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Year : 2020  |  Volume : 5  |  Issue : 4  |  Page : 159-170

Bile acid and cholesterol metabolism in atherosclerotic cardiovascular disease and therapy

1 Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
2 Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China

Date of Submission15-Sep-2020
Date of Acceptance09-Nov-2020
Date of Web Publication30-Dec-2020

Correspondence Address:
John Y. L. Chiang
Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 SR 44, P. O. Box 95, Rootstown, OH 44272
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2470-7511.305419

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Dysregulation of lipid metabolism is a major factor contributing to atherosclerotic cardiovascular disease (ACVD), which is the number one cause of death in western countries. The liver plays a central role in maintaining whole body cholesterol homeostasis via catabolism of cholesterol to bile acids, as well as biliary cholesterol excretion. The liver synthesizes lipoproteins that transport dietary cholesterol and fats to muscle and adipose tissue, directs reverse cholesterol transport of excess cholesterol from extrahepatic tissues and macrophages to the liver to convert to bile acids, and thus, protects against metabolism-related nonalcoholic fatty liver disease (NAFLD) and ACVD. Liver fibrosis/nonalcoholic steatohepatitis increases the risk and prevalence of cardiovascular disease morbidity and mortality. Bile acids are signaling molecules and metabolic regulators that activate farnesoid X receptor and G protein-coupled bile acid receptor-1 to regulate lipid, glucose, and energy metabolism. The bidirectional regulation of bile acids and the gut microbiota determine the rate of bile acid synthesis, the bile acid pool size, and the composition of the circulating bile acid pool. The liver-intestine-heart axis regulates lipid metabolism, inflammation, and the pathogenesis of metabolic diseases such as ACVD, NAFLD, diabetes, and obesity. This review focuses on the roles of liver-to-intestine, liver-to-heart and intestine-to-heart axes in cholesterol, lipoprotein, and bile acid metabolism; signaling in heart health and ACVD; and drug therapies for atherosclerosis.

Keywords: Atherosclerosis; Bile acid receptors; Bile acid synthesis; Cholesterol; Lipoprotein

How to cite this article:
Chiang JY, Ferrell JM, Wu Y, Boehme S. Bile acid and cholesterol metabolism in atherosclerotic cardiovascular disease and therapy. Cardiol Plus 2020;5:159-70

How to cite this URL:
Chiang JY, Ferrell JM, Wu Y, Boehme S. Bile acid and cholesterol metabolism in atherosclerotic cardiovascular disease and therapy. Cardiol Plus [serial online] 2020 [cited 2021 Jun 23];5:159-70. Available from:

  Introduction Top

Nonalcoholic fatty liver disease (NAFLD) is rapidly increasing worldwide and is an independent risk factor for atherosclerotic cardiovascular disease (ACVD).[1],[2],[3],[4] NAFLD can progress to nonalcoholic steatohepatitis (NASH) with macrovascular ballooning, macrophage infiltration, and inflammation and fibrosis of the liver. A recent study has shown that NASH fibrosis can predict ACVD events and that there is a strong association between NASH fibrosis and ACVD morbidity and mortality.[1] ACVD and NAFLD are the manifestations of metabolic syndrome in the heart and liver, respectively. Metabolic syndrome is a collection of five abnormal symptoms: hypertension, hyperglycemia, hypertriglyceridemia, insulin resistance, and obesity.[5]

Diabetic and obese persons have a higher risk of NASH and ACVD than nondiabetic and nonobese persons.[6] Both NASH and ACVD are inflammatory diseases having causative factors in common, such as insulin resistance, hyperglycemia, dyslipidemia, and systemic inflammation.[1],[6],[7],[8] Elevated serum low-density lipoprotein (LDL) cholesterol is a major risk factor for atherosclerosis. Accumulation of oxidized lipids in the intima of blood vessels causes thickening of the arterial wall, as well as inflammation and injury of the coronary artery. Cholesterol, fats, and other substances accumulate and form plaques in the aorta; this restricts blood flow and reduces elasticity of blood vessels.[7]

