exogenous cholesterol is ingested in experiments with baboons and humans. 49 , 50

Biosynthesis of cholesterol

Cholesterol can be synthesized by all nucleated cells, with most by hepatocytes, indicating the liver is the main site for cholesterol biosynthesis in vivo. 51 Acetyl-CoA is used as the starting material for cholesterol biosynthesis via the mevalonate pathway including nearly 30 enzymatic steps (Fig. 1 ). The biosynthesis of cholesterol can be divided into four stages: (I) Synthesis of mevalonate (MVA); (II) Production of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP); (III) Synthesis of squalene; (IV) Squalene cyclizes to form lanosterol and subsequently to synthesize cholesterol. The process is regulated by a negative feedback mechanism with the downstream products. 52 , 53 The SREBP pathway and the HMGCR degradation pathway serve as two major negative feedback regulatory mechanisms to regulate cholesterol de novo synthesis. 54

The pathway for cholesterol biosynthesis. In cholesterol biosynthesis, all the carbon atoms are derived from acetyl-CoA. The biosynthesis of cholesterol can be divided into four stages. (I) Synthesis of mevalonate (MVA). Two molecules of acetyl-CoA are reversely catalyzed by thiolase to form acetoacetyl-CoA. Acetoacetyl-CoA and acetyl-CoA are catalyzed to form 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) by HMG-CoA synthase (HMGCS). Finally, the HMG-CoA is catalyzed by HMG-CoA reductase (HMGCR) to convert to MVA, a step that requires two molecules of NADPH and H + and determines the rate of cholesterol biosynthesis. (II) Production of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). MVA is sequentially phosphorylated twice by mevalonate kinase and phosphomevalonate kinase to produce 5-pyrophosphate mevalonate, which is further decarboxylated by 5-pyrophosphatemevalonate decarboxylase to produce isopentenyl pyrophosphate (IPP). IPP is converted to dimethylallyl pyrophosphate (DMAPP) catalyzed by isopentanoyl pyrophosphate isomerase, and DMAPP is used together with IPP as the starting materials for the third step of cholesterol synthesis. (III) Synthesis of squalene. IPP and DMAPP are condensed by farnesyl transferase to form geranyl pyrophosphate (GPP), followed by a second condensation reaction between GPP and IPP to form farnesyl pyrophosphate (FPP), and finally two molecules of FPP are condensed by squalene synthase to form squalene. (IV) Squalene cyclizes to form lanosterol and subsequently to synthesize cholesterol. Squalene forms a closed loop catalyzed by squalene monooxygenase and 2,3-oxidosqualene lanosterol cyclase to form lanosterol. Lanosterol is converted into cholesterol in more than twenty steps totally

SREBPs, the transcription factors anchored to the ER, include three isoforms, SREBP1a, SREBP1c and SREBP2. The N-terminal sequences of SREBPs belong to the basic-helix-loop-helix-leucine zipper (bHLH-Zip) protein superfamily. 6 , 55 When cellular cholesterol is depleted, the N-terminus of SREBPs can be cleaved into the form of mature and functional SREBP, which can translocate with chaperone by SCAP to the nucleus where the mature SREBP identifies and binds to the SRE in the target gene promoter, followed by activation of these genes transcription.

Further studies revealed that SREBPs interact with SCAP to form a complex in a stoichiometric ratio of 4:4. 56 When ER membrane cholesterol is depleted, SCAP binds to COPII vesicles that allows the SCAP-SREBP complex to move from ER to Golgi for cleavage. When ER membrane cholesterol exceeds 5% of total ER lipids at molar basis, cholesterol and oxysterols, such as 25-hydroxycholesterol, trigger the interaction between SCAP sterol-sensing domain (SSD) and insulin-induced gene (INSIG), thereby blocking the binding of SCAP to COPII vesicles and keeping the SCAP-SREBP complex in the ER 57 , 58 (Fig. 2 ). At present, the structure of SCAP in cholesterol-free and cholesterol-bound states, as well as the structure of SCAP-INSIG or SCAP-COPII complex need to be verified by further ultrastructural study. In the recent studies, the conformation of SCAP-INSIG has been resolved by the cryo-electron microscopy technology. 59 , 60 These findings may benefit to the screening of the small molecules affecting the conformation change of SCAP to inhibit cholesterol synthesis.f

SREBP2 pathway in regulation of cholesterol biosynthesis. The process of cholesterol biosynthesis is strictly regulated by negative feedback, of which the sterol regulatory element binding protein (SREBP) pathway and the HMG-CoA reductase (HMGCR) degradation pathway are the two main mechanisms of negative feedback regulation. a SREBP2 forms a complex with SREBP cleavage activating protein (SCAP) at the ER. When sterol depletion occurs to cells, SCAP binds to COPII vesicles, allowing the SCAP-SREBP complex to translocate from the ER to the Golgi for cleavage. SREBP2 is sequentially cleaved by S1P and S2P in the Golgi, and the N-terminal of SREBP2 is subsequently transported to the nucleus, where the N-terminal of SREBP2 recognizes and binds to the SRE sequence on the target gene promoter to activate the target gene transcription. In addition, HMGCR is also prevented from binding to INSIGs and gp78 (ubiquitin ligase) during cholesterol depletion, thereby stabilizing HMGCR to activate cholesterol biosynthesis. b When the cell sterol is replete, it triggers the interaction of SCAP with INSIGs, resulting in blocking the binding of SCAP to COPII and keeping the SCAP-SREBP2 complex in the ER. At the same time, HMGCR also binds to INSIGs and gp78, which catalyzes the ubiquitination of HMGCR. The ubiquitinated HMGCR is eventually degraded in the proteasome via ER-related degradation (ERAD). Ub ubiquitin

In the process of cholesterol biosynthesis, HMGCR is subjected to strict feedback regulation 54 (Fig. 2 ). As a target gene of SREBP2, HMGCR is regulated by SREBP2 at the transcriptional level. In addition to this long-term transcriptional regulation, HMGCR is also subject to short-term epigenetic modulation. Ubiquitination and phosphorylation of HMGCR are two common post-translational modifications. 61

HMGCR is located in the ER and divided into an N-terminal transmembrane region and a C-terminal cytoplasmic region based on its function and structure. The amino acid sequence of the transmembrane region is highly conserved and the membrane structural domain can respond to increases of sterols and mediate its own degradation. 62 In 2005, Song et al. found that gp78, also known as autocrine motility factor receptor (AMFR), functions as a ubiquitin ligase to mediate HMGCR degradation. In cells with high cholesterol levels, INSIG binds to both HMGCR and gp78, which allows gp78 to catalyze the ubiquitination of the lysine residues at position 89 and 248 of HMGCR. 63 The ubiquitin fusion degradation 1 (Ufd1) protein contains ubiquitin binding sites, which serves as an accelerator of degradation by binding to gp78 to accelerate HMGCR degradation. 64 Meanwhile, gp78 is also involved in the ubiquitination and proteasomal degradation of INSIGs, and promotes SREBP maturation and lipid synthesis. Surprisingly, in hepatic gp78-deficient mice, both cholesterol and fatty acid synthesis were reduced despite enhanced HMGCR enzymatic activity, which resulted from reduced SREBP maturation to suppress downstream gene expression. 65 , 66 The recent studies have found that increased postprandial insulin and glucose concentrations enhance the effect of mechanistic target of rapamycin complex 1 (mTORC1) on phosphorylation of ubiquitin specific peptidase 20 (USP20). Once phosphorylated, USP20 can be recruited to HMGCR complex to antagonize HMGCR degradation. Thus, deleting or inhibiting USP20 significantly reduces diet-induced weight gain, serum and liver lipid levels, improves insulin sensitivity and increases energy expenditure. 67 Taken together, these studies suggest that ubiquitin ligase gp78 and USP20 could be the new targets for treatment of diseases with cholesterol metabolic disorders.

In addition to ubiquitination, HMGCR is also regulated by phosphorylation. Clarke and Hardie found that Ser-872 within the catalytic fragment of rat HMGCR can be phosphorylated by AMP-activated protein kinase (AMPK), which inactivates HMGCR and reduces the flux of the formaldehyde valerate pathway. 68 Meanwhile, Sato et al. found that AMPK-activated phosphorylation of Ser-872 did not affect sterol-mediated feedback regulation of HMGCR, but functioned when cellular ATP levels were depleted, thereby reducing the rate of cholesterol synthesis and preserving cellular energy stores. 69 In contrast, dephosphorylation of HMGCR activates itself and increases cholesterol synthesis. Studies have shown that miR-34a, a microRNA increased in nonalcoholic fatty liver disease (NAFLD), dephosphorylates HMGCR via inactivating AMPK, leading to dysregulation of cholesterol metabolism and increased risk of cardiovascular disease. 70 Subclinical hypothyroidism leads to elevated serum thyroid stimulating hormone (TSH) and elevated serum cholesterol levels. Zhang et al. found that TSH can reduce HMGCR phosphorylation to increase its activity in the liver via AMPK also, revealing a mechanism for hypercholesterolemia in subclinical hypothyroidism. 71

Uptake and transport of cholesterol

Dietary cholesterol absorbed by enterocytes or hepatic de novo synthesized cholesterol can form the protein-lipid complexes with lipoproteins and then release into circulation, followed by transportation to cells for utilization. In humans, about a quarter of excess cholesterol is excreted directly through enterocytes into feces, and the rest enters the liver via reverse cholesterol transport (RCT) and to be excreted with bile. Only a small percentage is re-circulated back into the free cholesterol (FC) pool 72 , 73 , 74 (Fig. 3 ). A variety of proteins are involved in cholesterol uptake and transport. Thus, targeting these key proteins to regulate cholesterol levels is also a potential strategy for treatment of hypercholesterolemia and CVD. 75

Regulation of cholesterol transport. Daily food and the hepatic endogenous synthesis are the two main sources of human cholesterol, of which dietary free cholesterol (FC) uptake is mediated by Niemann-Pick C1 Like 1 (NPC1L1) protein in enterocytes. The endocytosis of cholesterol by NPC1L1 responds to the change of cellular cholesterol concentration. FC taken up by NPC1L1 in enterocytes is esterified to cholesteryl ester (CE) by acyl-CoA:cholesterol acyltransferase 2 (ACAT2), which is loaded into ApoB-48 with triglycerides (TG) mediated by microsomal triglyceride transfer protein (MTP), to form chylomicron (CM). After TG in CM is hydrolyzed and utilized, most of the remaining cholesterol will be absorbed through low-density lipoprotein receptor (LDLR) in the liver. In contrast, some unesterified cholesterol is pumped back to the intestinal lumen by ATP-binding cassette (ABC) transport proteins G5 and G8 (ABCG5/ABCG8) or synthesized into pre-β-HDL by ABCA1 and released into circulation. Cholesterol synthesized endogenously in the liver is converted into VLDL with TG, ApoB-100, and most of VLDL is then converted into LDL, which is the main carrier for transporting endogenous cholesterol. LDL is taken up by scavenger receptors in macrophages, where expression of CD36, scavenger receptor A1 (SR-A1), and LDL receptor 1 (LOX1) is increased in atherosclerosis, further promoting cholesterol accumulation. LDL is endocytosed into macrophages and hydrolyzed by lipase (LAL) to produce FC. Excess FC is esterified by ACAT1 and stored as lipid droplets, and the excess accumulation of CE in macrophages can contribute to formation of foam cells. To mediate cholesterol efflux, macrophages hydrolyze CE into FC by the neutral cholesteryl ester hydrolase (NEH). Macrophage-mediated cholesterol efflux includes simple diffusion, SR-BI-facilitated diffusion, and ABCA1/ABCG1-mediated efflux. Among them, simple diffusion dominates cholesterol efflux in normal macrophages, regulated by cholesterol concentrations. In cholesterol overloaded macrophages, ABCA1 and ABCG1 are critical for cholesterol efflux. ABCA1 is able to bind to ApoA-I to mediate the production of pre-β-HDL, lecithin cholesterol acyltransferase (LCAT) further matures pre-β-HDL particles into HDL3, while ABCG1 and SR-BI mediate cholesterol flow directly to HDL3. HDL3 is further esterified by LCAT to produce HDL2, in which CE is eventually taken up by SR-BI in the liver and converted to FC. In addition, CE in HDL2 particles can be exchanged by cholesteryl ester transfer protein (CETP) to LDL particles, which are subsequently taken up by LDLR. Excess cholesterol in the liver is excreted into the bile mediated by ABCG5/ABCG8 and eventually enters the intestinal lumen for excretion in feces. Some other cholesterol in the blood can be excreted directly into the intestinal lumen via transintestinal cholesterol excretion (TICE) pathway in enterocytes

Cholesterol uptake and efflux in enterocytes

Dietary cholesterol is one of the main sources of cholesterol access in humans, and its uptake is mediated by NPC1L1 protein in enterocytes. 45 NPC1L1 contains 13 transmembrane helices, five of which form the SSD that mediates NPC1L1 movement between the plasma membrane and the endocytic recycling compartment in response to intracellular cholesterol concentrations. 76 , 77 In addition, the N-terminal structural domain of NCP1L1 has a sterol-binding pocket which interacts with cholesterol to change NPC1L1 conformation and allows cholesterol to enter cells. 78 In earlier years, Song et al. found that the VNXXF (X for any amino acid) sequence at the C-terminus of NPC1L1 is involved in clathrin/adaptin 2-dependent endocytosis to mediate cholesterol uptake. 79 , 80 However, NPC1L1-mediated cholesterol uptake is not mainly dependent on endocytosis. 81

In 2020, the NPC1L1 structure was fully elucidated by the cryo-electron microscopy, making it easier to understand the mechanism of NPC1L1-mediated cholesterol uptake. 82 After binding to the sterol-binding pocket, cholesterol triggers NPC1L1 conformation changes to form a delivery tunnel for cholesterol uptake by cells. 82 Recently, Hu et al. found that SSD in NPC1L1 can respond to cholesterol concentrations by binding different amounts of cholesterol. 83 In addition, the effective cholesterol uptake by NPC1L1 depends on its dimerization. 84 Based on the crucial role of NPC1L1 in cholesterol uptake, ezetimibe has been developed and used clinically as an inhibitor of hypercholesterolemia, and other NPC1L1 inhibitors are being developed. 85 , 86 Cellular cholesterol uptake by NPC1L1 is then esterified by acyl-CoA: cholesterol acyltransferase (ACAT) 2 in the ER and loaded with triglycerides (TG) into ApoB-48 to form chylomicrons. The mature chylomicrons are eventually transported into circulation, where TG is hydrolyzed for use in peripheral tissues and the majority of cholesterol is absorbed by the liver. In contrast, FC can be pumped back into intestinal lumen via ATP-binding cassette (ABC) transport protein G5 and G8 (ABCG5/8), or processed by synthesis of HDL-C and release into circulation directly via ABCA1. 87

Cholesterol uptake, esterification and efflux in macrophages

Macrophage cholesterol homeostasis plays an essential role in the development of atherosclerosis. 88 Excessive uptake of cholesterol, excessive intracellular cholesterol esterification and impaired cholesterol efflux can drive differentiation of macrophages into foam cells and formation of atherosclerotic plaques in the vessel wall. 89 Macrophage cholesterol uptake is mainly mediated through multiple scavenger receptors, the molecules lack of SRE, rather than LDLR. 90 Thus, without feedback control mechanisms, macrophage scavenger receptors may uptake cholesterol unlimitedly in patients with hypercholesterolemia. Macrophages scavenger receptors include scavenger receptor A1 (SR-A1), SR-BI, lectin-like oxidized LDL receptor 1 (LOX-1), CD36 and so on. Among them, SR-A1 and CD36 mediate most of the endocytosed LDL (75–90%). 91 , 92 , 93 Meanwhile, compared with LDL, these scavenger receptors have higher affinity for modified LDL, particularly the oxidatively modified LDL (oxLDL). 94 In atherosclerosis, expression of SR-A1, LOX-1, and CD36 in macrophages are increased. The activated scavenger receptors can elevate the levels of pro-inflammatory cytokines, oxLDL, lysophosphatidylcholine, advanced glycosyl end products (AGEs), and vasopressors in macrophages, further promoting cholesterol accumulation and foam cell formation. 89

After endocytosis, lipoproteins will be hydrolyzed in lysosomes by action of lysosomal acid lipase (LAL, also named as cholesterol ester hydrolase or lipase A) to generate FC. The excess FC is then esterified in the ER by ACAT1, which can attenuate FC cytotoxicity. The cholesteryl ester (CE) can be stored as lipid droplets (LD) in the cytoplasm. 95 However, if ACAT1 esterifies too much FC to CE, the excessive lipid accumulation can also result in conversion of macrophages into foam cells. Therefore, ACAT1 is also considered as a possible effective target in reduction of foam cells. Consistently, deletion or inhibition of ACAT1 in macrophages has an inhibitory effect on atherosclerosis in mouse models. 96 , 97 , 98 , 99 However, the ACAT1 inhibitors failed to produce desired athero-protective effects in clinic, which may be due to excessive accumulation of FC in cells and generation of lipotoxicity, resulting in profound cell death. 100 , 101 , 102 Macrophages are not able to degrade sterols, thus, CE needs to be hydrolyzed into FC for efflux. Neutral cholesteryl ester hydrolase (NEH) hydrolyzes CE to release FC. 103 There are three main NEHs, of which carboxylesterase 1 (CES1) and neutral cholesteryl ester hydrolase 1 (NCEH1) are mainly expressed in human macrophages for CE hydrolysis. 104 , 105

When cholesterol is abnormally accumulated in macrophages, the cells acquire a defense mechanism to combat the deleterious effects caused by excessive cholesterol uptake by promoting cholesterol efflux via the mechanisms involving simple diffusion, SR-BI-facilitated diffusion, and ABCA1 and/or ABCG1-mediated efflux. 95 , 106 Among them, the simple diffusion is a passive process regulated by cellular cholesterol concentrations and dominates the cholesterol efflux in normal cells, whereas in cholesterol-overloaded cells, ABCA1 and ABCG1 are critical for cholesterol efflux. 107 The cholesterol efflux mediated by ABCA1 is the most efficient way for macrophages to remove intracellular cholesterol. ABCA1 can bind to ApoA-I and drive cholesterol flow to ApoA-I to form nascent pre-β-HDL particles. Expression of ABCA1 strongly influences the level of plasma HDL-C. 108 , 109 In 2017, the elucidation of the crystal structure of ABCA1 established that ABCA1 forms hydrophobic tunnels to transport lipids, but the mechanism for cholesterol delivery from ABCA1 to ApoA-I still remains incompletely clarified. 110 In contrast to ABCA1, ABCG1 is not directly bound to the empty ApoA-I, instead, it mediates the cholesterol flow to pre-βHDL particles formed by ABCA1-mediated cholesterol efflux. 111 , 112 Meanwhile, expression of ABCA1 and ABCG1 are strictly controlled by liver X receptors (LXRs). The increased cellular cholesterol levels promote production of hydroxysteroids, the endogenous LXR agonizts, thereby increasing ABCA1 and ABCG1 expression. 113 Compared to ABCA1 and ABCG1, SR-BI was initially recognized as the receptor for HDL-mediated CE uptake and only a minor contributor in cholesterol efflux. 114

Liver cholesterol transport and RCT

The liver is the main site of cholesterol metabolism. It is also the most essential organ for effective RCT. In general, cholesterol is transported to the liver from peripheral cells (especially macrophages) by HDL particles, which is considered to be the first step in RCT. Thus, HDL particles play a key role for lipid homeostasis as lipid receptors in lymphatic fluid and plasma. 115 HDL is a smaller lipoprotein with a core of ApoA-I loaded with CE and TG, and an outer layer of phospholipids (PL) which allows the solubilization of FC to complete the transport. 116 According to the particle size, HDL can be divided into two subclasses, one is HDL2, which is rich in lipids with larger volume, and the another one is HDL3, which is rich in proteins with smaller volume. 117 , 118 Lipid-poor ApoA-I synthesized in hepatocytes or enterocytes accepts FC transported by ABCA1 from peripheral cells to form pre-β HDL particles. 119 , 120 Afterwards, lecithin cholesterol acyltransferase (LCAT) and phospholipid transfer protein (PLTP) further mature pre-β-HDL particles to produce HDL3, and HDL3 acts as an acceptor for FC discharged by ABCG1 and/or SR-BI to produce HDL2 finally. 121 , 122 , 123 Among them, LCAT mediates the cleavage of fatty acids at the sn -2 position of phospholipids and transesterification to the 3-β-hydroxyl group on the A ring to form CE. 124 , 125 PLTP mediates the transfer of PL from ApoB-containing lipoproteins to HDL to facilitate FC influx. 126 The liver selectively absorbs lipids from HDL via SR-BI and transfers CE to bile for intestinal excretion to complete the entire RCT process. 114

Based on the key role of HDL in RCT, it is widely believed that HDL-C is a “good” cholesterol to the extent that it inhibits the progression of atherosclerosis. The results of several clinical studies found that interventions to increase plasma HDL-C concentrations by inhibiting cholesteryl ester transfer protein (CETP) or using niacin did not reduce the development of atherosclerosis. 127 , 128 , 129 The esterification of cholesterol by LCAT is critical for the inhibition of atherosclerosis by RCT, whereas the rate of clearance of FC in HDL is much higher than that of LCAT esterification, due to the fact that FC can enter the liver directly through cell membrane without LCAT esterification, which may also explain the controversial protective effects of interventions targeting LCAT against atherosclerosis. 130 , 131 Meanwhile, several large studies also found a U-shaped curve between HDL-C concentrations and all-cause mortality in ASCVD patients, with both too low and too high levels of HDL-C leading to an increased risk of ASCVD. 132 , 133 In addition, the HDL collected from patients with CVD or chronic kidney disease lose the capacity of RCT by promoting LOX-1 mediated vascular dysfunction. Patients suffering from ASCVD with high HDL-C tend to lack PL in HDL, which leads FC to flow back to macrophages to facilitate foam cell formation. 131 Therefore, maintaining the normal function of HDL rather than simply increase of HDL-C concentrations is the more important aspect of RCT therapy.

In addition to uptake of HDL-C via SR-BI, the liver also uptakes LDL-C via LDLR to directly remove atherosclerotic lipoproteins from the plasma. In the hepatic ER, ApoB-100 is the main apolipoprotein to synthesize very low-density lipoprotein (VLDL) to transport endogenous TG and cholesterol. When TG contained in VLDL is hydrolyzed by LAL, the remaining particles are converted to LDL. 134 LDL is the primary carrier of endogenous cholesterol for transport, and two-thirds of TC in plasma binds to LDL to form LDL-C, which is absorbed and converted through hepatic LDLR. In humans, CE in mature HDL particles is also exchanged to LDL or VLDL particles by CETP, then the CE in these particles is absorbed by LDLR. 135 In mammals, LDLR is highly expressed in the liver to mediate more than 70% of LDL-C clearance. 136 LDLR deficiency is the most common cause of FH, in which patients present with markedly elevated LDL-C level and early ASCVD onset. 137 , 138 LDLR transcription is mainly regulated by SREBP2 and can respond to changes of intracellular cholesterol. 90 PCSK9 reduces LDLR expression in the post-translational manner. It binds to LDLR to induce LDLR entry into cells for lysosomal degradation and inhibits the ability of LDL uptake in the liver. 34 Similarly, the inducible degrader of LDLR (IDOL) can also promote LDLR degradation through polyubiquitination and lysosomal degradation pathways. 139 A recent cognitively subversive study found that HDL can bind to PCSK9 to increase PCSK9 activity and accelerate PCSK9-mediated LDLR degradation. This study further elucidates the interaction between circulating lipoproteins and PCSK9, and provides new therapeutic ideas for targeting PCSK9. Furthermore, coagulation factor prekallikrein (PK) was recently reported to regulate plasma cholesterol levels via binding to LDLR to induce its lysosomal degradation. Deficiency of PK stabilizes LDLR protein expression, promotes hepatic LDL-C clearance and inhibits atherosclerosis in mice. 140 All the evidence above suggest that LDLR still represents a promising therapeutic target for ASCVD treatment.

Cholesterol utilization and excretion

Utilization of cholesterol.

As an important component in biological membranes, cholesterol accounts for more than 20% of lipids in membranes. 141 , 142 Cholesterol is a largely hydrophobic molecule, and only the 3β-hydroxyl portion is a polar group, thus, cholesterol is amphiphilic and can be oriented in the phospholipid bilayer perpendicular to the membrane surface. 143 , 144 , 145 In domains or pools of biological and model membranes, cholesterol is usually non-randomly distributed, in which many structural domains are thought to be important for maintaining membrane structure and function. 146 , 147 , 148 Besides participating in the composition of biological membranes, cholesterol is the essential precursor for synthesis of oxysterols. Formation of oxysterols is the step converting cholesterol into more polar compounds, which can facilitate elimination of cholesterol. Meanwhile, oxysterols have different important physiological roles. Some oxysterols can activate LXR to regulate cholesterol efflux from macrophages, and some of them can bind to INSIG to regulate SREBP2 maturation, therefore, these oxysterols play an important role to maintain cholesterol homeostasis. 149 , 150 Oxidoreductases, hydrolases and transferases are the three main enzymes involved in the metabolism of oxysterols. Among the oxidoreductases, the enzymes catalyzing formation of oxysterols, cytochrome P450 (CYP) has been relatively well studied. The earlier identified two enzymes, cholesterol 7α-hydroxylase (CYP7A1) and cholesterol 27-hydroxylase (CYP27A1), participate in bile acid synthesis by producing 7α-hydroxycholesterol (7α-OHC) and 27-OHC, respectively. In addition, formation of OHC by CYP7A1 is the rate-limiting step for bile acid production. 151 , 152 Cholesterol 25-hydroxylase (CH25H), another key oxidoreductase, does not belong to the CYP450 superfamily. 153 CH25H catalyzes the production of 25-OCH, which is capable of acting as an agonist of estrogen receptor α. 154 In addition to the aforementioned enzymes, there are many other enzymes that catalyze synthesis of specific oxysterols, indicating the mechanisms for oxysterol production/metabolism still need further investigation. Moreover, cholesterol is the precursor for generation of all steroid hormones. Various steroid-producing tissues (adrenal glands, testes, ovaries) and brain cells produce steroid hormones. The inner mitochondrial membrane contains CYP450, a key enzyme to convert cholesterol to pregnenolone. Subsequently, pregnenolone leaves the mitochondria and is further catalyzed by the corresponding enzyme in the ER as a substrate for steroid hormone synthesis. 155

Excretion of cholesterol

The elimination of cholesterol from the liver to remove excess cholesterol is considered as the final step in RCT. Both ABCG5/8-mediated hepatobiliary secretion and transintestinal cholesterol excretion (TICE) pathways mediate this process. 156

During the hepatobiliary cholesterol secretion, ABCG5 and ABCG8 form a heterodimer to mediate cholesterol excretion into the bile and intestinal lumen. 157 , 158 At the same time, bile salt is the main acceptor for ABCG5/8-mediated hepatic cholesterol efflux. 159 , 160 Bile acids secreted from hepatocytes will combine with glycine or taurine to form bile salts. CYP7A1 is the key enzyme for bile acid synthesis, converting cholesterol (usually from LDL particles) to 7α-OCH through a multienzyme process. 151 Subsequently, CYP450 enzymes including CYP8B1, CYP27A1 and CYP7B1 located on the ER of hepatocytes are involved in many of the subsequent reactions. 161 , 162 , 163 Lee et al. determined the structure of ABCG5/8 heterodimer by extracting the crystals of phospholipid bilayer ABCG5 and ABCG8. The structure shows that the transmembrane structural domain of this heterodimer is coupled to the nucleotide binding site through different interaction networks between the active and inactive ATPases, indicating the catalytic asymmetry of ABCG5 and ABCG8 protein. 164 Similar to ABCA1 and ABCG1, ABCG5 and ABCG8 are also transcriptionally regulated by LXR. When hepatic cholesterol is overloaded, increased oxysterols activate LXR and enhance expression of ABCG5/8. 165 , 166

Another non-biliary TICE pathway of cholesterol excretion refers to cholesterol secretion directly to the proximal small intestine from the blood via enterocytes. 167 In both rodents and humans, TICE mediates about 30% of the total fecal cholesterol excretion and plays a significant role in cholesterol efflux. 166 , 168 , 169 When the synthesis of bile acids/salts is abnormal in the body, TICE takes on more to maintain normal cholesterol efflux. 170 Stöger et al. found that interleukin 10 (IL-10) receptor 1 (IL-10R1)-deficient LDLR −/− mice showed an increase in TICE-mediated cholesterol efflux and inhibited atherosclerosis, suggesting that TICE may have potential anti-atherosclerotic effects. 171 Since enhanced hepatobiliary cholesterol secretion has the side effect of causing gallstones, promoting TICE may be a new idea to combat atherosclerosis. 172 However, the molecular mechanism of TICE has not been fully clarified, and various factors of cholesterol metabolism can affect TICE to some extent, which is a direction worthy of the future attention. 173 , 174 , 175

Epigenetic modulation of cholesterol metabolism

In addition to the classical models of cholesterol metabolism regulation described above, the recent evidence has revealed multiple epigenetic regulatory mechanisms involved in uptake, synthesis and efflux of cholesterol, such as histone acetylation, DNA methylation and ubiquitylation.

Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that are recruited to chromatin in the presence of acetylated histones, thereby regulating gene expression. Inhibition of BET effectively reduces intracellular cholesterol levels by significant regulating genes involved in cholesterol biosynthesis, uptake and intracellular trafficking, indicating that most of the genes involved in regulation of cholesterol homeostasis can be regulated by epigenetic mechanisms. 176

Intestinal NPC1L1 is differentially expressed in the gastrointestinal tract, with much higher levels in small intestine than colon, which is associated with high levels of methylation upstream of NPC1L1 gene start site in the colon, suggesting a possible reduction in cholesterol uptake and prevention of atherosclerosis by alteration of DNA methylation. 177 Whereas data on the epigenetic regulation of ABCG5/8 in the intestine are very limited. A few studies in mouse liver suggest that the common promoters of ABCG5/8 are acetylated and unmethylated. Histone methyltransferase SET domain 2 (SETD2) catalyzes trimethylation on H3K36 (H3K36me3), and recent studies have revealed that STED2 is involved in regulating hepatic ABCA1 expression and cholesterol efflux homeostasis. 178

Brahma related gene 1 (BRG1, a chromatin remodeling protein) interacts with SREBP2 and recruits histone 3 lysine 9 (H3K9) methyltransferase (KDM3A) at the promoter of SREBP2 target genes to regulate the transcription of genes involved in cholesterol synthesis. 179 Euchromatic histone-lysine N-methyltransferase 2 (EHMT2) is a histone methyltransferase that catalyzes H3K9 of SREBP2 monomethylation and dimethylation (H3K9me1 and H3K9me2, respectively). Inhibition of EHMT2 is able to directly induce SREBP2 expression by reducing H3K9me1 and H3K9me2 at the promoter. 180 At the same time, the complex of histone acetylase cAMP response element binding protein 1 (CREB) binding protein (CBP)/P300 bromodomain acetylates the conserved lysine residues of SREBP protein, thereby preventing the ubiquitination and degradation of SREBP, prolonging its residence time in the nucleus and promoting its transcriptional activity. In contrast, sirtuin 1 (SIRT1) can antagonize the action of CBP/P300 by deacetylating SREBP. 181 Thus, the transcriptional activity of SREBP is regulated by multiple epigenetic mechanisms, keeping it in a complex dynamic equilibrium.

Various genes associated with cholesterol elimination, such as CYP7A1, CYP46A1 and CH25H, have been shown to be differentially regulated epigenetically. CYP7A1 can be regulated by indirect negative feedback from small heterodimeric chaperone (SHP) proteins. Several studies have identified the presence of BRG1-mediated chromatin remodeling and SIRT1-mediated histone deacetylation at the SHP promoter, which further regulates CYP7A1 expression. 182 , 183 CYP46A1 is regulated by the acetylation status of histones. in vitro, treatment of hepatocytes with deacetylase inhibitor, trichostatin A, significantly upregulates CYP46A1 mRNA levels. 184 The signal transducers and activators of transcription 1 (STAT1) pathway regulates CH25H expression, which also requires the involvement of histone acetylation. 185 , 186

The epigenetic regulation of cholesterol homeostasis is a promising research area, with multiple genes being differentially regulated. Research in this area could provide the basis for transcriptional therapies for related diseases, drug development and the clinical application of dietary epigenetic modulators. However, there are still many questions and gaps in this field that need to be solved.

Cholesterol-related diseases and interventions

Cholesterol and ascvd, role of cholesterol in the development of ascvd.

Deregulated cholesterol metabolism leads to the development of multiple human diseases, among which atherosclerosis is the major one. Atherosclerosis is the process of accumulation of lipids and fibrous substances in arterial intima, and results in ASCVD as the main cause of death worldwide. 187 The main reason of atherosclerotic plaque formation is the excessive accumulation of cholesterol-rich lipoproteins in the arterial intima (Fig. 4 ). 187 , 188

Inhibition of atherosclerosis by cholesterol-lowering interventions. Bempedoic acid and statins reduce acetyl-CoA and HMG-CoA production by inhibiting ACLY and HMGCR, respectively, thereby lowering cholesterol synthesis. Ezetimibe inhibits intestinal uptake of cholesterol by inhibiting NPC1L1. PCSK9 inhibitors reduce LDLR degradation by inhibiting PCSK9 expression/function. Bile acid sequestrants bind to BA in the small intestine, thus preventing BA from being reabsorbed into the liver. Lomitapide reduces the assembly of ApoB-containing lipoproteins in intestine and liver. Evinacumab restores LPL activity by inhibiting ANGPTL3. Fibrates reduce TG levels. All of the above interventions can reduce plasm LDL-C levels, which is the base for the development of atherosclerosis. The arterial wall consists of three layers: adventitia, media, and intima. The outermost layer, adventitia, is mainly composed of connective tissues. The middle layer, media, consists of smooth muscle cells. The innermost layer, intima, is bounded by endothelial cells (ECs) on the inner side of the lumen and internal elastic membrane on the outer side. Atherosclerotic plaques form in the intima. In the early stage of atherosclerosis, LDL particles enter the intima through EC layer and undergo oxidation and other modifications to form oxLDL, which makes it pro-inflammatory and immunogenic. ECs secrete adhesion molecules and chemokines after activation, and monocytes circulating in the blood bind to adhesion molecules and enter the intima under the promotion of chemokines. After entering the intima, the infiltrated monocytes then differentiate into macrophages and express scavenger receptors to bind and internalize oxLDL to form foam cells. A subset of smooth muscle cells from the media can also differentiate into a macrophage-like phenotype, which in turn phagocytoses oxLDL to form foam cells. As the lesion progresses, dead foam cells and SMCs aggregate with free lipoprotein and cholesterol crystals in the intima to form a necrotic core. SMCs migrate to endothelium and forms fibrous cap during the evolution of atherosclerotic plaque. As cholesterol crystals grow, they eventually penetrate the intima, causing plaque instability and further rupture of the plaques. Acetyl CoA acetyl coenzyme A, ACLY ATP citrate lyase, ANGPTL3 angiopoietin-like protein 3, BA bile acid, CE cholesteryl ester, CM chylomicron, EC endothelial cell, FA fatty acid, FC free cholesterol, HMGCR 3-hydroxy-3-methylglutaryl coenzyme A reductase, HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A, LDL low-density lipoprotein, LDLR LDL receptor, LPL lipoprotein lipase, MTP microsomal triglyceride transfer protein, NPC1L1 Niemann-Pick C1 like 1, oxLDL oxidatively modified low-density lipoprotein, PCSK9 proprotein convertase subtilisin/kexin type 9, SMC smooth muscle cell, TG triglyceride, VLDL very low-density lipoprotein

Accumulation and retention of ApoB-containing lipoproteins in the arterial intima are thought to induce atherosclerosis. 189 Recent evidence has suggested that SR-BI in endothelium is an important scavenger receptor that promotes LDL transcytosis/accumulation and atherosclerosis. 190 Retained LDL particles activate an initial immune response in the endothelium, thus, triggering chronic inflammation by releasing monocyte chemotactic protein-1 (MCP-1) and some other inflammatory factors. 191 Endothelial chemokines and cytokines including MCP-1, intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), E-selectin, macrophage colony stimulating factor (M-CSF), IL-18 and tumor necrosis factor α (TNF-α), further promote monocyte migration to endothelium. 192 , 193 Monocytes can differentiate into macrophages after migration to the underneath of endothelium, where macrophages bind and internalize modified LDL or lipoprotein residues in the intima to form foam cells. 194

Foam cell formation is the major hallmark of early lesions in atherosclerosis. 89 Macrophages differentiated from circulating monocytes are the main source of foam cells. 195 , 196 A small number of foam cells can be derived from endothelial cells (ECs) and/or vascular smooth muscle cells (VSMCs). ECs may differentiate into VSMC-like cells while VSMCs will further differentiate into macrophage-like cells, which become foam cells after lipid overload. 197

LDL must undergo oxidative modification before it can be rapidly taken up by macrophages and accumulated in lysosomes. 198 LOX-1 is one of the scavenger receptors and highly expressed in ECs, which binds oxLDL and transfers it to the intima infiltrated by macrophages. Next, macrophages bind oxLDL through scavenger receptors including SR-A1, CD36, and LOX-1. 89

The formation of CE is an important part in the transition of macrophages to foam cells. Disruption of the balance between esterification and de-esterification results in accumulation of CEs in macrophages, leading to foam cells formation. 17 As an important part of lipoprotein metabolism, RCT can prevent foam cell formation. Imbalanced conversion between CE and FC and dysregulation of HDL function lead to formation of cholesterol crystals. 199 As cholesterol crystals grow and accumulate in the extracellular space of the plaque necrosis core, it eventually reaches and penetrates the arterial intima. 200 This will lead to increased plaque instability, which in turn causes plaque rupture and further thrombus formation. 17

Cholesterol-lowering intervention therapy

LDL-C is involved in the occurrence and development of atherosclerosis, indicating LDL-C is the main risk factor for ASCVD. More and more studies show that lower LDL-C levels are better for cardiovascular system. 201 , 202 In the following sections, we will discuss the drugs that possess cholesterol-lowering capacities (Table 1 ).

Statins are competitive HMGCR inhibitors, which can effectively reduce the level of plasma cholesterol, especially LDL-C levels. Statins represent the mainstream therapy for CVD. 203 , 204 , 205 , 206 Historical studies have confirmed that statins are able to reduce the incidence of CVD by 23% which leads to statins as the first choice for the treatment of hypercholesterolemia. 207 Mevastatin is the first statin discovered in the world, and it was isolated from fungal species Penicillium citrinum . 208 But till the 1990s, the landmark Scandinavian Simvastatin Survival study (4S) showed convincing results that support the use of statins to reduce cholesterol and CVD. 209 By 2020, at least nine different statins have been developed, among which seven have been approved in USA and one has been withdrawn from the market. 203 Statins inhibit HMGCR activity by competitively binding to the enzymatic site of HMGCR, resulting in decreased cholesterol synthesis and reduced plasma cholesterol levels. 210 Low plasma cholesterol levels in turn increase hepatic LDLR expression via the SREBP2-dependent pathway. The increased LDLR expression in hepatocytes speeds up the uptake and clearance of LDL-C from plasma, another important mechanism of statins improving cholesterol metabolism systematically. 211 However, some studies have shown that statin can also induce PCSK9 expression since PCSK9 also contains SRE in its promoter. The increased PCSK9 expression substantially attenuates the expected efficacy of statins on cholesterol lowering. 212 , 213

Without the influence of PCSK9, the extent of LDL-C reduced by statins should be dose-dependent and may vary among different statins. According to the effect of lowering LDL-C, different types and doses of statin therapy are divided into three intensities: low, moderate and high. Low-intensity is defined as a daily dose of statin that can reduce LDL-C < 30%; moderate-intensity is indicated as reducing LDL-C to 30–50%; and high-intensity is to reduce LDL-C ≥ 50%. 214 A meta-analysis showed a 10% reduction in all-cause mortality for per 1 mmol/l (equivalent 39 mg/dl) reduction in LDL-C, mainly due to a reduction in deaths from CVD. 207 Further meta-analysis showed that statins can reduce all-cause mortality and the risk of cardiovascular events, regardless of age and sex. 215 , 216 Even in patients with low cardiovascular risk, statins could reduce all-cause mortality and cardiovascular events. 217

In addition to reduction of LDL-C, statins have been demonstrated to have many other beneficial effects, known as the pleiotropic effects of statins. 218 , 219 Statins have been reported to elevate HDL-C, which also varies with dose among different statins. 220 However, when LDL-C is below a certain level, statin-elevated HDL-C has little effect on disease regression. 221 The anti-inflammatory and antioxidant effects of statins may also make contributions to prevention and/or reduction of ASCVD, at least confirmed by in vitro and animal studies. However, the clinical significance of these positive effects on ASCVD may need more exploration. 222 , 223

Although the efficacy of statins in lowering LDL-C and treating ASCVD is unquestionable, there are still many controversies regarding the application of statins. 224 Myopathy is one of the most common clinical adverse reactions caused by statins. 225 The most severe form of statin-associated muscle symptoms (SAMS), rhabdomyolysis, is characterized by severe muscle pain, muscle necrosis, and myoglobinuria, which can lead to kidney failure or death. 226 However, the nocebo effect may outweigh the side effects caused by the statins themselves. 227 Thus, in all international guidelines, the availability of statins for the secondary prevention of ASCVD is consistent in patients without statins intolerance or adverse reactions, and the benefits of statins treatment are supported by a large amount of data. 228 When it comes to primary prevention, the international guidelines for the treatment of isolated adult patients with elevated LDL-C (defined as ≥190 mg/dL) have not yet reached consensus. At the same time, the application of statins in patients with chronic kidney disease, diabetes, the elderly over 75 years old, and patients with heart failure also demonstrated mixed results. 229 , 230 , 231 , 232 For those patients with intolerance to the recommended-intensity statins due to the adverse effects or those who do not achieve LDL-C reducing goals, the non-statin lipid-lowering drugs added to the maximally tolerated statins can be recommended. 233 , 234

Ezetimibe is an intestinal cholesterol absorption inhibitor, which can block intestinal uptake of cholesterol by interacting with NPC1L1 without effect on absorption of TG and fat-soluble vitamins. 235 , 236 In addition to lowering plasma cholesterol levels, similar to statins, ezetimibe also up-regulates LDLR expression in the liver, thereby enhancing LDL-C clearance. 237 Experiments have also shown that ezetimibe may reduce inflammation in atherosclerotic plaques by increasing LDL-C breakdown and promoting fecal excretion of LDL-derived cholesterol. 238 , 239