The liver plays a central role in lipid, glucose, and energy metabolism by absorbing dietary fats and cholesterol, synthesizing fatty acids and cholesterol from acetyl-CoA derived from glucose and free fatty acids (FFAs), and distributing fats and cholesterol in lipoproteins to other tissues and organs for energy metabolism.[9],[10] Impairment of lipid homeostasis by high fat diet, insulin resistance, and genetic factors results in dyslipidemia, in which increased serum triglycerides (TGs) and cholesterol are linked to the pathogenesis of ACVD and NASH in humans.[8] It has been suggested that “atherosclerosis is a liver disease of the heart” emphasizing the critical role of the liver in producing lipids and lipoproteins to maintain heart health and prevent diseases.[10] This review focuses on the role of the liver-intestine-heart axis in cholesterol and bile acid metabolism and in the pathogenesis of ACVD. Most of the references cited in this review have been published in the last 10 years. Some historical and landmark references have also been cited.

  Cholesterol Metabolism and Homeostasis Top

Cholesterol is an important component of biological membranes and serves as a precursor of steroids, sex hormones, and bile acids. The liver obtains cholesterol through three cholesterol input mechanisms: dietary absorption, LDL receptor (LDLR)-mediated uptake, and de novo synthesis.[11] The liver catabolizes cholesterol to bile acids, which facilitates biliary cholesterol secretion as the predominant cholesterol output mechanism. A small amount of cholesterol is used for cell membrane and steroid hormone synthesis. Cholesterol input and output need to be balanced to maintain whole body cholesterol homeostasis;[12] hence, alteration of cholesterol homeostasis contributes to the pathogenesis of NAFLD and ACVD. A brief description of cholesterol synthesis, lipoprotein metabolism, and bile acid synthesis are presented below.

  De novo Cholesterol Synthesis Top

All tissues and organs in our body can synthesize cholesterol. Cholesterol synthesis in the liver accounts for about 50% of the total cholesterol synthesized daily. In the postprandial state, excess glucose and fatty acids are oxidized to generate acetyl-CoA for the synthesis of cholesterol and fatty acids. In the de novo cholesterol synthesis pathway, β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) reductase is the rate-limiting enzyme for cholesterol synthesis. A series of enzymatic reactions convert mevalonate to farnesyl-pyrophosphate, squalene, lanosterol, and finally cholesterol. Cholesterol is a precursor to steroid hormones, vitamin D, and bile acids. De novo cholesterol synthesis is regulated by the intracellular levels of cholesterol/oxysterols, which regulate the maturation of sterol regulatory element binding protein-2 (SREBP-2), an important transcription factor that regulates the cholesterol synthesis pathway.[13] When intracellular cholesterol levels are high, the SREBP-2 precursor forms a complex with insulin-induced gene and SREBP cleavage-activating protein (SCAP), and the complex is retained in the endoplasmic reticulum (ER) membrane.[14] When intracellular cholesterol levels decrease, SCAP escorts the SREBP-2 precursor to the Golgi, where two steroid-sensitive proteases cleave an N-terminal fragment transcription factor that is subsequently translocated to the nuclei to activate transcription of its target genes, including LDLR and a number of key genes involved in de novo cholesterol synthesis.[15] Activated SREBP-2 binds to the steroid response elements located in the promoters of cholesterol synthesis genes and activates gene transcription. Oxysterols are endogenous ligands of liver X receptor (LXR),[16],[17] which plays an important role in the regulation of lipogenic pathways including cholesterol and fatty acid synthesis and transport. Activation of LXR by oxysterols promotes the pathogenesis of atherosclerosis.[18] In contrast, activation of LXR in macrophages protects against atherosclerosis.[19]

  Lipoprotein Metabolism Top

Lipoproteins contain a hydrophobic core, consisting of TGs and cholesterol esters (CEs), and an outer layer, consisting of phospholipids, free cholesterol (C) and apolipoproteins.[9] The major lipoproteins are chylomicrons (CMs), very LDL (VLDL), LDL, and high-density lipoprotein (HDL). These lipoproteins contain several classes of apolipoproteins: ApoA, ApoB, ApoC, ApoD, and ApoE, which serve as structural proteins and effectors or ligands for lipoprotein receptors. These lipoproteins contain different amounts of TGs and cholesterol and transport them to other organs and tissues. Dietary lipids are the major source of fats, phospholipids, and cholesterol in humans. Bile acids released from the gallbladder in the postprandial state emulsify fats to form lipid micelles, which are absorbed in the intestine and transferred to the liver for distribution to other organs and tissues.