Ezetimibe is a good option for patients with contraindications, statin intolerance and/or insufficient LDL-C reduction. 235 Clinical studies and meta-analyses show that ezetimibe monotherapy significantly reduces LDL-C and TC levels. It also slightly increases HDL-C levels in patients with hypercholesterolemia. 237 , 240 LDL-C lowering treatment with ezetimibe reduces the risk of cardiovascular events in patients aged ≥75 years with elevated LDL-C. 241 In a rabbit model of plaque erosion, ezetimibe lowered serum oxysterols, thereby reducing atherothrombotic complications following superficial plaque erosion. 242

In order to achieve better therapeutic effects, ezetimibe is often used in combination with a statin. In 2018, Ezetimibe was the most prescribed non-statin lipid-lowering therapy. In patients treated with statins, the addition of ezetimibe reduced LDL-C by an additional 23.8%, and fixed-dose combination (FDC) therapy reduced LDL-C by an additional 28.4% compared with statin therapy alone. However, treatment outcomes vary widely among individuals that only a small percentage of patients achieved recommended LDL-C levels (FDC, 31.5%; separate pills, 21.0%). 243 In addition, bempedoic acid plus ezetimibe FDC together with maximally tolerated statin therapy also significantly lowered LDL-C and had a favorable safety profile. 244 It has been reported that co-administration of ezetimibe with a bile acid sequestrant can reduce LDL-C by an additional 10–20%. 245 The combination of ezetimibe and PCSK9 inhibitor may have an additional effect in cholesterol lowering. 246

Notably, age, gender, or race do not affect the pharmacokinetics of ezetimibe, and no dose adjustment was required in patients who had mild hepatic impairment or mild to severe renal impairment. 235 Furthermore, ezetimibe also shows favorable drug interaction characteristics and has little effect on plasma levels of statins. In addition, the bioavailability of ezetimibe is not significantly affected by concurrent statin administration. 247

PCSK9 inhibitors

The discovery of PCSK9 provides a new idea for controlling plasma LDL-C levels. PCSK9 inhibitors can increase LDLR expression by attenuating PCSK9 expression/function, leading to the lowering plasma LDL-C. 248 In addition, it has been reported that inflammatory state could promote PCSK9 expression and increased PCSK9 would up-regulate LOX-1 expression, thus promoting oxLDL uptake and accelerating the progression of atherosclerosis. 249 , 250 At present, there are three approved PCSK9 inhibitors, among which alirocumab and evolocumab are the full human monoclonal antibodies, and the third one, inclisiran, is a double-stranded siRNA. 251 , 252

In meta-analysis, evolocumab and alirocumab could significantly reduce cardiovascular events, but had no significant effect on cardiovascular mortality. 253 , 254 , 255 , 256 Evolocumab and alirocumab, either alone or in combination with statins or other lipid-lowering drugs, can reduce LDL-C levels by an average of 60%. 235 When evolocumab and alirocumab were used in combination with the high-intensity statins, there was an additional 46–73% reduction in LDL-C compared to placebo, and an additional 30% reduction compared to ezetimibe. 235 Inclisiran is a novel PCSK9 inhibitor, which was approved for treatment of ASCVD by US FDA in 2021. 252 In the two phase 3 trials of inclisiran in the patients with elevated LDL-C, subcutaneous injection of inclisiran once every 6 months resulted in a 50% reduction in LDL-C levels. 257 Adverse events at the injection site of inclisiran were more frequent than placebo, but the reaction was usually mild. 257 Recently, a study showed that inclisiran inhibited foam cell formation by inhibiting oxLDL uptake by RAW264.7 macrophages, which was associated with activation of peroxisome proliferator-activated receptor γ pathway. This observation may provide new insights into the cholesterol-lowering mechanism of inclisiran. 258

Itching at the injection site and flu-like symptoms are the most common side effects of PCSK9 inhibitors. 259 PCSK9 inhibitors are effective. However, given the high cost and limited data on the long-term safety, they may be only cost-effective in patients with high risk of ASCVD, while not be available in some areas with no enough medical resources. 235 Therefore, lower-cost alternative drugs need to be developed.

Bempedoic acid (ETC-1002)

Bempedoic acid, an inhibitor of ACLY, is the first FDA-approved non-statin oral cholesterol-lowering drug in nearly 20 years. 40 , 260 In fact, bempedoic acid is a prodrug and needs to be converted into bempedoic acid-CoA thioester, the active form of ACLY inhibitor, by very long-chain acyl-CoA synthetase-1 (ACSVL1). 261 Interestingly, expression of ACSVL1 is tissue-dependent with little in the muscle and high in the liver. Therefore, inhibition of ACLY activity by bempedoic acid administration simply occurs to the liver, thereby avoiding the muscle-related side effects. 262 ACLY inhibition can also upregulate LDLR expression, which can make additional contributions to the reduction of plasma LDL-C levels. 263 Studies have shown that in high-fat and high-cholesterol diet-fed mice, in addition to inhibition of cholesterol synthesis and activation of LDLR expression, bempedoic acid also reduces inflammation by directly inhibiting ACLY and activating AMPKβ1 activity, thereby potently preventing atherosclerosis. 262 , 264

The CLEAR trials showed that adding bempedoic acid to current cholesterol-lowering therapy can further reduce LDL-C levels in patients with high risk for CVD. 244 , 263 , 265 When combined with statins, ezetimibe lowered LDL-C by an additional 25%, while bempedoic acid add-on therapy lowered LDL-C by an additional 16%. 266 , 267 This finding contrasted with the findings of the monotherapy arms in phase 3 trial, in which LDL-C was reduced by ~30% by bempedoic acid and ~21% by ezetimibe alone. 268

The application of bempedoic acid may cause an increase in serum uric acid and increase the risk of tendon rupture, so patients with gout or a history of tendon disease should avoid using bempedoic acid. 269 In view of some drug interactions found in clinical trials, the administration of drugs containing bempedoic acid is not recommended when using simvastatin at a dose >20 mg or pravastatin at a dose >40 mg. 268

For patients at high risk of ASCVD, bempedoic acid alone or in combination with ezetimibe can be considered as an additional treatment of statins. 270 Given the high cost of PCSK9 inhibitors, the use of bempedoic acid would be a higher priority than PCSK9 inhibitors, but lower than ezetimibe based on the limited data on the overall efficacy. Nonetheless, the combination of bempedoic acid or ezetimibe with statins is suggested for the patients who require greater LDL-C lowering than either drug alone. At present, the lipid-lowering ability of bempedoic acid is clear, but whether it can reduce the risk of ASCVD remains unknown, which needs further study.

Bile acid sequestrants

Bile acid sequestrants (BAS) are macromolecular polymers which can bind to bile acids in the small intestine, thus, BAS can prevent bile acids from being reabsorbed back into the liver. 271 Due to bile depletion in the liver, more bile acids than usually required are synthesized from liver cholesterol, which increases the demand for cholesterol in the liver, leading to increased LDLR expression and clearance rate of circulating LDL-C. 272 Three types of BAS have been approved for clinical use: cholestyramine, colestipol and colesevelam hydrochloride. The past clinical trials demonstrated that BAS was effective in lowering LDL-C and reduction of the risk of cardiovascular events in hypercholesterolemic patients. 272 , 273 , 274 , 275

Even low-dose BAS could also cause gastrointestinal adverse reactions, which limits its application. It has been reported that use of BAS can reduce the absorption of intestinal fat-soluble vitamins and sometimes increase the level of circulating TG in some patients. 235 In addition, BAS interacts with several commonly used drugs, so it must be used with caution in combination therapy. Among them, colesevelam is well tolerated and has less interaction with other drugs, thus, it can be used concurrently with drugs for other kinds of disease treatment. 276

Lomitapide is an oral microsomal TG transfer protein (MTP) inhibitor, which can reduce the assembly of lipoproteins containing ApoB in intestine and liver, so the reduction of LDL-C levels by MTP inhibitors is independent of LDLR. 277 Lomitapide has been proved to reduce LDL-C in homozygous FH (HoFH) patients by nearly 50% in combination with other lipid-lowering drugs. 278

In a real-world European study, lomitapide has been proved to be a very effective adjuvant drug to reduce LDL-C in HoFH patients for the longest follow-up period so far. 279 As lomitapide blocks MTP, it leads to impaired intestinal fat transport, making gastrointestinal symptoms as the most common adverse event in patients. 280 In terms of safety, lomitapide-related hepatic steatosis may not indirectly increase the risk of liver fibrosis, and the data suggest that lomitapide may reduce cardiovascular events in HoFH patients. 279

Evinacumab is a human monoclonal IgG4 antibody neutralizing angiopoietin-like protein 3 (ANGPTL3). ANGPTL3 is a protein secreted by the liver, which inhibits activity of lipoprotein lipase and endothelial lipase, the two lipases involved in the regulation of lipid hydrolysis in serum. 281 Inhibition of ANGPTL3 by evinacumab restores activity of the two lipases, thus reducing serum cholesterol and TG levels. 282

In 2021, evinacumab was approved in USA as an adjunctive cholesterol-lowering treatment for FH in adults and children 12 years of age or older. The previous clinical trials showed that evinacumab reduced TC and LDL-C by 45–55% in HoFH patients already receiving maximum tolerated doses of lipid-lowering drugs. 282 An animal study showed that alirocumab, evinacumab, and atorvastatin triple therapy significantly reduced hyperlipidemia and atherosclerosis. 283 , 284 Currently, no randomized clinical trials demonstrate that evinacumab can reduce cardiovascular events, so the further research is needed.

Frequent adverse events of evinacumab include mild local injection reaction, flu-like illness, headache, urinary tract infection and limb pain. 285 In addition, no clinically apparent liver injury or serious hepatic adverse events attributable to treatment were reported.

Fibrates are PPARα agonizts, which can increase HDL-C levels and decrease TG levels in plasma by regulating molecules related to lipid metabolism. 286 The clinical effects of fibrate class on blood lipids are different, but are estimated to reduce TG levels by 50% and LDL-C levels by ≤20%, and increase HDL-C levels by ≤20%. These effects are closely related to baseline lipid levels. 287 Meta-analysis showed that fibrates-treated patients with high TG and low HDL-C had a decrease of major cardiovascular events without reduced CVD or total mortality. 288 , 289 Recently, a novel fibrate, pemafibrate, was reported to significantly reduce TG-rich lipoproteins, such as chylomicrons and VLDL. 290 In addition, fibrates are well tolerated with common adverse effects of myopathy, elevated liver enzymes, and cholelithiasis. 291 Overall, the CVD benefit of fibrates requires further confirmation.

Lipoprotein apheresis

Lipoprotein apheresis (LA) is a non-drug lipoprotein-lowering therapy commonly used in patients with HoFH, heterozygous FH and other forms of hypercholesterolemia or CVD. 292 Although highly effective, LA is time-consuming and expensive, and has long been the last resort for treating uncontrolled dyslipidemia. 293

New targets for cholesterol-lowering therapy

In addition to the classical targets for drug mentioned above, some new targets for cholesterol lowering are also being investigated, which we will elaborate below (Table 2 ).

Apolipoprotein C3 (APOC3) is an apolipoprotein encoded by the gene APOC3 and mainly found in VLDL and chylomicron. 294 , 295 APOC3 can stimulate liver to synthesize and secrete VLDL. 296 It also reduces liver clearance of TG-rich lipoproteins by regulating LDLR/LDLR-related protein 1 (LRP1) pathway. 297 Epidemiological studies show that plasma APOC3 levels can be used to predict CVD risk and mortality. 298 , 299 , 300 , 301 It has been reported that carriers of rare heterozygous deletion mutations in APOC3 have lower TG, enhanced HDL-C, little change in LDL-C and lower cardiovascular risk. 302 , 303

Volanesorsen is a second-generation of antisense oligonucleotide (ASO) targeting APOC3 mRNA in hepatocytes to decrease APOC3 expression, thereby significantly reducing plasma TG levels. 304 APO-CIII-L Rx is a next-generation of N-acetylgalactosamine-conjugated ASO targeting APOC3. In a double-blind, placebo-controlled, dose-escalation phase 1/2a study, multiple injections of 30 mg/week APO-CIII-L Rx reduced APOC3, TG, VLDL, TC, LDL-C by ~80%, 70%, 70%, 15%, and 15%, respectively, and increased HDL-C by about 70%. 305

Based on these studies, it is suggested that inhibition of APOC3 also has cholesterol lowering potential, although the mechanism remains unclear.

Lipoprotein (a) [Lp(a)]

Lp(a) is a special form of LDL particle encoded by LPA , to which part of Apo(a) is covalently bound to ApoB. Lp(a) contains 35–46% CE and 6–9% cholesterol. 306 , 307 The concentration of Lp(a) is mainly determined by genes and varies greatly among individuals. 308 In the past, multiple studies have demonstrated that Lp(a) is another risk factor for ASCVD. 309 , 310 , 311 , 312

The in vitro and animal studies suggest that Lp(a) is important in the progression of atherosclerosis by influencing formation of foam cells, VSMC proliferation, and plaque inflammation and instability. 313 , 314 But in individuals with high Lp(a) levels, the content of atherogenic cholesterol carried by LDL is generally much higher than carried by Lp(a). 315 However, vascular dynamics studies have shown that Lp(a) accumulates preferentially in the vascular wall, which may indicate that the cholesterol carried by Lp(a) has more atherogenic potential than LDL-C. 316

So far, there is no approved pharmacological approaches to reduce Lp(a) to the level which can benefit ASCVD. 317 However, niacin, mipomersen and PCSK9 inhibitors show a certain effect on lowering Lp(a), although these effects may not translate into substantial clinical benefits. 318 , 319 , 320 The recently concluded phase 2 trial of pelacarsen demonstrated significant Lp(a) lowering capacity. Pelacarsen is a hepatocyte-directed ASO targeting liver LPA mRNA, and can significantly reduce Lp(a) production. 321 In addition, another siRNA drug, olpasiran, also shows a strong Lp(a)-lowering effect. 322 Taken together, existing evidence suggests that Lp(a) is a potential target to treat ASCVD, and drugs targeting it are under intense development.

The oxysterol-activated receptors, LXRα and LXRβ, are members of the nuclear transcription receptor family. LXRs play important roles in RCT through multiple mechanisms. In different mouse models, in vivo activation of LXRs increases the rate of RCT by increasing ABCG1 and ABCA1 expression in macrophages. 323 , 324 , 325 In addition, activation of LXRs also has a significant anti-inflammatory effect. 326 Therefore, targeting LXRs is a potential anti-atherosclerotic strategy. T0901317 and GW3965 are synthetic agonizts of LXRs that could significantly reduce plaque formation in atherosclerotic mice. 327 , 328 However, activation of LXRs also up-regulates liver SREBP1c, leading to hepatic steatosis and hypertriglyceridemia, which limits clinical application of LXR agonizts. 329 For this reason, some specific targeted agonizts have been developed. GW6340 is a gut-specific LXR agonist which promotes macrophage RCT but has no effect on TG levels in plasma. 330 Furthermore, IMB-808 significantly activates cholesterol efflux from RAW264.7 and THP-1-derived macrophages while has little effect on expression of lipogenic genes in HepG2 cells. 331

In order to avoid the side effects of LXRs agonizts, some methods of drug combination or targeted therapy have also been developed. We demonstrated that T0901317 in combination with a MEK1/2 inhibitor, U0126, inhibited atherosclerosis and blocked T0901317-induced hypertriglyceridemia. 332 We also reported that the combined treatment of metformin and T0901317 not only blocked T0901317-induced hypertriglyceridemia, but also enhanced the atherosclerosis-inhibiting effect of T0901317 by selectively activating LXRβ but not LXRα. 333 In view of the good targeting of nanomaterials, the side effects of liver can be avoided by using nano-carriers to deliver LXR agonizts. Last year, we reported a nanofibrous hydrogel, encapsulated T0901317 by the small peptide D-Nap-GFFY, selectively targeted macrophages but not hepatocytes. Thus, the hydrogel-encapsulated T0901317 inhibited the development of atherosclerosis without increasing TG levels. 334 Although LXR agonizts have been shown the potential to slow atherosclerosis progression in animal models, they are still a long way from clinical use.

CETP inhibitors can reduce LDL-C and increase HDL-C levels by inhibiting the transfer of cholesterol esters from HDL to LDL particles. 188 It has been reported that CETP activity is significantly elevated in patients with metabolic disorders and a high cardiovascular risk, indicating CETP can be a potential indicator of cardiovascular risk. 335 In vivo experiments show that elimination of CETP activity inhibits cholesterol diet-induced atherosclerosis in rabbits. 336 These results provide a basis for the potential of CETP inhibitors to improve blood lipids and reduce ASCVD risk.

CETP inhibitors to date include torcetrapib, dalcetrapib, evacetrapib, anacetrapib and obicetrapib. Since CETP is not existing in mice, most translational studies of CETP inhibitors are performed in ApoE3*CETP Leiden mice. Unfortunately, the first CETP inhibitor, torcetrapib, has been observed to increase the incidence of cardiovascular events and overall mortality, although it increased HDL-C while decreased LDL-C. 337 When used in treatment of patients with acute coronary syndrome, dalcetrapib had no effect on reduction of the recurrent cardiovascular events, therefore, use of dalcetrapib was discontinued early. 338 Similarly, evacetrapib adversely affected the cardiovascular outcomes in patients who had high risk of vascular disease. 339 On the other hand, anacetrapib significantly improved lipids and reduced the incidence of major coronary events in patients with a good tolerance. 340 However, anacetrapib was also discontinued due to its long half-life. A 12-week monotherapy trial of obicetrapib, the latest CETP inhibitor, showed a 45.3% reduction in LDL-C compared to placebo. 341 Current studies are evaluating obicetrapib in patients who are intolerant of statins in a phase 3 study.

LOX-1 is a scavenger receptor for oxLDL and plays an important role in oxLDL uptake by cells. 342 In atherosclerotic plaques and surrounding tissues, LOX-1 is highly expressed. It promotes uptake of oxLDL by ECs, VSMCs, monocytes and macrophages, resulting in foam cell formation. 342 At the same time, some studies have shown that LOX-1 deletion significantly reduces oxidative stress, nitric oxide degradation and inflammatory responses, reducing the progression of atherosclerosis. 343 , 344 Therefore, it is suggested that LOX-1 promotes the atherosclerosis progression. Contradictorily, liver overexpression of LOX-1 promoted oxLDL uptake, decreased plasma oxLDL, and inhibited the progression of atherosclerosis in ApoE-deficient mice. 345 Hence, LOX-1 is also a key regulator in the mechanisms of atherosclerotic plaque formation, progression and instability which may need further investigation.

Currently, some natural products, such as Tanshinone II-A, curcumin and Gingko biloba extract, have been shown to prevent atherosclerosis through LOX-1 inhibition. 346 , 347 , 348 The LOX-1 molecule consists of a hydrophobic channel that is the primary binding site for the phospholipid moiety of oxLDL. 349 Chemically synthesized small molecules targeting this channel can effectively reduce oxLDL uptake in vitro. 350 In addition to chemically synthesized inhibitors, many monoclonal antibodies are available to block LOX-1 activity. However, these antibodies are currently limited to cell and animal experiments because LOX-1 molecule contains a highly conserved C-type lectin-like domain in mammals, making it challenging to develop human LOX-1 antibodies. 351 At present, the research of chimeric LOX-1 antibody is still in progress.

SR-BI is a member of the scavenger receptor family. Liver SR-BI regulates RCT by taking up HDL-C and transporting cholesterol to bile. Liver SR-BI regulates HDL composition, mediates cholesterol efflux, and reduces inflammation and oxidation through selective uptake of HDL lipids. In macrophages and ECs, SR-BI is important in inhibiting atherosclerosis and reducing foam cell formation by regulating cholesterol transport. 352 Therefore, SR-BI is a potential multifunctional target for inhibiting atherosclerosis.

The current study has identified the protective role of SR-BI in mice with atherosclerosis. Genomic analysis reveals increased risk of CVD in loss-of-function carriers of scavenger receptor class B member 1 ( SCARB1 ) variant, which encodes SR-BI, suggesting the protective role of SR-BI in atherosclerosis. 353 Given the recent appreciation of endothelial SR-BI in LDL transcytosis, SR-BI targeted therapies need to be assessed with caution. 354 At present, the mechanism by which SR-BI works in human body is still unclear, so exploring its detailed mechanism is crucial for the development of new treatments for atherosclerosis.

LCAT is the only enzyme in plasma that esterifies cholesterol, and its activity is a major determinant of HDL-C levels. 355 LCAT plays a central role in HDL metabolism and RCT, so it is generally considered to be anti-atherosclerotic. However, studies in humans and animals obtained different results, so whether its activity can improve the function of HDL is controversial. 356 , 357 This may be related to the levels of LDL-C, the presence or absence of CETP and SR-BI, and the degree of overexpression of LCAT. 356

AlphaCore Pharmaceuticals developed the original recombinant human LCAT (rhLCAT) for clinical testing. In a phase 1 clinical trial, this early rhLCAT formulation, ACP501, increased plasma HDL-C by 50% and promoted cholesterol efflux without serious adverse reactions. 358 Since then, a new formulation of rhLCAT, MEDI6012, has been developed, which can raise plasma HDL-C in patients with atherosclerosis by injection three times a week. 359 However, it was abandoned in phase 2 for safety or efficacy reasons. Compound A is the first identified small molecular activator of LCAT that can covalently bind to residue C31 of LCAT, and has been shown to increase LCAT activity in vitro with unclear function on atherosclerosis. 360 , 361

In addition, another class of activators bind LCAT in a non-covalent and reversible manner. Previous studies have shown that such activators stabilize the open, active conformation of the enzyme, thereby facilitating lipid transport to the active site. 362 DS-8190a is an orally bioavailable and novel small-molecular LCAT activator that can directly interact with human LCAT. It inhibited atherosclerosis in mice expressing human LCAT, which was associated with enhanced the RCT process. Oral administration of DS-8190A also stimulated RCT process in primate cynomolgus monkeys. 363 These studies suggest that LCAT activation may help to reduce residual risk of ASCVD.

MiR-33 and miR-122

MicroRNAs (miRNAs) belong to a family of endogenous noncoding RNAs that can regulate gene expression post-transcriptionally. By binding to the 3′-untranslated region (3′UTR) of target genes, miRNAs promote translational repression or mRNA degradation. 364 Recent studies have shown that miRNAs are involved in cholesterol uptake, synthesis, and efflux, and are expected to be potential targets for regulating cholesterol metabolism. 365 , 366 , 367

miRNA-33 (miR-33) is composed of miR-33a and miR-33b, located in the SREBP2 and SREBP1 gene introns, respectively, and co-expressed under different stimulation conditions. 368 , 369 miR-33 inhibits expression of the genes involved in cholesterol efflux and HDL synthesis, such as ABCA1 and ABCG1 . 370 Studies have shown that inhibition of miR-33 induces hepatic ABCA1 expression, thereby increasing plasma HDL-C levels, and the inhibition also promotes RCT in macrophages and regression of atherosclerosis. 371 , 372 In addition, some studies have investigated the role of miR-33 on VLDL/LDL metabolism. It has been reported that global knockout of miR-33 in mice increases plasma LDL-C/VLDL-C levels. 373 However, mice may experience these effects due to their genetic background. The levels of VLDL-C and VLDL-TG were increased in LDLR deficient mice but not ApoE deficient mice fed Western diet after miR-33 knockout, which may be due to a high basal level of VLDL in ApoE deficient mice. 374 , 375 Based on the existing studies, although inhibition of miR-33 can effectively improve cholesterol efflux and HDL synthesis, its side effects remain to be clarified.

miRNA-122 (miR-122) is the most abundant hepatic miRNA. Its levels are positively correlated to human plasma cholesterol levels, suggesting that miR-122 can be involved in regulation of cholesterol metabolism. 376 miR-122 inhibitors have been reported to reduce plasma TC levels in mice and non-human primates. 377 , 378 , 379 However, miR-122 deletion is accompanied by significant hepatic steatosis, so the safety of miR-122 treatment remains to be investigated. 380 Moreover, to designate miR-122 as a potential therapeutic target for regulating cholesterol metabolism, the further elucidation on its physiological role is required.

Prekallikrein

Recently, the coagulation factor PK [encoded by the kallikrein B1 ( KLKB1 ) gene] was identified as a binding protein of LDLR. 140 In this study, it was found that PK binds to LDLR and causes LDLR lysosomal degradation, while plasma PK concentrations in humans are positively correlated to LDL-C levels. Loss of KLKB1 increases hepatic LDLR and reduces FC, attenuating atherosclerosis progression in multiple rodent models. In addition, the use of anti-competitive neutralizing antibodies can also reduce plasma lipids by up-regulating liver LDLR. This study suggests that PK may represent a potential treatment target for ASCVD.

Benefits of improving cholesterol homeostasis in other diseases

In addition to ASCVD, cholesterol metabolic disorders are also involved in the pathogenesis of other diseases and cholesterol lowering can ameliorate them. Interestingly, improving cholesterol homeostasis may be beneficial to several diseases even the role of cholesterol in these diseases remains unclear.

NAFLD is a chronic liver disease caused by excessive lipid deposition in liver cells without significant alcohol intake. 381 NAFLD includes nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). 382 The accumulation of FC in the liver is also relevant to the pathogenesis of NAFLD. 383 , 384 Epidemiological studies have found that intake of excess dietary cholesterol significantly increases the risk of NAFL and NASH. 385 , 386 A study of lipidomic analysis of liver biopsies from patients with NAFLD showed that hepatic FC level was positively correlated to the severity of liver histopathology. 382 Animal studies also showed that exogenous induction of FC accumulation in the liver can promote the progression of NAFL to NASH. 387 , 388

In NAFLD, hepatic cholesterol homeostasis is imbalanced, resulting in elevated levels of hepatic cholesterol. 389 This dysregulation may involve multiple metabolic pathways, including activation of cholesterol biosynthetic pathway (elevated expression and activity of SREBP2 and HMGCR), and cholesterol de-esterification (enhanced hydrolysis of CE to FC by hepatic neutral CE hydrolase), and reduced cholesterol export and BA synthesis (reduced expression of ABCG8 and CYP7A1). 70 , 384 , 390 , 391 However, the contributions of these pathways to NAFLD need to be further explored.

The exact mechanism of excess cholesterol toxicity in NAFLD remains incompletely described. Excess cholesterol accumulation in hepatocytes stimulates the formation of cholesterol crystals. 392 The presence of cholesterol crystals in hepatocytes activates NLRP3 inflammation, ultimately leads to hepatocyte death. Küpffer cells (KCs) aggregate around necrotic hepatocytes and trigger the formation of “crown-like structures”. Subsequently, KCs process these cholesterol crystals released from the dead hepatocytes and transform into foam cells. 383 , 392 Meanwhile, cholesterol crystals-induced activation of KCs triggers the activation of hepatic stellate cells (HSCs) by releasing inflammatory cytokines and transforming growth factor β, further accelerating the progression of NASH to fibrosis. 393 Furthermore, transcriptional coactivator with PDZ-binding motif (TAZ) is a transcriptional regulator that promotes NASH fibrosis and its expression is significantly increased in the NASH process. 394 , 395 , 396 Wang et al. firstly demonstrated that cholesterol prevents TAZ proteasomal degradation via the soluble adenylate cyclase-protein kinase A-inositol trisphosphate receptor-calcium-RhoA pathway. 397 This provides a new mechanism for the importance of hepatocyte cholesterol in the development of NASH. In summary, the cholesterol accumulation in hepatocytes and hepatic non-parenchymal cells accelerates the pathological process of NAFLD.

Clinical data show that statin treatment in patients with NAFLD reduces intrahepatic cholesterol levels. 398 , 399 , 400 Interestingly, the effect of ezetimibe on NAFLD in clinical trials is controversial. Several clinical studies suggest that ezetimibe may be beneficial for NAFLD. 401 , 402 However, a randomized, double-blind, placebo-controlled trial showed that ezetimibe had no significant effect on liver histology in NASH patients, 403 indicating more studies are needed to address the effect of ezetimibe. In addition to classic cholesterol-lowering drugs, other interventions to lower cholesterol may also be beneficial for NAFLD. Lanifibranor is a pan-PPAR agonist. In a recent phase 2b clinical study, lanifibranor not only showed good tolerability but also significantly improved liver fibrosis in NASH patients. 404 Lanifibranor improved NASH may be partially related to lowering cholesterol. Yang et al. found that knockout of E3 ligase SH3 domain-containing ring finger 2 ( SH3RF2 ) in hepatocytes resulted in accumulation of acetyl-CoA, which directly promoted cholesterol synthesis and aggravated the development of NAFLD. 405 Furthermore, miRNAs are key factors in regulating hepatic cholesterol synthesis. 406 Targeting SH3RF2 or miRNAs may be a new approach to alleviate NAFLD by lowering cholesterol.

Obesity is the manifestation of metabolic syndrome in the adipose tissue, which is associated with various chronic diseases, particularly CVD, diabetes, and certain types of cancers. 407 , 408 , 409 Changes in diet composition are one of the main reasons for the increasing trend of obesity. Chung et al. demonstrated that high dietary consumption of cholesterol was sufficient to induce an increase in visceral adipose cholesterol content and promote inflammation with adipose tissue in monkeys. 410 In addition, the genome-wide association studies have found the significant association between NPC1 and obesity. 411 This may provide a new explanation for familial obesity.

Adipose tissue plays a central role in energy metabolism and adaptation to the nutritional environment, and about 25% of the person’s cholesterol is stored in adipose tissues. 412 In obesity, cholesterol imbalance triggers inflammation in adipocytes and fat-resident immune cells, thus disrupting metabolic homeostasis. 413 In the initial stages of obesity, white adipose tissue exhibits physiological expansion and releases acute pro-inflammatory factors in order to store more energy. 414 Therefore, this initial pro-inflammatory response may be only physiologically adaptive. However, when cholesterol crystals accumulate in adipocytes and immune cells, it activates NLRP3 inflammasome, leading to increased inflammation. 415 Meanwhile, local inflammation in adipose tissue may directly affect brown adipocyte thermogenesis and beige adipocyte recruitment, which also hinders thermogenesis. 414 Taken together, excessive accumulation of cholesterol in adipose tissues causes inflammation and adipocyte dysfunction. Therefore, cholesterol-lowering therapies may be beneficial for obesity.

Triiodothyronine (T3) is the biologically active form of thyroid hormone. Grover et al. demonstrated that T3 regulates cholesterol metabolism via acting thyroid hormone receptor β signaling. 416 Both clinical and animal studies have shown that T3 treatment increased the rate of cholesterol metabolism. 416 , 417 However, the pharmacological benefits of T3 are limited by its side effects, particularly on heart rate. A novel strategy preferentially delivers T3 to the liver, thus mitigating its side effects. 418 Some new cholesterol-lowering targets may also be beneficial for obesity. Berbe´e et al. demonstrated that β3-adrenergic receptor-stimulated activation of brown adipose tissue reduces obesity by decreasing plasma cholesterol levels. 419 The selective thyroid hormone receptor modulator GC-1 has been shown to have better cholesterol-lowering efficacy than atorvastatin in animal studies. 420 These observations deserve further studies and hopefully offer new perspective for the treatment of lipid disorders and obesity. Interestingly, diet and lifestyle changes can also lower cholesterol. In a clinical trial with 82 healthy overweight and obese subjects, an isocaloric Mediterranean diet intervention was found to lower plasma cholesterol and alter the microbiome and metabolome. 421 Moreover, dietary and exercise interventions produced better outcomes for obese children. 422 Solving the obesity problem is a daunting challenge that seems to inevitably require multiple interventions. The development of drugs to treat obesity has been underway for more than a century and is continuing. 423 Consequently, for obese patients, lowering cholesterol may need to be used in combination with other interventions.

The relationship between TG and diabetes has been proposed at a fairly early stage. 424 , 425 , 426 However, the role of cholesterol has been underrecognized. The specific cholesterol homeostasis in pancreatic β cells plays a key role in insulin secretion. In 2007, two studies demonstrated that excess cholesterol inhibits insulin secretion from β cells. Brunham et al. reported that mice with specific knockout of ABCA1 in β cells had increased cholesterol levels and impaired glucose-stimulated insulin secretion. 427 Likewise, Hao et al. proved that accumulation of cholesterol in β cells influenced the translocation and activation of glucokinase, further inhibiting insulin secretion. 428 Subsequently, Vergeer et al. confirmed that carriers of loss-of-function mutant ABCA1 have pancreatic β-cell dysfunction. 429 The final step in insulin secretion is the fusion of insulin granules with plasma membrane and then secreted outside the cell through exocytosis. Xu et al. found that excess cholesterol can reduce insulin exocytosis through a dynamic-dependent process activated by phosphatidylinositol 4,5-bisphosphate. 430 Meanwhile, cholesterol accumulation also induces apoptosis of pancreatic β cells by enhancing mitochondrial bioenergetic damage, inflammation, oxidative stress and ER stress. 431 , 432 , 433 In addition, imbalanced cholesterol homeostasis in β cells increases obesity, reduces skeletal muscle mass and causes systemic inflammation. 434 This may provide a new explanation for the link between diabetes and obesity.

Given the harmful effects of cholesterol on β-cell function, cholesterol-lowering therapies may be therapeutically beneficial. In a randomized, double-blinded study, subjects taking a CETP inhibitor significantly increased postprandial insulin secretion. 435 This may be due to increased cholesterol efflux from pancreatic β cells. 435 Surprisingly, there is growing evidence showing that statin therapy could increase the risk of diabetes in a dose-dependent manner. 436 , 437 , 438 A recent animal study explains that atorvastatin impairs β-cell function by modulating small G protein, which subsequently dysregulating islet mTOR signaling and reducing functional β-cell mass. 439 Therefore, statins may need to be combined with other drugs for a better use in diabetic patients with hypercholesterolemia. Interestingly, ezetimibe promotes insulin secretion and protects β-cell function in diabetic mice. 440 Exploring the specific mechanism of ezetimibe to promote insulin secretion will be an interesting future investigation. Moreover, miR-33a and miR-145 can downregulate ABCA1, leading to cholesterol accumulation and reduction of insulin secretion. 441 , 442 Thus, targeting microRNAs or other epigenetic mechanisms may offer a promising therapeutic strategy for diabetes and its complications.

Neurodegenerative diseases

The brain is the cholesterol-rich organ in the body, accounting for approximately 20% of the body’s cholesterol. 443 Cholesterol homeostasis in the brain must be accurately controlled to ensure the brain to work properly. 444 Imbalance of cholesterol homeostasis in the brain is involved in the development of neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD).

Several reviews have linked cholesterol to the pathophysiology of AD, revealing the importance of cholesterol homeostasis in AD. 445 , 446 , 447 In an early clinical study, FH was shown to be an early risk factor for AD. 448 Plasma cholesterol can be oxidized to 27-hydroxycholesterol, which is able to cross the blood-brain barrier (BBB) and reach the central nervous system (CNS). 449 This establishes a critical link between FH and increased brain cholesterol. Xiong et al. stained brain sections from AD patients and found that cholesterol levels increased with disease progression. 450 A recent animal study has shown that a high-cholesterol diet disrupts BBB and impairs cognitive function. 448 Cutler et al. found that oxidative stress induced disturbances in cholesterol metabolism, leading to enrichment of cholesterol in neurons, which exacerbates the process of AD. 451 It is necessary to note that lipoproteins can’t cross the intact BBB. 444 The accumulation of cholesterol in the brain may be due to a disruption of BBB or a disturbance in the brain’s own cholesterol metabolism. However, the exact mechanism needs to be further explored.

Amyloid protein is cleaved to β-amyloid (Aβ) by β and γ-secretase. Aβ aggregation is the predominant pathological marker of AD. 445 Sparks et al. identified the effect of cholesterol on Aβ accumulation in 1994. 452 They found that feeding a cholesterol-rich diet to rabbits for eight weeks led to accumulation of intracellular Aβ in neurons in the hippocampal region. Many subsequent experiments have also demonstrated that cholesterol promotes Aβ accumulation. A key reason for the sensitivity of Aβ to cholesterol is that the activity of β and γ secretase is positively correlated to cholesterol levels. 446 , 453 Furthermore, cholesterol not only promotes Aβ secretion, but also impairs autophagy-mediated clearance of Aβ. Pathological accumulation of phosphorylated Tau (pTau) is another major biochemical marker of AD. Meanwhile, hyperphosphorylation of tau is accompanied with formation of neurofibrillary tangles (NFTs). 454 , 455 Imbalance in cholesterol homeostasis also increases pTau. A case-control study found a significant tau deposition in the brains of Niemann-Pick type C patients. 456 CE are the major storage form of excess cholesterol, and Kant et al. found that CE inhibited pTau degradation by inhibiting proteasome activity. 457 Conversely, Fan et al. demonstrated that cholesterol deficiency also leads to tau hyperphosphorylation, 458 indicating the exact mechanism of cholesterol effects on p-Tau remains to be further explored.

PD is the second most common progressive neurodegenerative disease after AD, and its pathological features include the loss of dopaminergic neurons and the formation of Lewy bodies from the accumulation of α-synuclein. 459 Increasing evidence suggests that cholesterol metabolism may also play a role in the pathogenesis of PD. However, the role of TC in PD is controversial. Some clinical studies found no difference in TC levels between PD patients and healthy controls. 460 , 461 In contrast, other prospective studies even found that high levels of TC were associated with a lower risk of PD. 462 , 463 This may be due to the fact that cholesterol levels decrease with age, and PD usually occurs more often in older age. As reported by Hu et al., the high TC levels increases the risk of PD in individuals aged 25-54 years, but this association is not significant after 55 years. 464 Thus, high TC levels in young and middle-aged individuals may promote PD development, which has been demonstrated in animal models with high-fat diets. 465 , 466

In spite of the unclear role of cholesterol in PD pathogenesis, several possible hypotheses have been proposed. Bar-On et al. treated B103 cells with cholesterol and found more α-synuclein aggregates while statin can reduce the aggregation. 467 The subsequent studies found that α-synuclein has a similar structure to apolipoproteins. 468 , 469 Thus, there is an interaction between cholesterol and α-synuclein. Fantini et al. found that cholesterol promotes α-synuclein insertion into lipid rafts through a virus-like fusion mechanism. 469 Hsiao et al. found that α-synuclein promotes cholesterol efflux in SH-SY5Y cells. 470 However, the relationship between cholesterol and α-synuclein remains to be further explored.

HD is an autosomal dominant neurodegenerative disorder caused by an abnormal expansion of the CAG trinucleotide repeat of the Huntington ( HTT ) gene. 471 Cholesterol homeostasis is altered in HD, which may be an effective disease-modifying strategy in the future. 472 An early investigation showed no significant changes in plasma cholesterol concentrations in HD patients. 473 However, another study found reduced mRNA levels of HMGCR, and 7-dehydrocholesterol reductase in postmortem tissues of HD patients. 474 Subsequently, Leoni et al. reported reduced blood cholesterol levels in HD patients. 475 Similarly, reduced brain cholesterol levels were also found in a variety of HD animal models. 476 , 477 , 478

Interestingly, reduced cholesterol level is more likely a phenomenon in the process of HD pathogenesis. There is evidence showing that mutant Huntington (m HTT ) interferes with SREBP2 activation, leading to reduced expression of HMGCR and cholesterol synthesis. 479 Brain-derived neurotrophic factor (BDNF) can also stimulate cholesterol synthesis. 480 Normal HTT promotes vesicular transport of BDNF vesicles along microtubules. 481 However, this process is inhibited by m HTT , resulting in decreased BDNF levels in the striatum, which may be another pathway leading to reduced cholesterol synthesis. 478 In contrast, cholesterol accumulates in mHTT­expressing neurons despite the downregulation of cholesterol synthesis. 482 Daniel et al. found that mHTT ­expressing neurons show elevated levels of the lipid raft marker ganglioside GM1, suggesting that cholesterol accumulation is associated with an increase in lipid rafts. 483 The present evidence suggests that reduced cholesterol synthesis and cholesterol accumulation in neurons are the main manifestations of imbalanced cholesterol homeostasis in HD. Determining which aspect of cholesterol dysregulation primarily affects the pathological process of HD will be a major challenge in the future.

Based on the reports above, modulation of cholesterol homeostasis could be a potential therapeutic target for neurodegenerative diseases. Lipophilic statins can cross the BBB and have the potential to modulate cholesterol homeostasis in the brain. 484 Several preclinical trials have shown multiple potential benefits of statins in neurodegenerative diseases. 484 , 485 , 486 , 487 Although the protective effects of statins in preclinical trials are consistent, the results of clinical trials remain controversial. Epidemiological studies have shown a 70% reduction in incidence of AD in subjects taking statins. 488 Treatment of subjects with statin at doses used in the clinical management of hypercholesterolemia resulted in a nearly 40% reduction in Aβ production in human plasma. 489 Li et al. reported that NFT burden was significantly reduced in subjects who had taken statins by brain autopsy. 490 By contrast, a cohort study that included 2798 individuals found that statin treatment was not associated with the risk of AD. 491 Similarly, most observational studies have shown that the use of statins reduces the risk of PD, 492 , 493 , 494 whereas some clinical trials have found that statins have no effect on PD or even increase the odds of PD. 495 , 496 However, no clinical trials have been conducted to evaluate the role of statins in HD to date. Due to the specificity of cholesterol homeostasis in HD, the benefit of statins in HD may be through anti-inflammation, anti-oxidative stress, and neuroprotection, rather than the ability to regulate cholesterol metabolism. Therefore, well-designed preclinical trials are needed to prove the effects of statins on HD. Other cholesterol-lowering drugs have also shown protection against neurodegenerative diseases in preclinical animal models. Efavirenz reduces p-Tau in a dose-dependent manner by decreasing CE production. 457 BM15.766, a specific inhibitor of cholesterol synthesis, showed inhibition of Aβ in transgenic AD mice model. 497 In addition, LXRs are major regulators of cholesterol homeostasis and inflammation in the CNS. 498 LXRs agonizts were shown to have alleviating effect in neurodegenerative diseases in preclinical trials. 499 , 500 , 501 β-Cyclodextrin and its derivatives also have a beneficial effect on the neurodegenerative diseases as drugs or drug carriers. 502 , 503 The pathogenesis of neurodegenerative diseases is mediated by a variety of factors, and cholesterol disorders may intricately aggravate the disease process. Considering the importance of cholesterol for the brain cell membrane integrity, cholesterol-lowering drugs should be used precisely with tailored needs. In other words, they are recommended for patients of neurodegenerative diseases with a relatively high cholesterol background.