  Cholesterol Transport from Liver to Other Tissues Top

The liver synthesizes lipoproteins and assembles VLDL for the transport of TGs to extrahepatic tissues for energy metabolism[9] [Figure 1]. In the postprandial state, dietary TGs transported to the liver by CMs are hydrolyzed to FFAs and glycerol for energy metabolism. CEs are hydrolyzed to free cholesterol by cholesteryl esterase (CES) for bile acid synthesis. Excess FFAs are re-esterified to glycerol to form TGs and free cholesterol is re-esterified to CE by acyl-CoA:cholesterol acyltransferase 2 for storage and transport to other tissues. Liver microsomal TG transfer protein transfers TGs to ApoB100 (B-100) in the ER to form nascent VLDL, which acquires ApoE and ApoCII from HDL via cholesteryl ester transfer protein (CETP) to form mature VLDL for secretion into blood circulation. On the surface of the blood capillary wall of muscle and adipose tissue, lipoprotein lipase is activated by ApoCII carried by VLDL to hydrolyze TGs to FFAs and glycerol for energy metabolism. VLDL releases some TGs to reduce its size and increase its density to form LDL, which is bound by LDLR, an ApoB100 receptor.
Figure 1: Cholesterol and lipoprotein metabolism. (1) Cholesterol transport from the liver to peripheral tissues; (2) Reverse cholesterol transport from peripheral tissues and macrophages to the liver. ER: endoplasmic reticulum, CYP7A1: cholesterol 7-hydroxylase, CYP8B1: sterol 12-hydroxylase, CYP27A1: sterol 27-hydroxylase, CA: cholic acid, BACS: bile acid CoA synthase, CDCA: chenodeoxycholic acid, DCA: deoxycholic acid, LCA: lithocholic acid, UDCA: ursodeoxycholic acid, CYP7B1: oxysterol 7-hydroxylase

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In the liver and other tissues, LDLRs bind ApoB-100 carried by LDL to deliver CEs to cells via receptor-mediated endocytosis.[20] Free cholesterol is sorted to the ER and Golgi membranes and is redistributed to intracellular and plasma membranes. Mutations of the LDLR gene impair LDL binding and internalization, as well as lysosomal hydrolysis, recycling and secretion, and cause hypercholesterolemia and severe familial hypercholesterolemia (FH).[21] Patients with FH have very high serum LDL cholesterol (>500 mg/dl) and premature ACVD. More recent studies have identified a natural LDLR inhibitor, proprotein convertase subtilisin kexin type 9 (PCSK9), which regulates the LDLR secretory pathway by stimulating degradation of LDLRs.[22] Mutations in the PCSK9 gene impair LDLR endocytosis in FH.[23],[24] Hepatic PCSK9 expression is regulated by insulin and SREBP-1C.[25]

  Reverse Cholesterol Transport Top

The transport of cholesterol from peripheral tissues and macrophages to the liver for conversion to bile acids is called reverse cholesterol transport (RCT). RCT is the major route for removing excess cholesterol and oxysterols from macrophages to prevent foam-cell formation in the aortic wall and protect against atherosclerosis.[8],[26],[27] ATP-binding cassette transporter A1 (ABCA1; synthesized in liver and intestine) and ATP-binding cassette transporter G1 (ABCG1) efflux cholesterol and phospholipids to ApoAI to form nascent HDL [Figure 1]. CETP catalyzes the exchange of TGs for CEs and transfers ApoCII and ApoE from VLDL to nascent HDL to form mature HDL.[28],[29] In hepatocytes, HDL binds to scavenger receptor-B1 (SR-B1) to deliver TGs and CEs to the liver[9] [Figure 1]. Hepatic lipase on the surface of the hepatic blood capillary wall hydrolyzes TGs to FFAs to deliver FFAs to hepatocytes.[30] In hepatocytes, CE is hydrolyzed to free cholesterol, which is catabolized to bile acids, and this completes the RCT process. Stimulating RCT from macrophages to liver accelerates conversion of cholesterol to bile acids and protects against atherosclerosis.