Cholesterol is an essential neutral lipid which is necessary for membrane integrity and fluidity. 504 The increasing evidence demonstrate that tumor cells need an increased supply of cholesterol and can accumulate it. 505 , 506 , 507 It has been reported that during cancer progression, cholesterol influx and synthesis is increased and cholesterol efflux is decreased. 508 Aberrant activation of SREBPs is the main cause of increased tumor cholesterol synthesis. For example, in hepatocellular carcinoma, the sustained activation of protein kinase B (PKB) phosphorylates phosphoenolpyruvate carboxykinase 1, which in turn activates SREBPs and promotes tumor growth. 509 The alteration of the extracellular microenvironment of tumor cells also leads to activation of SREBPs. In breast cancer models, hypoxia induces PKB phosphorylation, which in turn activates hypoxia-inducible factor 1 and subsequently upregulates expression of SREBPs. 510 In addition, increased inflammatory factors, lower pH and excess glucose in the microenvironment can also activate SREBPs. 510 , 511 LXR promotes expression of cholesterol efflux proteins, ABCA1, ABCG1 and ABCG5, to reduce intracellular cholesterol concentrations. However, LXR is inhibited in tumors, which contributes to cholesterol accumulation in cancer cells. 512 , 513 Interestingly, CE levels were also significantly increased in tumors. 513 , 514 ACAT involves in synthesis of CE, which has been shown to be associated with a variety of tumors. 513 , 515 A latest study found that loss of P53 increased ubiquitin specific peptidase 19, which in turn stabilized ACAT1 and led to CE accumulation. 516 This study provides an important mechanism indicating the involvement of CE in hepatocellular carcinogenesis.

Similar to tumor cells, activation of cholesterol synthesis pathway is necessary to maintain T cell function. However, excessive cholesterol in the tumor microenvironment leads to ER stress in CD8 + T cells. Furthermore, the ER stress sensor X-box-binding protein 1 is activated to regulate transcription of programmed death 1 and natural killer cell receptor 2B4, which ultimately leads to T cell exhaustion. 517 It can be seen that the effect of increased extrinsic supply of cholesterol on T cells seems to be negative in the situation where tumor cells have a greater capacity to absorb cholesterol. In another study, ovarian cancer cells promoted tumor-associated macrophage (TAM) cholesterol efflux by secreting hyaluronic acid, which induced TAM conversion from M1 to M2 type and promoted tumor growth. 518

Statins have been shown to have good inhibitory effects on estrogen receptor-negative breast cancer, multiple myeloma, prostate cancer and some other specific tumors. 519 , 520 , 521 However, in several phase 3 clinical trail studies, treatment of 40 mg/day pravastatin or simvastatin to patients with small cell lung cancer, metastatic colorectal cancer, advanced hepatocellular carcinoma, or advanced gastric cancer had no additional benefit. 522 , 523 , 524 , 525 Therefore, a precision medicine approach is necessary if statins are to be incorporated into the treatment of cancer patients. Avacizimibe, a potent inhibitor of ACAT1, has been shown to affect the survival and proliferation of tumor cells in several preclinical studies. 526 , 527 , 528 The clinical application of Avacizimibe in anti-tumor needs to be further explored. In addition, drugs targeting the absorption and efflux of cholesterol have been tried for cancer treatment. LXR agonist, T0901317, suppressed the development of prostate cancer by upregulating ABCA1 and ABCG1 expression. 529 Ezetimibe significantly inhibited the growth of prostate and liver cancers. 530 , 531 Yuan et al. found that the tumor microenvironment could inhibit LDLR expression in CD8 + T cells via activating PCSK9, which suppressed the antitumor activity of CD8 + T cells. 532 Therefore, PCSK9 may be a novel target for tumor immunotherapy. The anti-tumor effects of PCSK9 inhibitors need to be further explored. In summary, drugs targeting cholesterol metabolic pathways have been demonstrated in many cancers. Considering the complexity of cancer metabolism, there are still many open questions that need to be addressed. For example, at what stage of tumorigenesis do these drugs act specifically, such as tumor metastasis? Do statins affect the function of circulating tumor cells? How do statins affect tumor cell metabolism in tumor microenvironment?

Osteoporosis

Osteoporosis most commonly occurs to postmenopausal women caused by impaired bone formation and/or excessive bone resorption. Bone mineral density (BMD) is considered as the key standard for determining osteoporosis. 533 Vitamin D, one of the important metabolites of cholesterol, induces synthesis of calcium-binding proteins to promote Ca 2+ absorption and enhances BMD. 534 Interestingly, epidemiological evidence indicates that high serum cholesterol levels represent a risk factor for osteoporosis. 535 , 536 , 537 , 538 Also, this phenomenon has been confirmed in several animal experiments. 539 , 540 , 541

Previous studies have given several possible explanations for why cholesterol increases the risk of osteoporosis. Cutillas-Marco et al. found that vitamin D levels were negatively associated with TC and LDL-C levels in a population-based survey. 542 This may be the most important cause of osteoporosis due to high cholesterol. However, the exact mechanism needs to be further explored. Bone homeostasis is maintained by osteoclastic bone resorption and osteoblastic bone formation. Experimental animal studies have shown that osteoclast functions are significantly cholesterol-dependent. 543 , 544 A high cholesterol diet leads to increased osteoclast numbers and bone resorption. 544 Conversely, inhibition of proliferation and differentiation of osteoblast MC3T3-E1 cells by cholesterol was determined in a dose-dependent manner, while resulted in decreased expression of the bone formation markers, bone morphogenetic protein-2 and runt-related transcription factor 2.

The clinical use of statins to prevent and/or treat osteoporosis is controversial. In 2018, an investigation found a reduced risk of osteoporosis in stroke patients using statins. 545 Ann et al. showed that statin increased BMD and appeared to be more effective in men with osteoporosis by meta-analysis. 546 However, in 2019, a cross-sectional retrospective study of healthy subjects reported that high doses of statins significantly increased the risk of osteoporosis. 547 This may indicate that statins are more appropriate for patients with severe hypercholesterolemia and high risk for osteoporosis. Furthermore, less of the statins reach the bone after the drug has been metabolized. This explains the fact that statins are often used at much higher doses than clinical ones to relieve osteoporosis. 548 Consequently, local delivery of statins needs further exploration.

Virus infection

A lipid raft is a subdomain of the plasma membrane enriched in cholesterol and sphingolipids, which also act as vectors for viruses to enter the host cells. 549 , 550 Studies have shown an association between cholesterol levels and virus infections. 551 , 552 , 553 Louie et al. found that additional 2% cholesterol in the diet causes inflammatory imbalance and exacerbates morbidity in mice infected with influenza A virus. 554 Wang et al. proved that pseudorabies virus (PRV) increases self-infection capability by suppressing LXR expression to increase total intracellular cholesterol levels. 555 COVID-19 is caused by an infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Sphingolipid- and cholesterol-rich regions recruit several receptors and molecules involved in pathogen recognition and cell signaling. 556 Angiotensin-converting enzyme 2 (ACE2) can be recruited to these regions as the primary functional receptor for SARS-CoV-2. 556 Therefore, cholesterol may be functionally important as a mediator of COVID-19 infection. Radenkovic et al. suggested that lipid rafts rich in ACE2 receptors may be increased in a state of high cholesterol levels, thus enhancing the endocytosis process of SARS-CoV-2. 557 Sanders et al. proved that SARS-CoV-2 requires cholesterol for viral entry and pathological syncytia formation. 558 Similarly, Li et al. also found that cholesterol depletion impaired virus entry in vitro. 559 , 560 In addition, cholesterol plays a role in binding and altering the SARS-CoV N-terminal fusion peptide oligomeric state, which is required for virus entry into the host cells. 561 Although many reports suggest that cholesterol plays an important role in virus entry, this still needs to be confirmed in vivo. In particular, the effect of SARS-CoV-2 on cholesterol homeostasis remains unclear and the molecular mechanisms need to be further explored.

PCSK9 is another interesting mediator involved in viral infection. Several clinical studies have found that hepatitis C virus (HCV) infection is associated with increased PCSK9 serum levels. 562 , 563 , 564 PCSK9 negatively regulates the hepatocyte surface proteins (LDLR, SR-BI, VLDLR) involved in HCV entry in vitro. 565 Meanwhile, HCV infection upregulates PCSK9 expression. 566 This indicated a complex interaction between PCSK9 and HCV. A recent preclinical study indicated that dengue virus (DENV) infection also induced PCSK9 expression, which led to downregulation of LDLR expression with a sequester of cholesterol in the intracellular space, providing a more favorable environment for virus entry. 567 Therefore, PCSK9 appears to contribute to DENV infection. However, the relationship between PCSK9 and SARS-CoV-2 infection is unclear.

25-hydroxycholesterol (25HC) is one of the metabolites of cholesterol catalyzed by CH25H. 568 Unlike cholesterol, 25HC and its synthetic enzyme CH25H have been shown to have potent broad-spectrum antiviral activity. 569 Li et al. reported that 25HC and CH25H protected hosts from Zika virus infection in a mouse model. 570 Xiang et al. found that 25HC and CH25H inhibited HCV infection by blocking SREBP maturation to inhibit viral genome replication. 571 Similarly, several studies have also shown that 25HC and CH25H inhibit SARS-CoV-2 infection by blocking membrane fusion. 572 , 573 LXR has been shown to induce the activation of interferon-γ (IFN-γ), which stimulates the expression of CH25H. 569 , 574 Interestingly, our studies reported that 25HC can also induce CH25H expression in an LXR-dependent manner, and demonstrated that LXR activation, interaction between CH25H and IFN-γ, and 25HC metabolism may form an antiviral system in which LXR plays a central role. 575 , 576

There is an interaction between COVID-19 infection and CVD. Li et al. reported an increased prevalence of CVD in patients after COVID-19 infection. 577 Similarly, patients infected by COVID-19 who previously experienced CVD had an increased case fatality rate. 578 Thus, lowering cholesterol levels may reduce the risk of COVID-19-induced complications. Statins have been reported to have anti-viral activity. 579 Therefore, they were quickly used in clinical trials for patients with COVID-19 infection. An observational study of hospitalized COVID-19 infected patients indicated that statins might be effective against COVID-19. 580 Similar observations have been reported in several subsequent studies. 581 , 582 , 583 Subir et al. recommended that COVID-19 infected patients at a high CVD risk should continue statin therapy unless absolutely contraindicated. 584 Statins may lower membrane cholesterol levels, thereby decreasing the attachment and internalization of SARS-CoV-2. 557 Surprisingly, Reiner et al. identified several statins as potential SARS-CoV-2 major protease inhibitors by molecular docking, especially pitavastatin with the strongest binding. 585 Therefore, the benefits of statins for patients with COVID-19 may be exerted through their direct cholesterol lowering effects and beyond. Future research is needed to depict the precise mechanism of cholesterol-aimed viral entry, survival and discover the new cholesterol-lowering therapies in COVID-19 patients. In addition, a preclinical study has shown that LXR agonist, T0901317, significantly inhibits herpes simplex virus type 1 infection. 576 Similarly, T0901317 also showed better prevention of PRV infection in mice. 555 A monoclonal antibody of PCSK9 (alirocumab) was shown to inhibit DENV infection in vitro. 567 Boccara et al. firstly evaluated the efficacy and safety of evolocumab in reducing LDL-C levels in HIV patients in a multinational, randomized, double-blind study. 586 However, no clinical trials on the effects of PCSK9 inhibitors in SARS-CoV-2-infected patients to date. Nevertheless, experts believe that use of PCSK9 inhibitors is still beneficial for COVID-19 patients with familial hypercholesterolemia. 587 , 588

Summary and outlook

High circulating cholesterol level is a major risk factor for ASCVD and promotes the progression of atherosclerosis, making key molecules involved in cholesterol homeostasis as the attractive therapeutic targets for ASCVD treatment. By reducing cholesterol biosynthesis and enhancing cholesterol metabolism, statins are used widely to reduce the levels of plasma TC and LDL-C to prevent or reduce CVD. However, due to the side effects and intolerance of statins, non-statin cholesterol-lowering drugs are being developed and more other novel targets than cholesterol lowering have been characterized. Moreover, combination of non-statin cholesterol-lowering drugs (for example, ezetimibe or PCSK9 inhibitors) with statins may be more effective in reducing LDL-C levels. A very exciting development is the concept “the lower the better” of LDL-C reduction, indicating that a lower LDL-C is tightly correlated to a better attenuation of ASCVD. In addition, cholesterol lowering has been demonstrated to be beneficial in many other diseases (Table 3 ). Therefore, cholesterol-lowering therapy is a rapidly developing field with various new targets and drugs.

In the future, the investigations related to cholesterol may face more challenges. For example, characterizing the relationship between inflammation and cholesterol metabolic disorders and developing the specific anti-inflammatory therapeutic intervention in reducing inflammation in ASCVD. Beyond LDL-C, the intervention on other lipoproteins needs more efforts to investigate. Nowadays, various cholesterol-lowering drugs are used in clinics. However, the studies on personalized therapy, lifestyle and targeting the right patient with the right time still need more attention. Moreover, exploring the role of cholesterol in other diseases, especially the complications of metabolic disorders, may accelerate the translation of research to the clinic.

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The work was funded by the National Natural Science Foundation of China (NSFC) Grants 81973316 to J.H., 82173807 to Y.D. Tianjin Municipal Science and Technology Commission of China Grant 20JCZDJC00710 and the Fundamental Research Funds for the Central Universities (Nankai University) 63211045 to J.H.

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Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

Yajun Duan & Suowen Xu

Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China

Yajun Duan, Ke Gong, Feng Zhang, Xianshe Meng & Jihong Han

College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China

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Duan, Y., Gong, K., Xu, S. et al. Regulation of cholesterol homeostasis in health and diseases: from mechanisms to targeted therapeutics. Sig Transduct Target Ther 7 , 265 (2022). https://doi.org/10.1038/s41392-022-01125-5

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Statin alternative significantly reduces heart disease deaths, new study finds

An alternative to statins may help reduce deaths from heart disease among people with high levels of LDL, or “bad” cholesterol, new research finds.

When taken as a daily pill, bempedoic acid lowered LDL cholesterol and showed a significant 39% reduction in heart disease deaths and heart attacks, researchers reported Saturday at the American Diabetes Association’s annual meeting. The findings were simultaneously published in JAMA.

“What we saw really surprised me,” said the study’s lead author, Dr. Steven Nissen, chief academic officer of the Heart, Vascular & Thoracic Institute at the Cleveland Clinic. “I hope this will be a wake-up call for patients and physicians.”  

Right now, fewer than half the people who should be prescribed a cholesterol-lowering medication because of heart disease risk are getting it, according to Nissen. That needs to change, he said.

“Treating people who have risk factors before their first cardiovascular event would have large benefits,” not just in preventing complications but also in preventing deaths, he said.

What is a healthy level of cholesterol?

Bempedoic acid, which was approved in 2020 by the Food and Drug Administration , is not as effective as statins, which are considered the gold standard in treating high cholesterol. However, many people stop or refuse to take statins because of possible side effects such as muscle pain, headaches, sleep problems and digestive problems.

Recent research found that about 20% of people at high risk for heart disease refuse to take statins when prescribed by their doctor. Women in particular were less likely to accept a statin prescription, according to the study published in JAMA Network Open.

Although the new study looked at only the impact of bempedoic acid on people who had adverse reactions to statins, it found that lowering cholesterol resulted in a significant decrease in heart attacks and heart-disease related deaths.

What's most important is to get blood cholesterol to healthy levels, whether by taking a statin or bempedoic acid or other lipid-lowering medication, Nissen said in an interview.

More on heart health

• 'Good' cholesterol may not protect against heart disease as much as thought
• Covid infection raises cholesterol levels, even in people with no prior problem
• Too many people stop their lifesaving statins, research shows

LDL, or low density lipoprotein, is the type of cholesterol that contributes to the buildup of fatty deposits in the arteries and raises the risk of cardiovascular events, such as heart attack and stroke. According to the American Heart Association , the optimal total cholesterol level for an adult is about 150 mg/dL, with LDL levels at or below 100 mg/dL.

The 4,206 patients enrolled in the new study are part of a larger group described in a New England Journal of Medicine article in March. The NEJM study included both patients who had experienced a cardiovascular event, such as a stroke or heart attack, as well as those who only had risk factors.

In the new research, Nissen and his colleagues focused only on participants who had never been diagnosed with heart disease, but were at high risk because of factors such as high LDL, diabetes and hypertension.

The average age of the participants in the new study was 68, and 59% were women. Two-thirds had diabetes. At the outset, the average LDL level in the participants was 142.5 mg/dL.

Six months into the study, compared with patients taking a placebo, participants who received a daily dose of bempedoic acid experienced a 23.2% reduction in LDL cholesterol and a 22.7% decrease in inflammation caused by a protein in the blood associated with heart and stroke risk.

Other key findings of the study, which tracked most participants for a little more than three years, showed that:

• Risk of heart attacks among people who received the medication were cut by 39%.
• Risk of heart disease-related death had been reduced by 39%.
• The combined risk of a patient dying, having a heart attack or a stroke had been cut by 36%.

There was a small increased risk of complications in those who were treated with bempedoic acid versus placebo, including the development of gout and gallstones.

Statins as 'first-line therapy'

While bempedoic acid may not cause as many muscle-related symptoms, it is more expensive than generic statins, Dr. Druv S. Kazi, a cardiologist, noted in an editorial accompanying the JAMA study.

"Patients are likely to face substantially higher out-of-pocket costs for bempedoic acid than for a generic statin," Kazi wrote.

Sheldon Koenig, CEO and president of Esperion, which makes the medication sold as Nexletol and funded the study, said the drug is now covered by many insurance companies.

“For Medicare, the company has preferred status and the copay is generally only $45 per month,” Koenig said.

The new findings are “exciting and very promising,” said Dr. Marc Eisenberg, a cardiologist and an associate professor of medicine at Columbia University’s Vagalos College of Physicians and Surgeons. “But statins should still be offered and tried as a first-line therapy.” Eisenberg was not associated with the new study.

While the study is “well designed,” Eisenberg said, “we still need more studies.”

These “are very important findings,” said Dr. Robert Rosenson, director of metabolism and lipids for the Mount Sinai Health System and a professor of medicine at the Icahn School of Medicine at Mount Sinai.

The benefits seen in the new study are greater than you would expect simply based on the reductions seen in LDL level, said Rosenson, who was not associated with the research.

The new study reinforces the idea that “targeting LDL cholesterol reduces cardiovascular risk,” said Dr. Jeffrey Berger, director of the Center for the Prevention of Cardiovascular Disease at NYU Langone Health.

Patients with risk factors, such as high LDL and diabetes, but who haven’t yet been diagnosed with cardiovascular disease “are the largest group of patients we take care of,” Berger said. Berger was not part of the new study.   

For people who can’t or won't take statins, bempedoic acid offers an alternative, Berger said.

“But I do think it’s important to recognize that there are important side effects with this drug. Like everything in medicine, there are risks and benefits,” Berger said.

CORRECTION (June 25, 2023, 6:56 p.m. ET): A previous version of this article misspelled Dr. Marc Eisenberg’s affiliation. It is Columbia University Vagelos College of Physicians and Surgeons, not Columbia University’s Vegelos College of Physicians and Surgeons.

Linda Carroll is a regular health contributor to NBC News. She is coauthor of "The Concussion Crisis: Anatomy of a Silent Epidemic" and "Out of the Clouds: The Unlikely Horseman and the Unwanted Colt Who Conquered the Sport of Kings." 

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Dietary Cholesterol and the Lack of Evidence in Cardiovascular Disease

Cardiovascular disease (CVD) is the leading cause of death in the United States. For years, dietary cholesterol was implicated in increasing blood cholesterol levels leading to the elevated risk of CVD. To date, extensive research did not show evidence to support a role of dietary cholesterol in the development of CVD. As a result, the 2015–2020 Dietary Guidelines for Americans removed the recommendations of restricting dietary cholesterol to 300 mg/day. This review summarizes the current literature regarding dietary cholesterol intake and CVD. It is worth noting that most foods that are rich in cholesterol are also high in saturated fatty acids and thus may increase the risk of CVD due to the saturated fatty acid content. The exceptions are eggs and shrimp. Considering that eggs are affordable and nutrient-dense food items, containing high-quality protein with minimal saturated fatty acids (1.56 gm/egg) and are rich in several micronutrients including vitamins and minerals, it would be worthwhile to include eggs in moderation as a part of a healthy eating pattern. This recommendation is particularly relevant when individual’s intakes of nutrients are suboptimal, or with limited income and food access, and to help ensure dietary intake of sufficient nutrients in growing children and older adults.

1. Introduction

Cardiovascular disease (CVD) is a leading cause of death in the US with approximately one in every four deaths occurring from heart diseases [ 1 ]. According to the CDC, 610,000 individuals die from CVD in the US [ 2 ]. The landmark of CVD is atherosclerosis, which is a chronic inflammatory condition instigated by deposition of cholesterol and fibrous tissues in the arterial walls which build up and eventually lead to narrowing and thickening or blocking of the arterial lumen. The inflammation regulates the plaque formation as well as the thrombotic complications of atherosclerosis [ 3 ]. The hypothesis that dietary cholesterol contributes to the risk of heart disease was initially suggested in 1968 and based on the research literature at the time [ 4 , 5 ]. Subsequently, the American Heart Association adopted a recommendation of limiting dietary cholesterol intake to 300 mg/day for healthy individuals in the United States, and with recommendations of restricting egg consumption to a maximum of three whole eggs per week [ 6 ]. However, the totality of scientific evidence and experimental data did not validate the hypothesis that dietary cholesterol increases blood cholesterol, and by extension increases the risk of CVD. Investigators have reported that increased intake of dietary cholesterol (exogenous) is associated with decreased synthesis of endogenous de novo cholesterol, possibly as a compensatory mechanism that keeps cholesterol homeostasis constant [ 7 , 8 ]. In fact, the 2015–2020 Dietary Guidelines for Americans removed the recommendations of setting a limit to the maximum intake of 300 mg/day cholesterol. The Guidelines still advised eating as little as possible of dietary cholesterol while maintaining a healthy eating pattern. The following review will summarize the current literature regarding dietary cholesterol, blood cholesterol, saturated fatty acids and the risk of cardiovascular disease (CVD).

2. Dietary Cholesterol Food Sources

Dietary cholesterol is a main steroid from animal tissues. The main food sources include egg yolk, shrimp, beef, and pork, poultry, as well as cheese and butter. According to NHANES data, the top five food sources of cholesterol in the American population (2005–2006) are eggs, and mixed egg dishes, chicken, beef, and beef mixed dishes, burgers, and regular cheese [ 9 ]. There are two main sources that contribute to and make up the liver cholesterol pool, namely dietary cholesterol (exogenous), and de novo (endogenous) cholesterol which is synthesized in the liver or extra-hepatic tissue.

The relationship between dietary cholesterol and total plasma cholesterol has been reported to be linear based on observational cohort studies [ 10 , 11 ]. However, the limitation of the observational studies is the presence of confounding variables that may amplify positive or negative correlations as well as the existence of selection biases [ 12 ]. Additionally, the intake of dietary cholesterol is usually associated with an increased intake of saturated fatty acids which is documented to increase LDL Cholesterol and the risk of cardiovascular disease [ 13 ]. In fact, eggs are the only dietary source of cholesterol that is low in saturated fatty acid but is also nutrient-dense, economical and affordable. The average large whole egg (50 g), contains only 1.56 g of saturated fat, 1.83 g monounsaturated fat and 0.96 g polyunsaturated fat ( Table 1 ). Egg yolk is also rich in dietary choline (147 mg) [ 14 ], which is an essential nutrient for human liver and muscle functions [ 15 ]. Choline intake is inadequate in 9 out of 10 American Adults [ 16 ]. Additionally, choline is essential for fetal and neonatal brain development [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ], and inadequate intake during these critical developmental stages is associated with negative outcomes [ 24 , 25 , 26 ]. Also, inadequate choline in pregnant women increases the risk of neural tube defects in the offspring even in the era of folate fortification of food [ 27 , 28 ]. As noted, each egg (50 g) contains choline (147 mg, i.e., 34% of the recommended daily Adequate Intake (AI) for adult female, and 26.5% AI for adult male) and is also rich in vitamin A (270 International Unit IU), and 80 µg Retinol Activity Equivalents (RAE) i.e., 9% RDA for adult male, 11% RDA for adult female, lutein and zeaxanthin (252 µg), folate (24 µg Dietary Folate Equivalents (DFE) i.e., 6% RDA for adult male and female), phosphorous (99 mg, i.e., 15% RDA for adult male and female), potassium (69 mg, i.e., 1% AI for adult male and female) and calcium (28 mg, i.e., 2.8% RDA for adult male and female), [ 16 , 29 ]. In addition to these micronutrients, the egg is also rich in high-quality animal protein (6.28 g, i.e., 11% of the recommended RDA) ( Table 1 ).

Nutrient Composition of Most Commonly Consumed Cholesterol-Containing Foods

a Egg: the reference is one large eggs (50 g), 01123, egg, whole, raw, fresh. b Beef reference is retail cut beef, 13019, beef, retail cuts, separable fat, raw; c Cheese, reference is natural cheese, 45352301, natural cheese UPC: 049646936410; d chicken: the reference is 05006, chicken, broilers or fryers, meat, and skin, raw; e Butter: the reference is unsalted butter, 45118176, White rose, unsalted butter, UPC: 074807101161; f Shrimp: the reference is shrimp raw medium-UCP = 041625114505; g eggs: the reference is two large eggs (50 g each for total of 100 g), 01123, egg, whole, raw, fresh. h Saturated fat content is in bold font, and i cholesterol content is in bold. Data obtained from the USDA National Nutrient Database for Standard Reference 1 April 2018 Software v.3.9.4 2018-05-02 [ 14 ].

3. Cholesterol Homeostasis

Cholesterol, a major sterol in animal tissues, has a significant function in the human body. Cholesterol is a structural component of cell membranes and plays an integral role in membrane fluidity. Cholesterol is also important in the synthesis of lipid rafts which are needed for protein sorting, cellular signaling, and apoptosis [ 30 ]. The characteristic structural feature of cholesterol is a fused four hydrocarbon ring referred to as a steroid nucleus, and a hydrocarbon tail consisting of eight hydrocarbon chain [ 31 ]. The cholesterol ring is the precursor of steroid hormones including estrogen, progesterone, testosterone, as well as vitamin D. As a hydrophobic molecule, cholesterol is transported in the blood via spherical macromolecules in the plasma termed lipoproteins including chylomicrons, VLDL, LDL, and HDL. The lipoproteins consist of a neutral lipid core containing cholesteryl ester and triacylglycerol surrounded by amphipathic apoproteins, phospholipids and non-esterified cholesterol. As such, the LDL particles transport cholesterol to peripheral tissues, and thus if the LDL-cholesterol is elevated, lipids can deposit in the arterial lumen leading to plaque formation, and thickening or narrowing of the blood vessel, the hallmark of atherosclerosis. On the other hand, HDL is responsible for the reverse cholesterol transport from peripheral tissues to the liver for bile acid synthesis, and steroid synthesis or for disposal of cholesterol ring via bile. As mentioned earlier, blood cholesterol is derived from two sources, exogenous dietary cholesterol and endogenous de novo synthesized cholesterol, and there is a balance and negative feedback to maintain cholesterol homeostasis. Endogenous cholesterol is synthesized by all cells and tissues, but predominantly in the liver, intestine and reproductive organs [ 32 ]. The rate-limiting and key regulatory step in endogenous cholesterol synthesis is mediated via 3-hydroxy-3-methylglutaryl CoA Reductase (HMG CoA Reductase), which reduces HMG CoA molecules to mevalonate, in the presence of NADPH as a reducing agent. Expression of HMG CoA reductase is inhibited by cholesterol as well as by statin drugs (atorvastatin, lovastatin, and Simvastatin). Thus, to maintain cholesterol balance, if dietary cholesterol absorption is increased, the endogenous synthesis is decreased [ 33 ]. The autoregulation of cholesterol synthesis encompasses control of HMG-CoA reductase by two mechanisms: (a) Feedback loop via cholesterol (which is referred to as bulk control), as well as (b) feedback loop via oxysterols, which functions to prevent accumulation of sterol intermediates and to fine tune the cholesterol regulation [ 34 ]. At the cellular level, cholesterol homeostasis is orchestrated by several regulatory transcriptional factor networks including the sterol regulatory element binding protein (SREBP), which regulates the biosynthesis and uptake of cholesterol as well as the liver X Receptor (LXR) family which regulates the excretion of excess cholesterol [ 35 , 36 , 37 ]. Another level of regulation is contributed by the farnesoid X receptor (FXR) which regulates bile acid metabolism [ 35 , 38 , 39 , 40 ].

4. Dietary Cholesterol and Cardiovascular Disease (CVD) Risk

4.1. animal models studies.

Guinea pigs are an ideal animal model to study human lipoprotein metabolism because they are LDL animals, they carry cholesterol in the LDL fraction, and they have CETP (Cholesteryl Ester Transfer Protein) similar to humans. Thus, the lipoprotein metabolism and remodeling is similar to humans. Lin et al., evaluated the cholesterol and lipoprotein metabolism in guinea pigs fed 0 dietary cholesterol (control), 0.08 (equivalent to 600 mg/day in human), 0.17 (equivalent to 1275 mg/day in human) or 0.33% dietary cholesterol (equivalent to 2475 mg/day in human) [ 8 , 41 , 42 ]. The authors reported a dose-response relationship between intake of dietary cholesterol and plasma LDL cholesterol. This effect led to decreased synthesis of endogenous cholesterol as evidenced by a reduction in HMG CoA reductase, the rate-limiting enzyme and commitment step in cholesterol synthesis, as a compensatory mechanism. The hepatic LDL receptor numbers also decreased as cholesterol concentration increased. Plasma cholesterol increased with intake of 0.17% and 0.33% cholesterol and with saturated fatty acid intake [ 8 ]. Similar to humans, guinea pigs have individualized response to dietary cholesterol, emphasizing the notion that these animals could be hypo-responders or hyper-responders to dietary cholesterol [ 43 ]. Indeed, studies in humans have demonstrated that individuals could be hypo-responders or hyper-responders to dietary cholesterol [ 44 ]. Studies conducted in 1913 in rabbits showed that dietary cholesterol in rabbits induces atherosclerosis [ 45 ]. In mice deficient in Apolipoprotein E, animals fed either a control diet (AIN-93) or a diet containing 0.2 g cholesterol or 0.2 g oxysterol, showed an increase in liver and serum levels but the dietary cholesterol did not promote atherosclerosis and did not significantly accumulate in the aorta [ 46 ].

4.2. Human Studies

4.2.1. observational studies.

In 1971, Kannel et al. reported that serum cholesterol was associated with increased risk of cardiovascular disease in the Framingham prospective cohort study [ 47 ]. Subsequently, risk factors for heart diseases were identified in this longitudinal study and the diet-heart disease hypothesis was established. For decades, the notion that elevated blood cholesterol is resultant from dietary intake cholesterol and saturated fatty acids were universally accepted. However, several follow-up studies showed no association between dietary cholesterol (egg consumption) and serum cholesterol, all-cause death, total coronary heart disease, or other heart disease problems such as angina pectoris or myocardial infarction [ 48 ]. Nevertheless, the recommendations of decreasing dietary cholesterol remained in effect. In 1988, Snowden reported that egg consumption was associated with all-cause mortality and coronary heart disease in females in a large cohort of California Seventh-Day Adventist adults [ 49 ]. However, Bechthold et al. conducted a meta-analysis study to investigate the relative risk between egg consumption and the risk of coronary heart disease (CHD) and stroke. There was no correlation between highest (75 g) and lowest intake of eggs (0 g) and the risk of CHD or the risk of stroke, and there was no evidence that smaller studies had an outcome reporting bias. Furthermore, in a dose-response sub-analysis with increased increments of egg intake (50 g), there was no association between egg consumption, heart disease or stroke. However, there was a positive correlation between egg intake and the risk of heart failure [ 50 ]. On the contrary, reports from the two large prospective cohort studies, namely, the Nurses’ Health Study (1980–1994) and the Health Professionals Follow-up Study (1986–1994), indicated that intake of dietary cholesterol consumed as one egg per day was not associated with increased risk of CHD in healthy men and women. Similar findings were summarized by Kritchevsky and colleagues [ 51 , 52 ]. In a recent study (2018), Li et al., reported that in Guangzhou Biobank Cohort Study, there were no statistical differences in the adjusted hazard ratio in all-cause mortality, mortality from CVD, ischemic heart disease or stroke and intakes of high egg consumption (7+ eggs per week) versus low egg consumption (<1 egg per week), in a meta-analysis study design that included 28,024 participants without heart disease at the time of participation [ 53 ].

Regarding patients diagnosed with diabetes, investigators of the Health Professional Follow-up Study and Nurses’ Health Study reported that in diabetic subjects, a high intake of eggs was correlated with increased risk in diabetic men [ 54 ]. Geiker et al. reviewed the literature regarding egg consumption in diabetic subjects and reported that dietary cholesterol and egg consumption was associated with increased risk of CVD [ 55 ]. However, Tran et al. did not find a correlation between egg consumption and CVD in diabetic patients [ 56 ]. In a cross-sectional study of 130,420 adult subjects aged 40–69 years in China, Shin and colleagues reported that a consumption of 7 eggs/week decreased the risk of metabolic syndrome (OR 0.77 CI, 0.70–0.84) compared with an intake of 1 egg/week [ 57 ]. Similarly, Park et al. analyzed Korea National Health and Nutrition Examination Survey (KNHANES) and found that the consumption of 4–6 eggs/week was associated with decreased risk of metabolic syndrome compared to the intake of 1 egg/month (OR 0.82, CI 0.71–0.95) [ 58 ]. However, in the US, most cohort studies reported to date suggest either a negative correlation between egg consumption in diabetic patients or no effect. For example, Djousse et al. followed a cohort of 20,703 men from the Physician Health Study and 36,295 women from the Women Health study for 20 years. The authors reported that consumption of 7 eggs/week was associated with increased risk of type 2 diabetes (Hazard Ratio 1.58, CI 1.25–2.01) in men and (1.77, CI 1.28–2.43) in women, compared to participants who consumed less than one egg per week. Additionally, the risk of heart diseases and mortality was also associated with consumption of 7 eggs/week (hazard ratio 2.01, CI: 1.26–3.20) compared to groups that consumed less than one egg per week among diabetic patients in the Physician Health Study [ 10 ]. The discrepancies of these findings could be attributable to confounding variables or differences in dietary patterns between populations. Some of the limitations of the observational studies are the inability to determine causality rather than reporting associations, possible selection bias, and the presence of confounding variables.

Based on the conflicting results, the limitations of the observational studies by confounding variables and selection bias, and a lack of causality identification; it seems that additional research methodology including meta-analysis or Mendelian Randomizations of genetically determined diabetes, metabolic syndrome, and heart disease are warranted in patients diagnosed with type 2 diabetes.

4.2.2. Randomized Controlled Trial Studies

A meta-analysis study of 17 randomized control trial studies conducted from 1974 to 1999, revealed that the addition of 100 mg of dietary cholesterol increased the total/HDL cholesterol ratio [ 59 ]. On the contrary, in a randomized controlled trial, Missimer et al. [ 60 ] found that the intake of two eggs per day did not have an adverse effect on heart disease biomarkers compared to the intake of oatmeal cereal. There was an increase in both HDL and LDL cholesterol, and therefore the LDL/HDL ratio, a marker to high risk of heart disease, remained constant, and thus the net cardiovascular risk did not increase. In the agreement, a randomized controlled trial (DIABEGG) compared the intake of a high-egg diet (2 eggs/day) with a low-egg diet (less than 2 eggs/day). The results showed that there were no differences in total cholesterol, LDL cholesterol or glycemic control in overweight and obese prediabetic or patients with type 2 diabetes [ 61 ]. Furthermore, to investigate the effects of egg on endothelial functions in patients with coronary heart disease, Katz et al., conducted a randomized, single-blind, cross-over, controlled trial for 6 weeks to compare breakfast containing 2 eggs, egg beaters, or a high carbohydrate breakfast [ 62 ]. The results indicated that there were no differences between groups in regards to lipids, flow-mediated dilation, systolic and diastolic blood pressure or body weight. Similarly, in a long-term randomized control trial, van der Made and colleagues [ 63 ] compared the consumption of lutein-enriched egg yolk in a buttermilk drink with a placebo group for one year. The authors reported that total cholesterol, LDL, and HDL cholesterol, as well as the total cholesterol to HDL cholesterol ratio, were not different between the two groups. Similar findings were reported in a randomized controlled trial comparing the intake of three eggs per day to Choline Bitartrate Supplement in healthy young men [ 64 ]. The study found that HDL-Cholesterol to LDL-cholesterol was maintained, indicating that exogenous cholesterol intake downregulated Sterol Regulatory element binding protein-2, and HMG-CoA reductase expression, thereby reducing endogenous cholesterol synthesis and thus maintaining the LDL/HDL ratio constant [ 64 ]. Blesso and colleagues conducted a randomized controlled trial ( n = 40) where participants with metabolic syndrome were randomly assigned to either 3 whole eggs/day or yolk-free egg substitutes for 12 weeks, and both groups maintained a carbohydrate-restricted diet (25–30%) [ 65 ]. The authors reported that participants who consumed whole eggs showed an improved lipid profile and decreased insulin resistance [ 65 ].

Several other randomized controlled trials indicated that egg consumption increased HDL cholesterol and decreased the risk factors associated with metabolic syndrome [ 66 , 67 , 68 ]. Along the same line, Fuller and colleagues reported that consumption of a high egg diet in pre-diabetes and patients with type 2 diabetes who had energy-restricted diets, had no adverse effect on blood glucose or glycated hemoglobin [ 61 , 69 ]. In a systematic review and meta-analysis, Berger et al. [ 70 ] compared the results from 19 randomized controlled trials of healthy individuals consuming dietary cholesterol (doses ranged between 501 and 1415 mg/day), or control groups (0 to 415 mg/day cholesterol). The authors reported a significant effect of dietary cholesterol on both LDL-Cholesterol as well as HDL-Cholesterol. As a result, the net LDL/HDL ratio was constant (0.17 net change) [ 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 ]. The increase in HDL cholesterol was pronounced with dietary cholesterol interventions doses between 650 and 900 mg/day [ 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 ].

5. Dietary Cholesterol, Saturated Fat, Trans Fatty Acids, and Cardiovascular Disease

As shown in Table 1 , most foods that contain high cholesterol content are also rich in animal-based saturated fatty acids (SFA). As such, for each 100 g beef (untrimmed) that contains 99 mg cholesterol, it has 29.4 gm SFA; natural cheese, 107 mg cholesterol, and 19 gm SFA; 214 mg cholesterol, and 50 gm SFA; and chicken (meat and skin) contains 101 mg cholesterol, and has 3.8 gm SFA. The exceptions are egg and shrimp. Shrimp contains 124 mg cholesterol and 0 g SFA, and one large egg (50 g) contains 186 mg cholesterol and 1.56 g SFA ( Table 1 ). While shrimp is arguably expensive, egg is an economical and nutrient-dense food item with high-quality protein which is convenient and affordable to low-income families and is a good source of nutrients for growing children and older adults.

A large body of literature documented the negative effects of saturated fatty acids on the development of CVD as reviewed by Yu and Hu 2018 [ 94 ]. Further, the American Heart Association reviewed the scientific evidence from prospective observational studies and randomized controlled trials and concluded that the replacement of dietary saturated fatty acids with polyunsaturated or monounsaturated fatty acids decreased the risk of CVD [ 95 ]. Trans-fatty acids are found naturally in a small amount in some meat and dairy products. However, most food consumption of trans-fatty acids is from manufactured hydrogenated unsaturated fatty acids. These partially hydrogenated trans-fatty acids that introduce at least one hydrogen bond in the trans configuration were originally developed to improve the quality and shelf life of baked goods and are used in margarine and commercial cooking. However, mounting evidence indicated that trans-fatty acids increased the risk of coronary heart disease mortality and cardiovascular disease incidence in a manner similar to saturated fatty acids [ 96 , 97 , 98 , 99 , 100 ]. As such, several European Countries introduced laws to limit the amount of trans-fatty acids in food [ 97 ]. In the United States, the FDA ruled that the content of trans fat should be included in the food label since 1990. The 2015–2020 Dietary Guidelines recommended limiting the intake of saturated fat and trans fat as part of a healthy eating pattern.

Thus, the totality of scientific evidence guided the 2010 and 2015 Dietary Guidelines for Americans and developed the recommendations to decrease intake of saturated fatty acids to less than 10% of calories and replacing it with monounsaturated and polyunsaturated fatty acids. Additionally, the American Heart Association recommends less than 7% of calories from saturated fatty acids. Fielding et al. found that an intervention with an intake of 600 mg cholesterol with a diet high in the saturated fatty acids led to increased LDL cholesterol much more than when cholesterol was administered with polyunsaturated fatty acids [ 75 ]. As noted earlier, several of the high cholesterol foods are also rich in saturated fatty acids such as beef (untrimmed and with marble), natural cheese, and butter ( Table 1 , and the USDA Nutrient Composition Database), and thus may increase the risk of CVD due to the saturated fatty acid content. The exceptions are shrimps (zero saturated fatty acids) and eggs (1.56 gm saturated fatty acids per large egg which accounts for 0.65% of calories).

6. Conclusions

The current literature does not support the notion that dietary cholesterol increases the risk of heart disease in a healthy individuals. However, there is an ample evidence that saturated fatty acids and trans-fats increase cardiovascular disease risk. The fact that dietary cholesterol is common in foods that are high in saturated fatty acids might have contributed to the hypothesis that dietary cholesterol is atherogenic. In contrast, eggs are affordable, rich in protein and micronutrients, nutrient-dense and low in saturated fatty acids. The healthy eating pattern can incorporate nutrient-dense, calorie controlled meals with balanced nutrients and a variety of colorful vegetables and fruits. The body of literature regarding dietary cholesterol and cardiovascular disease in patients diagnosed with diabetes is still inconclusive and warrants further research.

Author Contributions

G.S. researched, designed, analyzed, interpreted the results and wrote the manuscript.

The investigator’s work and publication costs are funded by an institutional start-up fund.

Conflicts of Interest

The authors declare no conflict of interest.

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Monday, November 21, 2022

Study challenges “good” cholesterol’s role in universally predicting heart disease risk

Lower levels of HDL cholesterol were associated with increased risks for heart attacks in white but not Black adults, and higher levels were not protective for either group.

A National Institutes of Health-supported study found that high-density lipoprotein (HDL) cholesterol, often called the “good cholesterol,” may not be as effective as scientists once believed in uniformly predicting cardiovascular disease risk among adults of different racial and ethnic backgrounds. 

The research, which published in the Journal of the American College of Cardiology , found that while low levels of HDL cholesterol predicted an increased risk of heart attacks or related deaths for white adults – a long-accepted association – the same was not true for Black adults.  Additionally, higher HDL cholesterol levels were not associated with reduced cardiovascular disease risk for either group.  

“The goal was to understand this long-established link that labels HDL as the beneficial cholesterol, and if that’s true for all ethnicities,” said Nathalie Pamir, Ph.D., a senior author of the study and an associate professor of medicine within the Knight Cardiovascular Institute at Oregon Health & Science University, Portland. “It’s been well accepted that low HDL cholesterol levels are detrimental, regardless of race. Our research tested those assumptions.”

To do that, Pamir and her colleagues reviewed data from 23,901 United States adults who participated in the Reasons for Geographic and Racial Differences in Stroke Study (REGARDS). Previous studies that shaped perceptions about “good” cholesterol levels and heart health were conducted in the 1970s through research with a majority of white adult study participants. For the current study, researchers were able to look at how cholesterol levels from Black and white middle-aged adults without heart disease who lived throughout the country overlapped with future cardiovascular events.  