  Bile Acid Synthesis Top

The liver exclusively contains all the enzymes required for catabolism of cholesterol to bile acids, which is the predominant use of cholesterol in the body. Bile acid synthesis involves 17 enzymes located in microsomes, cytosol, mitochondria, and peroxisomes.[31],[32],[33] Here, only the regulatory cytochrome P450 (CYP) enzymes in bile acid synthesis are described. In humans, cholic acid (CA) and chenodeoxycholic acid (CDCA) are the two primary bile acids synthesized in the liver [Figure 2]. Cholesterol 7α-hydroxylase (CYP7A1) catalyzes the first and rate-limiting step in the classic bile acid synthetic pathway to synthesize 7α-hydroxycholesterol, which is converted to 7α-hydroxy-4-cholesten-3-one (C4). Serum C4 levels are currently used as a surrogate marker for the rate of bile acid synthesis. Sterol 12α-hydroxylase (CYP8B1) is required for hydroxylation at the C-12 position leading to synthesis of CA; in the absence of this step, CDCA is produced. Mitochondrial sterol 27-hydroxylase (CYP27A1) oxidizes the steroid sidechain of intermediates leading to cleavage of a 3C unit to produce C24 bile acids. Bile acids recycled to the liver and bile acid-CoA synthesized in the liver are immediately conjugated to the amino acid taurine (T) or glycine (G) by bile acid:amino acid transferase and bile acid:CoA synthase, respectively, to form T-or G-conjugated bile acids, which are secreted into bile. The alternative bile acid synthesis pathway is initiated by CYP27A1 to generate 27-hydroxycholesterol from cholesterol. The nonspecific oxysterol 7α-hydroxylase (CYP7B1) catalyzes 7α-hydroxylation of 27-hydroxycholesterol. CYP27A1 is highly expressed in macrophages to generate 27-hydroxycholesterol, which is 7α-hydroxylated by CYP7B1.[34] 27-Hydroxycholesterol is an endogenous LXR agonist in cholesterol-loaded macrophages.[35] Cholesterol-loading activates LXR to induce ABCA1 and ABCG1 in macrophages to efflux cholesterol and oxysterols [Figure 2]. It has been suggested that the transport of 27-hydroxycholesterol from macrophages to the liver for bile acid synthesis is a RCT process to protect against atherosclerosis.[36] CYP27A1 and CYP7B1 are expressed in many extrahepatic tissues, such as the heart, brain, and kidney, and play a key role in the regulation of oxysterol synthesis and steroid hormone synthesis in the adrenal glands.[34]
Figure 2: Bile acid synthesis in the liver, heart and other tissues, and biotransformation in the intestine. LDLR: LDL receptor, SR-A1: scavenger receptor A1, CE: Cholesterol esters, ACAT2: acyl-CoA: cholesterol acyltransferase 2, C: cholesterol, MTTP: microsomal triglyceride transfer protein, HL: Hepatic lipase, SR-B1: scavenger receptor B1, PCSK9, proprotein convertase subtilisin kexin type 9, LDLR: LDL receptor, VLDL: very low-density lipoprotein, LRP: LDL receptor related protein, HL: Hepatic lipase, TG: triglycerides, FFA: free fatty acids, CETP: cholesteryl ester transfer protein

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  Transformation of Bile Acids in the Gut Top