Study participants enrolled in REGARDS between 2003-2007 and researchers analyzed information collected throughout a 10- to 11-year period. Black and white study participants shared similar characteristics, such as age, cholesterol levels, and underlying risk factors for heart disease, including having diabetes, high blood pressure, or smoking. During this time, 664 Black adults and 951 white adults experienced a heart attack or heart attack-related death. Adults with increased levels of LDL cholesterol and triglycerides had modestly increased risks for cardiovascular disease, which aligned with findings from previous research.  

However, the study was the first to find that lower HDL cholesterol levels only predicted increased cardiovascular disease risk for white adults. It also expands on findings from other studies showing that high HDL cholesterol levels are not always associated with reduced cardiovascular events. The REGARDS analysis was the largest U.S. study to show that this was true for both Black and white adults, suggesting that higher than optimal amounts of “good” cholesterol may not provide cardiovascular benefits for either group.  

“What I hope this type of research establishes is the need to revisit the risk-predicting algorithm for cardiovascular disease,” Pamir said. “It could mean that in the future we don’t get a pat on the back by our doctors for having higher HDL cholesterol levels.”  

Pamir explained that as researchers study HDL cholesterol’s role in supporting heart health, they are exploring different theories. One is quality over quantity. That is, instead of having more HDL, the quality of HDL’s function – in picking up and transporting excess cholesterol from the body – may be more important for supporting cardiovascular health .       They are also taking a microscopic look at properties of HDL cholesterol, including analyzing hundreds of proteins associated with transporting cholesterol and how varying associations, based on one protein or groups of proteins, may improve cardiovascular health predictions.   

“HDL cholesterol has long been an enigmatic risk factor for cardiovascular disease,” explained Sean Coady, a deputy branch chief of epidemiology within the National Heart, Lung, and Blood Institute (NHLBI)’s Division of Cardiovascular Sciences. “The findings suggest that a deeper dive into the epidemiology of lipid metabolism is warranted, especially in terms of how race may modify or mediate these relationships.”      The authors conclude that in addition to supporting ongoing and future research with diverse populations to explore these connections, the findings suggest that cardiovascular disease risk calculators using HDL cholesterol could lead to inaccurate predictions for Black adults.    

“When it comes to risk factors for heart disease, they cannot be limited to one race or ethnicity,” said Pamir. “They need to apply to everyone.”  

The REGARDS study is co-funded by the National Institute of Neurological Disorders and Stroke and the National Institute of Aging and received additional support from NHLBI.     To learn more about cholesterol and heart health, visit https://www.nhlbi.nih.gov/health/blood-cholesterol .     To learn about heart-healthy living, visit https://www.nhlbi.nih.gov/health/heart-healthy-living .                  About the National Heart, Lung, and Blood Institute (NHLBI): NHLBI is the global leader in conducting and supporting research in heart, lung, and blood diseases and sleep disorders that advances scientific knowledge, improves public health, and saves lives. For more information, visit https://www.nhlbi.nih.gov/ . 

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov .

NIH…Turning Discovery Into Health ®

Zakai NA, Minnier J, Safford MM, et al. Race-dependent association of high-density lipoprotein cholesterol levels with incident coronary artery disease.  J Am Coll  Cardiol .  2022; doi: 10.1016/j.jacc.2022.09.027.  

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Coronary Heart Disease Research

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For almost 75 years, the NHLBI has been at the forefront of improving the nation’s health and reducing the burden of  heart and vascular diseases . Heart disease, including coronary heart disease, remains the leading cause of death in the United States. However, the rate of heart disease deaths has declined by 70% over the past 50 years, thanks in part to NHLBI-funded research. Many current studies funded by the NHLBI focus on discovering genetic associations and finding new ways to prevent and treat the onset of coronary heart disease and associated medical conditions.

NHLBI research that really made a difference

The NHLBI supports a wide range of long-term studies to understand the risk factors of coronary heart disease. These ongoing studies, among others, have led to many discoveries that have increased our understanding of the causes of cardiovascular disease among different populations, helping to shape evidence-based clinical practice guidelines.

• Risk factors that can be changed:  The NHLBI  Framingham Heart Study (FHS)  revealed that cardiovascular disease is caused by modifiable risk factors such as smoking,  high blood pressure ,  obesity , high  cholesterol  levels, and physical inactivity. It is why, in routine physicals, healthcare providers check for high blood pressure, high cholesterol, unhealthy eating patterns, smoking, physical inactivity, and unhealthy weight. The FHS found that cigarette smoking increases the risk of heart disease. Researchers also showed that cardiovascular disease can affect people differently depending on sex or race, underscoring the need to address health disparities. 
• Risk factors for Hispanic/Latino adults:  The  Hispanic Community Health Study/Study of Latinos (HCHS/SOL)  found that heart disease risk factors are widespread among Hispanic/Latino adults in the United States , with 80% of men and 71% of women having at least one risk factor. Researchers also used HCHS/SOL genetic data to explore genes linked with central adiposity (the tendency to have excess body fat around the waist) in Hispanic/Latino adults. Before this study, genes linked with central adiposity, a risk factor for coronary heart disease, had been identified in people of European ancestry. These results showed that those genes also predict central adiposity for Hispanic/Latino communities. Some of the genes identified were more common among people with Mexican or Central/South American ancestry, while others were more common among people of Caribbean ancestry.
• Risk factors for African Americans:  The  Jackson Heart Study (JHS) began in 1997 and includes more than 5,300 African American men and women in Jackson, Mississippi. It has studied genetic and environmental factors that raise the risk of heart problems, especially high blood pressure, coronary heart disease,  heart failure ,  stroke , and  peripheral artery disease (PAD) . Researchers discovered a gene variant in African American individuals that doubles the risk of heart disease. They also found that even small spikes in blood pressure can lead to a higher risk of death. A community engagement component of the JHS is putting 20 years of the study’s findings into action by turning traditional gathering places, such as barbershops and churches, into health information hubs.
• Risk factors for American Indians:  The NHLBI actively supports the  Strong Heart Study , a long-term study that began in 1988 to examine cardiovascular disease and its risk factors among American Indian men and women. The Strong Heart Study is one of the largest epidemiological studies of American Indian people ever undertaken. It involves a partnership with 12 Tribal Nations and has followed more than 8,000 participants, many of whom live in low-income rural areas of Arizona, Oklahoma, and the Dakotas. Cardiovascular disease remains the leading cause of death for American Indian people. Yet the prevalence and severity of cardiovascular disease among American Indian people has been challenging to study because of the small sizes of the communities, as well as the relatively young age, cultural diversity, and wide geographic distribution of the population. In 2019, the NHLBI renewed its commitment to the Strong Heart Study with a new study phase that includes more funding for community-driven pilot projects and a continued emphasis on training and development. Read more about the  goals and key findings  of the Strong Heart Study.

Current research funded by the NHLBI

Within our  Division of Cardiovascular Sciences , the Atherothrombosis and Coronary Artery Disease Branch of its  Adult and Pediatric Cardiac Research Program and the  Center for Translation Research and Implementation Science  oversee much of our funded research on coronary heart disease.

Research funding  

Find  funding opportunities  and  program contacts for research on coronary heart disease. 

Current research on preventing coronary heart disease

• Blood cholesterol and coronary heart disease: The NHLBI supports new research into lowering the risk of coronary heart disease by reducing levels of cholesterol in the blood. High levels of blood cholesterol, especially a type called low-density lipoprotein (LDL) cholesterol, raise the risk of coronary heart disease. However, even with medicine that lowers LDL cholesterol, there is still a risk of coronary heart disease due to other proteins, called triglyceride-rich ApoB-containing lipoproteins (ApoBCLs), that circulate in the blood. Researchers are working to find innovative ways to reduce the levels of ApoBCLs, which may help prevent coronary heart disease and other cardiovascular conditions.
• Pregnancy, preeclampsia, and coronary heart disease risk: NHLBI-supported researchers are investigating the link between developing preeclampsia during pregnancy and an increased risk for heart disease over the lifespan . This project uses “omics” data – such as genomics, proteomics, and other research areas – from three different cohorts of women to define and assess preeclampsia biomarkers associated with cardiovascular health outcomes. Researchers have determined that high blood pressure during pregnancy and low birth weight are predictors of atherosclerotic cardiovascular disease in women . Ultimately, these findings can inform new preventive strategies to lower the risk of coronary heart disease.
• Community-level efforts to lower heart disease risk among African American people: The NHLBI is funding initiatives to partner with churches in order to engage with African American communities and lower disparities in heart health . Studies have found that church-led interventions reduce risk factors for coronary heart disease and other cardiovascular conditions. NHLBI-supported researchers assessed data from more than 17,000 participants across multiple studies and determined that these community-based approaches are effective in lowering heart disease risk factors .

Find more NHLBI-funded studies on  preventing coronary heart disease  on the NIH RePORTER.

Learn about the impact of COVID-19 on your risk of coronary heart disease.

Current research on understanding the causes of coronary heart disease

• Pregnancy and long-term heart disease:  NHLBI researchers are continuing the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b)   study to understand the relationship between pregnancy-related problems, such as gestational hypertension, and heart problems. The study also looks at how problems during pregnancy may increase risk factors for heart disease later in life. NuMoM2b launched in 2010, and long-term studies are ongoing, with the goal of collecting high-quality data and understanding how heart disease develops in women after pregnancy.
• How coronary artery disease affects heart attack risk: NHLBI-funded researchers are investigating why some people with coronary artery disease are more at risk for heart attacks than others. Researchers have found that people with coronary artery disease who have high-risk coronary plaques are more likely to have serious cardiac events, including heart attacks. However, we do not know why some people develop high-risk coronary plaques and others do not. Researchers hope that this study will help providers better identify which people are most at risk of heart attacks before they occur.
• Genetics of coronary heart disease:  The NHLBI supports studies to identify genetic variants associated with coronary heart disease . Researchers are investigating how genes affect important molecular cascades involved in the development of coronary heart disease . This deeper understanding of the underlying causes for plaque buildup and damage to the blood vessels can inform prevention strategies and help healthcare providers develop personalized treatment for people with coronary heart disease caused by specific genetic mutations.

Find more NHLBI-funded studies on understanding the  causes of coronary heart disease  on the NIH RePORTER.

Recent findings suggest that cholesterol-lowering treatment can lower the risk of heart disease complications in people with HIV.

Current research on treatments for coronary heart disease

• Insight into new molecular targets for treatment: NHLBI-supported researchers are investigating the role of high-density lipoprotein (HDL) cholesterol in coronary heart disease and other medical conditions . Understanding how the molecular pathways of cholesterol affect the disease mechanism for atherosclerosis and plaque buildup in the blood vessels of the heart can lead to new therapeutic approaches for the treatment of coronary heart disease. Researchers have found evidence that treatments that boost HDL function can lower systemic inflammation and slow down plaque buildup . This mechanism could be targeted to develop a new treatment approach for coronary heart disease.
• Long-term studies of treatment effectiveness: The NHLBI is supporting the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial EXTENDed Follow-up (EXTEND) , which compares the long-term outcomes of an initial invasive versus conservative strategy for more than 5,000 surviving participants of the original ISCHEMIA trial. Researchers have found no difference in mortality outcomes between invasive and conservative management strategies for patients with chronic coronary heart disease after more than 3 years. They will continue to follow up with participants for up to 10 years. Researchers are also assessing the impact of nonfatal events on long-term heart disease and mortality. A more accurate heart disease risk score will be constructed to help healthcare providers deliver more precise care for their patients.
• Evaluating a new therapy for protecting new mothers: The NHLBI is supporting the Randomized Evaluation of Bromocriptine In Myocardial Recovery Therapy for Peripartum Cardiomyopathy (REBIRTH) , for determining the role of bromocriptine as a treatment for peripartum cardiomyopathy (PPCM). Previous research suggests that prolactin, a hormone that stimulates the production of milk for breastfeeding, may contribute to the development of cardiomyopathy late in pregnancy or the first several months postpartum. Bromocriptine, once commonly used in the United States to stop milk production, has shown promising results in studies conducted in South Africa and Germany. Researchers will enroll approximately 200 women across North America who have been diagnosed with PPCM and assess their heart function after 6 months. 
• Impact of mental health on response to treatment:  NHLBI-supported researchers are investigating how mental health conditions can affect treatment effectiveness for people with coronary heart disease. Studies show that depression is linked to a higher risk for negative outcomes from coronary heart disease. Researchers found that having depression is associated with poor adherence to medical treatment for coronary heart disease . This means that people with depression are less likely to follow through with their heart disease treatment plans, possibly contributing to their chances of experiencing worse outcomes. Researchers are also studying new ways to treat depression in patients with coronary heart disease .

Find more NHLBI-funded studies on  treating coronary heart disease  on the NIH RePORTER.  

Researchers have found no clear difference in patient survival or heart attack risk between managing heart disease through medication and lifestyle changes compared with invasive procedures. 

Coronary heart disease research labs at the NHLBI

• Laboratory of Cardiac Physiology
• Laboratory of Cardiovascular Biology
• Minority Health and Health Disparities Population Laboratory
• Social Determinants of Obesity and Cardiovascular Risk Laboratory
• Laboratory for Cardiovascular Epidemiology and Genomics
• Laboratory for Hemostasis and Platelet Biology

Related coronary heart disease programs

• In 2002, the NHLBI launched  The Heart Truth® ,  the first federally sponsored national health education program designed to raise awareness about heart disease as the leading cause of death in women. The NHLBI and  The Heart Truth®  supported the creation of the Red Dress® as the national symbol for awareness about women and heart disease, and also coordinate  National Wear Red Day ® and  American Heart Month  each February. 
• The  Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC)  facilitates access to and maximizes the scientific value of NHLBI biospecimen and data collections. A main goal is to promote the use of these scientific resources by the broader research community. BioLINCC serves to coordinate searches across data and biospecimen collections and provide an electronic means for requesting additional information and submitting requests for collections. Researchers wanting to submit biospecimen collections to the NHLBI Biorepository to share with qualified investigators may also use the website to initiate the application process. 
• Our  Trans-Omics for Precision Medicine (TOPMed) Program  studies the ways genetic information, along with information about health status, lifestyle, and the environment, can be used to predict the best ways to prevent and treat heart, lung, blood, and sleep disorders. TOPMed specifically supports NHLBI’s  Precision Medicine Activities. 
• NHLBI  population and epidemiology studies  in different groups of people, including the  Atherosclerosis Risk in Communities (ARIC) Study , the  Multi-Ethnic Study of Atherosclerosis (MESA) , and the  Cardiovascular Health Study (CHS) , have made major contributions to understanding the causes and prevention of heart and vascular diseases, including coronary heart disease.
• The  Cardiothoracic Surgical Trials Network (CTSN)  is an international clinical research enterprise that studies  heart valve disease ,  arrhythmias , heart failure, coronary heart disease, and surgical complications. The trials span all phases of development, from early translation to completion, and have more than 14,000 participants. The trials include six completed randomized clinical trials, three large observational studies, and many other smaller studies.

Learn how heart disease may be different for women than for men.

Explore more NHLBI research on coronary heart disease

The sections above provide you with the highlights of NHLBI-supported research on coronary heart disease. You can explore the full list of NHLBI-funded studies on the NIH RePORTER .

To find more studies:

• Type your search words into the  Quick Search  box and press enter. 
• Check  Active Projects  if you want current research.
• Select the  Agencies  arrow, then the  NIH  arrow, then check  NHLBI .

If you want to sort the projects by budget size — from the biggest to the smallest — click on the  FY Total Cost by IC  column heading.

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High Cholesterol: Prevention, Treatment and Research

Featured Experts:

Michael Joseph Blaha, M.D., M.P.H.

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Cholesterol is a natural component in everyone’s blood, and supports normal function of cell membranes, hormone levels and more. However, having too much, is considered hyperlipidemia, hypercholesterolemia or high blood cholesterol — a major risk factor for heart attack, heart disease and stroke. About 71 million Americans have high cholesterol.

Here’s what happens in your body when you have high cholesterol: The waxy cholesterol builds up in artery walls and contributes to plaque, a hard deposit that narrows and clogs the arteries. (You may hear this referred to as atherosclerosis, or “hardening of the arteries.”)

When plaque builds up, it becomes harder for the heart to circulate blood and oxygen, which can cause chest pain or shortness of breath with increased exertion (angina). If a blood clot forms at the site of a disrupted plaque in a narrowed artery, it can block blood flow to the brain (a stroke) or to the heart (a heart attack).

There are actually several different types of cholesterol, one of which is high density lipoprotein (HDL) cholesterol. High levels of some kinds of cholesterol, including low density lipoprotein (LDL) cholesterol, can be harmful to your heart and blood vessels.

To keep blood cholesterol numbers in a desirable range, it helps to follow these practices:

• Know your numbers. Adults over age 20 should have their cholesterol measured at least every five years. That gives you and your doctor a chance to intervene early if your numbers start to rise.
• Stick to a healthy diet. Saturated fats, trans fats and dietary cholesterol can all raise cholesterol levels. Foods thought to keep cholesterol low include monounsaturated fats (such as nuts and olive oil), polyunsaturated fats (such as fish and canola oil) and water-soluble fiber (such as oats, beans and lentils). Get practical ideas to on eating for cardiovascular health .
• Exercise and manage your weight. Along with a healthy diet, staying fit and maintaining a normal weight for your height lower your cardiovascular risks by minimizing the odds of other contributing health problems like obesity and diabetes. If you’re overweight, losing as little as 5 to 10 percent of your weight can significantly lower your risk of cardiovascular disease. Learn how implementing an exercise routine helps your heart in The ABCs of Moving More for Heart Health .

Only one in three people who have high LDL cholesterol have the condition under control. The main goal of treatment is to lower, or control, your LDL level to minimize your personal risk for heart attack or cardiovascular disease, based on your cholesterol numbers and other risk factors, such as a history of cardiovascular disease.

Lifestyle changes are recommended for anyone with high cholesterol. These include:

Diet upgrades . First on the treatment menu is a heart-healthy diet. “I find that my patients generally love the Mediterranean diet ,” says Johns Hopkins Ciccarone Center cardiologist  Michael Blaha, M.D., M.P.H. “It tastes great, it’s satiating, and there’s excellent evidence that it reduces cholesterol and cardiovascular risk.”

Highlights of the Mediterranean diet include reducing saturated fat (found in animal products, butter, whole and 2% dairy products, coconut oil and palm oil) and trans fats (found in fried foods and baked goods). Eat mostly polyunsaturated or monounsaturated fats (found in fish, avocadoes, olive oil, nuts, and canola and soybean oil). Alcohol can raise triglycerides, so you may be advised to cut back.

Regular exercise . Aim for at least 30 minutes of exercise a day, most days. The American Heart Association recommends 40 minutes of moderate to vigorous exercise three to four times per week.

Weight management . This step is especially important for those who are overweight and who have high triglyceride levels or too-big waistlines (above 40 inches for men or 35 inches for women).

Medications . In addition to lifestyle changes, some people are prescribed drugs designed to lower cholesterol. Here are some of those medications:

• Statin medications slow the liver’s production of cholesterol and can help remove cholesterol circulating in the blood.
• Selective cholesterol absorption inhibitors (like ezetimibe) prevent the absorption of cholesterol from the intestine and help removal in the liver.
• PCSK9 inhibitors may be available for patients with high cholesterol in certain circumstances.
• Resins (bile acid sequestrants) bind to bile, a digestive acid, which causes the liver to produce more bile and thus use up more cholesterol.
• Fibrates lower triglycerides (rather than LDL levels).
• Niacin (nicotinic acid) is a B vitamin that affects the production of fats in the liver.
• Omega-3 fatty acid medications derived from fish oils also work to lower high triglyceride levels.

Lowering Your Cholesterol

Working to lower your cholesterol can be a long-term effort, and changing your health habits is key, Blaha says. To increase your odds of success:

• Don’t count on medications alone . You have to make lifestyle changes as well, according to Blaha.
• Start small . Modifying your diet and lifestyle in minor ways will make it easier to incorporate those changes into your life over the long haul. For example, rather than embarking on a drastic calorie-cutting diet, start by swapping out high-cholesterol and high-fat foods you love for healthier choices. For instance, buy skim milk instead of whole. Substitute olive oil for butter when you cook. Purchase foods with “no trans fats” on the labels.
• Know your cholesterol-lowering drugs . Some of these medications interact with grapefruit and pomegranate (and their juices). Pay close attention to your doctor’s guidelines about cholesterol drugs, and never stop taking them without consulting your physician. Be sure to report medication side effects to your doctor.

New guidelines for LDL levels and addressing cardiovascular disease risk

New guidelines for assessing your heart disease give you and your doctor powerful tools for estimating your cardiovascular disease risk and lowering your LDL cholesterol levels. Working with your health care team, you can create a plan with a customized combination of lifestyle changes, medications and continued monitoring.

A cost-effective test can detect the early risk factors for heart disease

Using computerized tomography (CT), a coronary artery calcium scan can detect calcium and plaque in the walls of your heart’s arteries. The test is relatively inexpensive and can reveal early warning signs of heart disease so you can take action to lower your risk.

PSCK9 inhibitors can lower your LDL cholesterol: a lot

PSCK9 inhibitors may be a good choice for people with an inherited form of high cholesterol. These new drugs can lower dangerous LDL levels by half or more. The drugs’ costs are high, but the health care industry is working with manufacturers and pharmacists to bring the price down and make PSCK9 inhibitors available to more people.

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Personalized nutrition more effective than general diet advice, study finds

by King's College London

Personalized nutrition approaches can improve several key health metrics, including lower weight, lower cholesterol, better mood, improved gut health, lower heart disease risk, and better metabolic health.

Improvements for those following personalized guidance were also greater in some areas than for those following current, generalized government advice.

Numerous chronic diseases and health issues can be linked back to our diets, including stroke risk, heart disease , and some cancers. New research emerges all the time, deepening our understanding of how nutrition affects our health. Changing our diet can make us healthier and reduce the risk of chronic disease, but it has been found that people often don't follow generalized health advice.

There is also wide variation in how people's bodies respond to food, even between identical twins. Despite this, little research has been done into the effectiveness of personalized dietary approaches.

In this study, researchers from the School of Life Course & Population Sciences wanted to see if a personalized diet plan, tailored to an individual's biology, lifestyle, and health history, would have a greater impact than generic nutrition advice such as avoiding red meat. The personalized diet programs were created by ZOE, a science and nutrition company co-founded by King's Professor Tim Spector which aims to help members improve their health with personalized advice.

347 Americans took part in the study, with researchers comparing the effects of following an 18-week personalized program to generic US government-issued nutrition advice. While both groups improved their health overall, participants on the personalized diet plan lost more weight than the control group and lowered their triglyceride levels more—decreasing their risk of heart disease.

Participants following the personalized diet plan were also twice as likely to report improved mood, twice as likely to feel less hungry, and more than four times more likely to report better sleep quality and energy levels compared with the control group .

"It is clear that some current population advice isn't working as well as it could, with many people struggling to stick to it. ZOE advice shows that thinking about foods in a totally different way with the emphasis on quality, personalization, and gut health can have massive benefits if adopted more widely," says Professor Spector.

"ZOE's METHOD trial builds on growing evidence that a personalized dietary approach can be an effective tool for improving health. Personalized approaches can improve both how well people follow the advice as well as the efficacy of the advice. Targeting multiple features of personalization is key to success, including people's biology, lifestyles, barriers, and preferences," says Dr. Sarah Berry, Chief Scientist of ZOE.

The paper is published in the journal Nature Medicine .

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Cholesterol-transporting molecule may increase Alzheimer’s risk

May 13, 2024 – Having higher levels of a certain lipoprotein—a molecule that helps carry fat around the body—may increase people’s risk of developing Alzheimer’s disease , according to a study by researchers at Harvard T.H. Chan School of Public Health and the University of Mississippi.

The study, published in the journal Communications Biology, was featured in an April 24 article by the University of Mississippi.

The researchers focused on a molecule called apolipoprotein B-100, or APOB, which is a major component of low-density lipoprotein (LDL) cholesterol —also known as “bad” cholesterol. They analyzed genetic data from 21,982 individuals with Alzheimer’s disease and 41,944 individuals without. They found that higher APOB levels were linked with shorter healthspans—the time between birth and the development of chronic disease—and an increased risk of Alzheimer’s disease.

“The method that we used, Mendelian randomization, removes many of the problems that happen in correlational research. For instance, using Mendelian randomization reduced the chance that something else was responsible for the signal we saw between higher apolipoprotein and Alzheimer’s,” said co-author Charleen Adams , research fellow in environmental health at Harvard Chan School. She added that future research is needed to identify the specific biological mechanism that increases Alzheimer’s risk.

Other Harvard Chan School co-authors of the study were Leah Martin, PhD student in the Population Health Sciences program , and Carmen Messerlian , assistant professor of environmental reproductive, perinatal, and pediatric epidemiology.

Read the study: Mendelian randomization reveals apolipoprotein B shortens healthspan and possibly increases risk for Alzheimer’s disease

Read the University of Mississippi article: High level of fat-transporting molecule linked to Alzheimer’s

Image: iStock/Makhbubakhon Ismatova

Low-Dose Colchicine for Secondary Prevention of Coronary Artery Disease: JACC Review Topic of the Week

Affiliations.

• 1 Mount Sinai Heart, Icahn School of Medicine at Mount Sinai Health System, New York, New York, USA.
• 2 Mount Sinai Heart, Icahn School of Medicine at Mount Sinai Health System, New York, New York, USA; Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
• 3 Center for Cardiovascular Disease Prevention, Divisions of Preventive Medicine and Cardiovascular Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: [email protected].
• PMID: 37558377
• DOI: 10.1016/j.jacc.2023.05.055

Among statin-treated patients, inflammation assessed by means of high-sensitivity C-reactive protein (hsCRP) is a more powerful determinant of cardiovascular death and all-cause mortality than low-density-lipoprotein cholesterol (LDL-C). Several therapies that target residual inflammatory risk significantly reduce vascular event rates. For coronary artery disease patients already taking guideline-directed medical care, including statins, low-dose colchicine (0.5 mg/d orally) has been shown to safely lower major adverse cardiovascular events by 31% among those with stable atherosclerosis and by 23% after recent myocardial infarction. These magnitudes of benefit are larger than those seen in contemporary secondary prevention trials of adjunctive lipid-lowering agents. Low-dose colchicine is contraindicated in patients with significant renal or liver dysfunction and should be temporarily discontinued when taking concomitant agents such as clarithromycin, ketoconazole, and cyclosporine that share metabolism pathways. Lipid lowering and inflammation inhibition are not in conflict but are synergistic. In the future, combined use of aggressive LDL-C-lowering and inflammation-inhibiting therapies may become standard of care for most atherosclerosis patients. In June 2023, the U.S. Food and Drug Administration approved the use of low-dose colchicine to reduce the risk of myocardial infarction, stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease.

Keywords: atherosclerosis; colchicine; inflammation; residual inflammatory risk.

Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Publication types

• Atherosclerosis* / drug therapy
• Cholesterol, LDL
• Colchicine / therapeutic use
• Coronary Artery Disease* / drug therapy
• Coronary Artery Disease* / prevention & control
• Hydroxymethylglutaryl-CoA Reductase Inhibitors* / therapeutic use
• Inflammation / drug therapy
• Myocardial Infarction* / drug therapy
• Secondary Prevention
• Hydroxymethylglutaryl-CoA Reductase Inhibitors

New drug makes exercise, everyday tasks easier for people with common heart condition

Potential treatment for hypertrophic cardiomyopathy.

People with a common heart condition were able to use significantly more oxygen while exercising after taking an investigational drug in an international clinical trial, according to a study published today in the New England Journal of Medicine. The finding wasalso presented today at the European Society of Cardiology's Heart Failure 2024 meeting in Lisbon, Portugal.

Oregon Health & Science University is part of the randomized, double-blind Phase 3 trial that is evaluating the experimental drug aficamten, which was developed by Cytokinetics to treat the obstructive form of hypertrophic cardiomyopathy, or HCM. Of the 282 adults participating in the trial, 19 enrolled through OHSU -- the most of any trial center.

"By having more oxygen available during exercise, patients with obstructive hypertrophic cardiomyopathy can more easily walk, perform household chores, and do other everyday tasks," said cardiologist Ahmad Masri, M.D., M.S., who co-wrote today's paper and directs the OHSU Knight Cardiovascular Institute's Hypertrophic Cardiomyopathy Center. "Our latest clinical trial results suggest aficamten is a promising treatment for HCM."

HCM affects about 1 in 500 people and is one of the most common causes of sudden death for youth and otherwise healthy athletes. Often caused by inherited gene mutations, it thickens heart muscles and makes it difficult for the heart to work as it should. It causes shortness of breath and reduces people's ability to exercise. The obstructive form of HCM reduces blood flow out of the heart.

About half of the trial's participants were given the experimental drug, and the other half took a placebo and served as the study's control group. Scientists measured the participants' oxygen levels while they used treadmills or bicycles. Those who took aficamten had a significant increase in their maximum oxygen use -- 1.7 milliliters per kilogram per minute more than those in the control group.

Having an increased peak oxygen uptake can improve a patient's ability to be physically active, whereas reduced oxygen uptake can increase the risk of experiencing heart failure, needing a heart transplant, and dying.

Non-drug treatment options for obstructive HCM include surgery to remove excess heart muscle. In 2022, the Food and Drug Administration also approved mavacamten as the first drug designed to target the underlying cause of obstructive HCM. However, mavacamten may increase the risk of heart failure and it interacts with several commonly used medications. As a result, patients who use mavacamten must also undergo intense monitoring.

During the past decade, OHSU has been involved in many research studies exploring new HCM treatment options. It has been a center for several mavacamten studies and is participating in gene therapy research. The university is also currently involved in four other aficamten trials that are evaluating it as a potential treatment for various forms of HCM and in different types of patients, including children.

"This is an exciting time for treating HCM," Masri said. "While we continue to offer traditional surgical and procedural therapies for HCM, we are now also able to offer patients other treatment options: therapies that were recently approved by the FDA and investigational therapies that are available by participating in clinical trials."

• Heart Disease
• Pharmacology
• Diseases and Conditions
• Stroke Prevention
• Personalized Medicine
• Cholesterol
• Obstructive sleep apnea
• Bulimia nervosa
• Sleep apnea
• Cardiac arrest
• Oxygen therapy

Story Source:

Materials provided by Oregon Health & Science University . Original written by Franny White. Note: Content may be edited for style and length.

Journal Reference :

• Martin S. Maron, Ahmad Masri, Michael E. Nassif, Roberto Barriales-Villa, Michael Arad, Nuno Cardim, Lubna Choudhury, Brian Claggett, Caroline J. Coats, Hans-Dirk Düngen, Pablo Garcia-Pavia, Albert A. Hagège, James L. Januzzi, Matthew M.Y. Lee, Gregory D. Lewis, Chang-Sheng Ma, Michelle Michels, Iacopo Olivotto, Artur Oreziak, Anjali T. Owens, John A. Spertus, Scott D. Solomon, Jacob Tfelt-Hansen, Marion van Sinttruije, Josef Veselka, Hugh Watkins, Daniel L. Jacoby, Stephen B. Heitner, Stuart Kupfer, Fady I. Malik, Lisa Meng, Amy Wohltman, Theodore P. Abraham. Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy . New England Journal of Medicine , 2024; DOI: 10.1056/NEJMoa2401424

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Real-life data highlights need for patient-centered management of unhealthy cholesterol

14-May-2024 - Last updated on 14-May-2024 at 10:01 GMT

• Email to a friend

Presented at ISPOR 2024, the findings emphasize the need for integrating patient needs and preferences into strategies for managing unhealthy cholesterol (low-density lipoprotein cholesterol or LDL-C).

The community-led research, a first of its kind by Global Heart Hub, aims to drive action towards changing the course of atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality worldwide.

Neil Johnson, executive director of global heart hub, said: “ASCVD remains a significantly under-recognized disease that continues to grow on a global scale and deserves urgent attention as a public health priority. We believe it’s time to take a different approach in how we address unhealthy cholesterol given that it is a critical modifiable risk factor for ASCVD.”

Launched in August 2023, IPEC was designed to better understand the experiences, opinions, and needs of individuals whose cholesterol levels are not at target, including those who have been hospitalized for an ASCVD event. Lowering LDL-C levels plays a crucial role in reducing the risk of ASCVD events.

Consequences of unhealthy cholesterol levels

Most instances of high LDL-C were diagnosed during routine health check-ups. However, some patients did not access healthcare services until they experienced signs and symptoms associated with ASCVD or a symptomatic co-occurring condition. Patients also faced challenges adhering to lifestyle changes and medications recommended by their healthcare providers due to factors like work schedules, travel, and out-of-pocket costs for medicines and healthcare.

The findings highlighted the importance of family support and the proactive integration of lifestyle changes into daily routines, which made adherence to treatment easier. Patients expressed a preference for treatment options that support adherence through a less frequent regimen, minimal side effects, and specific dosing methods like injections or patches.

Celina Gorre, chief executive officer of WomenHeart and IPEC Steering Committee member, emphasized, “With these findings from IPEC, we have gained important insights directly from patients in the US about their needs and preferences to support the delivery of optimal care. To truly address the consequences of unhealthy cholesterol levels and improve clinical care and patient outcomes, the patient voice must be integrated across the entire decision-making process.”

The qualitative patient experience findings were also highlighted as a best-methods case example at the ISPOR Patient-Centered Research Summit co-located at this key international meeting. The IPEC data generation program is a pillar of Invisible Nation, Global Heart Hub’s advocacy program aimed at addressing the risks of ASCVD-related heart attacks, strokes, and deaths among more than 500 million people worldwide.

As part of this ongoing effort, the Global Cholesterol Action Plan was created to continue activating change to address unhealthy cholesterol levels, supported by the global patient community.

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Pickleball as prevention: How staying active can drastically reduce your risk for heart disease

Anurag mehta, m.d., director of preventive cardiology at the vcu health pauley heart center, bonds with his patient on the pickleball court..

5/14/2024 12:00:00 AM

By Liz Torrey “Do as I do – and as I say.” You could call this the motto of Anurag Mehta , M.D., director of preventive cardiology at the VCU Health Pauley Heart Center . He emphasizes the vital importance of physical activity and regular exercise to all his heart patients—and follows his own advice to boot. Just ask patient Andy Randazzo.

“I was playing pickleball, and all of a sudden, I was like, ‘Wait a minute – is that my cardiologist?’” Andy recalled. Randazzo and Mehta both play pickleball, usually with their wives, at Pouncey Tract Park in Glen Allen, a suburb of Richmond. They’ve bumped into each other quite a few times on the courts since Randazzo became a Pauley Heart patient in June 2023. Randazzo has a family history of heart attack and heart disease, and in recent years his heart health has become top of mind. Not only have these health concerns led him to work out at the pickleball courts more — they also brought him to VCU Health.

Preventive testing to learn about heart disease risks

On the advice of a family member who is a cardiologist, Randazzo underwent a calcium scoring test. This simple, painless diagnostic procedure can identify conditions associated with an increased risk of heart disease — such as hardened arteries — at an early stage, often before symptoms are present. The test involves a CT scan, which generates cross-sectional images of the arteries that supply blood to the heart; the images are then reviewed for deposits of calcium in the arteries.

“I use this test frequently in my practice,” Mehta said. “It’s very useful on multiple grounds. If you don’t have coronary artery calcium, the chances of you having a heart attack or even a stroke in the next five to ten years is very low. But if you have a high calcium score, that tells us a lot about your risk of having heart problems down the line, and your blood vessels are hardening through a disease process called atherosclerosis.”

I’ve trusted VCU for my healthcare in the past. I’ve always felt that VCU Health focuses on doing the right thing, and I’ve always been satisfied with all my physicians there.  Andy Randazzo, VCU Health patient

Calcium deposits are caused by plaque buildup in the arteries. Plaque is a composite of many substances, including cholesterol and other fats, inflammatory cells, fibrous tissue, and calcium. “Calcium deposition is essentially a marker of the final stages of atherosclerosis,” Mehta said. “Your body is trying to heal and stabilize that plaque. Essentially, your arteries are becoming bone.” A calcium score of between 100 and 400 means a patient has a moderate to high risk of heart attack or other forms of heart disease over the next ten years; a score of more than 400 indicates extensive calcium deposits and a high risk of heart attack. Randazzo’s score was 200, and his primary care physician recommended that he see a cardiologist. “I’ve trusted VCU for my healthcare in the past,” Randazzo said. “I’ve always felt that VCU Health focuses on doing the right thing, and I’ve always been satisfied with all my physicians there. So, when my PCP asked me to see a cardiologist, I reached out to the Pauley Heart Center.” 

Know your risk for heart disease

Under the care of Mehta, Randazzo first underwent several tests to better understand his risks for heart disease and other serious heart conditions. First, he had an echocardiogram — an ultrasound of the heart — which revealed the volume of blood being pumped out of his heart was lower than it should be. This volume measurement is referred to as the ejection fraction. A low ejection fraction can be caused by several different conditions, including atherosclerosis, high blood pressure, and diabetes.

Randazzo then had a cardiac MRI with stress testing for more detailed images of his heart and its blood flow. This was followed by a cardiac catheterization and coronary angiography. In this procedure, a tube is guided through a blood vessel to the heart, where it is used to both test for and treat clogged arteries. In Randazzo’s case, no significant blockages or narrowing of the arteries were found during his cardiac cath. “With all of this information — the family history, the calcium score, the low ejection fraction on both the echo and the MRI, but no evidence of significant blockages on catheterization — the goal then becomes: how do we protect your cardiovascular health and prevent cardiovascular disease five, ten, twenty years down the line?” Mehta said. “One thing we can do is use generic, widely available medications to control and curb the risk factors responsible for the development and progression of heart disease.”

Preventative approaches to improve heart health

Randazzo now takes blood pressure medication, cholesterol medication, and aspirin to keep his heart healthy in the short and long term. “But when it comes to preserving your health, as important — maybe even more important — than medication is physical activity and exercise,” Mehta continued. “I can’t stress enough how essential it is for anyone and everyone to get aerobic exercise and muscle training. It’s highly protective for your heart in the long run.” This is where pickleball comes in. Randazzo says he took up the sport during the COVID-19 pandemic, when he was “stuck at home” and needed an activity that would allow him to get out and socialize safely. But he notes that even outside the pandemic, life had slowed him down in different ways.

Research shows that when you transition from a sedentary lifestyle to even being just a little bit physically active, you get the biggest bang for your buck. Something that I share with all of my patients... is that even small amounts of physical activity done consistently are extremely beneficial. Anurag Mehta, M.D., VCU Health Pauley Heart Center

“I’ve always been interested in physical activity, and I’ve played pretty much every sport there is,” he said. “But as we get older, as we get into our jobs, you’re pretty much stuck at your desk all day. That of course impacts you long-term because you’re not active.” He has also seen how many desk-based or corporate jobs have become significantly more stressful in recent decades. In some instances, “the job becomes your life,” he continued. “The stress not only has a mental toll on you — it also has a physical toll.” Randazzo chose to take up pickleball in part because it is not as strenuous as tennis or other sports he had played previously. “Unfortunately, as we get older, things like your knees start to give out, and it’s a little bit harder to get moving,” he said. “But to me, it’s always seemed like doing something is better than doing nothing.” Mehta couldn’t agree more with this sentiment. “Research shows that when you transition from a sedentary lifestyle to even being just a little bit physically active, you get the biggest bang for your buck,” he said. “Something that I share with all of my patients — especially those who are in a demanding job, or who have young kids, or any other lifestyle factors that might prevent them from making time for exercise — is that even small amounts of physical activity done consistently are extremely beneficial.” For his part, Mehta squeezes in time for exercise by meeting his wife at the courts and fitting in 30 to 60 minutes of pickleball before picking up their son from daycare. But he acknowledges that finding time for any physical activity can be a challenge for a variety of reasons beyond the logistical. “I’m very thankful to, for example, Henrico County for prioritizing parks,” he said. “These are public courts, they’re free, they’re available all the time, there’s good lighting for those who want to play in the evening, there’s a playground nearby for those with children. Sometimes our health comes down to things that are beyond our direct control: health policy, having access to walking spaces or good quality food. All of those things play a huge role in population cardiovascular health.” Like Randazzo, Mehta notes the Pouncey Tract pickleball courts are “an amazing place to socialize.” “Playing pickleball, I’ve become friends with everyone from teenagers to people in their eighties—and of course, my patient Andy here,” he said. “The social benefits of physical activity, which we maybe don’t talk about as much, are also very important for your health.” “My reflexes aren’t what they used to be, I don’t move as fast as I used to, but it’s not about winning when we go there,” Randazzo agreed. “It’s just about having a good time.” “That said, I promise to go easy on Dr. Mehta next time we play,” he couldn’t help but add.

Inspired? Read more stories about our patients and providers.

For more heart health stories, check out the VCU Health Pauley Heart Center Blog.

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This High Cholesterol Symptom Appears On Your Feet At Night; Other Warning Signs To Note

E ven though high cholesterol usually itself does not show any symptoms, it can dangerously affect your heart. According to experts, cholesterol - a waxy, fat-like substance that your liver produces, builds up in the arteries and leads to serious problems like heart attack or stroke.

Even though there are not many signs to identify issues occurring due to high cholesterol in your body, it does lead to conditions that trigger pain and discomfort, especially at night.

Doctors say high cholesterol levels in your body can cause Peripheral Artery Disease or PAD, which occurs when narrowed arteries reduce blood flow to the arms or legs.

Related News | Groundbreaking Research Claims Oreo Cookies Lower Cholesterol Better Than Statins 5-Year-Old Dies Of Heart Attack; Experts Identify Signs Of Heart Issues In Kids

How does pad affect at night.

This buildup leads to plaque formation which narrows and hardens the arteries, reducing blood flow to the extremities like legs. As the flow reduces, you may suffer from extreme leg pain and cramps, especially during the night when you are resting. 1

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Doctor Shares Six Signs Of High Blood Sugar You Can Spot On Your Feet

According to doctors, PAD is often underdiagnosed, and those who do not report symptoms may likely be physically inactive or mistake any muscle discomfort as a sign of ageing.

The risk of PAD increases with older age.

Specific symptoms of PAD on your legs and feet

When your arteries are partly blocked by cholesterol, it becomes hard to get blood to areas far from the heart for stable temperature maintenance. 2

These ulcers usually happen far from the heart on the legs, feet, ankles, or toes. The wounds can also be slow and difficult to heal.

Changes in skin and hair

PAD affects your hair as well – as you may lose your leg hair because of poor blood flow.

Thick toenails

Ways to prevent pad.

• Take care of your diet by eating foods that are high in fibre and low in saturated fat, salt, and added sugars
• Maintain a healthy weight
• Exercise and workout regularly
• Quit smoking
• Stop alcohol abuse