The gut-to-liver axis plays a critical role in bile acid synthesis and metabolism.[37] The gut microbiota metabolizes primary bile acids to secondary bile acids, which in turn control gut bacterial overgrowth. In the postprandial state, the duodenum releases cholecystokinin to stimulate gallbladder contraction and secretion of bile into the gastrointestinal tract for emulsification of fats and nutrients. Most bile acids (~95%) are reabsorbed in the ileum. A small amount of bile acids enter the colon, where gut bacterial bile salt hydrolases (BSHs) de-conjugate T/GCA and T/GCDCA [Figure 2].[38],[39] Subsequently, bacterial 7α-dehydroxylase removes a 7-hydroxyl group from CA and CDCA to form the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA), respectively. These secondary bile acids are highly insoluble and toxic and are mostly excreted in the feces. Some DCA is passively reabsorbed in the colon and secreted into the circulating bile acid pool. Most LCA is excreted in feces; a small amount of LCA circulated to the liver is rapidly sulfur-conjugated by sulfotransferases and excreted in urine. In humans, a small amount of CDCA is converted to ursodeoxycholic acid (UDCA) by bacterial 7α/β-hydroxysteroid dehydrogenase. Isomerization of CDCA to UDCA converts the highly hydrophobic CDCA to the highly soluble UDCA. In humans, the bile acid pool consists of the hydrophobic bile acids CA, CDCA, and DCA in an approximate 40:40:20 ratio, and bile acids are conjugated to G and T in a ratio of 3:1. The gut bacterial enzymes BSH and 7α-dehydroxylase play a critical role in the regulation of bile acid synthesis, pool size, and homeostasis. Alteration of bile acid composition and pool size by gut bacteria causes dysbiosis and significantly impacts the host metabolism, as well as pathogenesis of metabolic liver and heart diseases.[39],[40],[41],[42],[43]

  Enterohepatic Circulation of Bile Acids Top

In the ileum, conjugated bile acids are reabsorbed along with fats, cholesterol, and lipid-soluble vitamins for delivery to the liver and distribution to other organs and tissues. This enterohepatic circulation (EHC) of bile acids from the intestine to the liver is highly efficient, recovering ~95% of bile acids in the pool to inhibit bile acid synthesis in the liver [Figure 3].[31],[44] A small amount (5%) of bile acids lost in feces is replenished by de novo synthesis in the liver. The EHC of bile acids involves several bile acid transporters [Figure 3].[32] At the canalicular membrane, bile salt export pump (BSEP, ABCB11) effluxes bile acids to bile, multidrug resistance associated protein (ABCC2, MRP2) effluxes conjugated-bile acids, multi-drug resistant protein 2 (MDR2, ABCB4) effluxes phospholipids and the ABCG5/G8 heterodimer effluxes cholesterol into bile. Bile acids, phospholipids, and cholesterol form mixed micelles in bile to increase cholesterol solubility and reduce bile acid toxicity. Bile acids are reabsorbed into intestinal cells by apical sodium-dependent bile acid transporter (ASBT) located in the brush border membrane and are transported to the basolateral membrane for secretion into portal blood by the heterodimeric organic solute transporters (OSTα and OSTβ). In the apical membrane of enterocytes, the ABCG5/G8 transporter effluxes plant sterols and cholesterol to prevent absorption of plant sterols and limit dietary cholesterol absorbed by Niemann-Pick C1-like protein (NPC1 L1). In hepatocytes, the bile acid transporter Na+-dependent taurocholate co-transport peptide (NTCP) located in the sinusoidal membrane absorbs bile acids in exchange for Na+. These bile acid transporters may play an important role in protection against cholestasis when bile acids accumulate in hepatocytes. Interrupted EHC of bile acids contributes to metabolic syndrome, cholestatic liver disease, inflammatory bowel disease, diarrhea, and gallstone disease.[32],[45]
Figure 3: Farnesoid X receptor regulation of enterohepatic circulation of bile acids and transintestinal cholesterol excretion. FGF19: fibroblast growth factor 19, SHP: small heterodimer partner, FXR: farnesoid X receptor, CYP7A1: cholesterol 7-hydroxylase, NTCP: Na+-dependent taurocholate co-transport peptide, BSEP: bile salt export pump, ASBT: apical sodium-dependent bile acid transporter, TGR5: Takeda G protein receptor 5, GLP-1: glucagon-like peptide 1, TICE: transintestinal cholesterol excretion, NPC1L1: Niemann-Pick C1-like protein

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  Transintestinal Cholesterol Excretion Top

Biliary cholesterol secretion and catabolism of cholesterol to bile acids are the main mechanisms for cholesterol excretion from the body. RCT is the main pathway for removing excess cholesterol from peripheral tissues and macrophages. However, recent studies have implicated a role for the intestine in nonbiliary cholesterol excretion via direct fecal neutral sterol excretion called transintestinal cholesterol excretion [TICE; [Figure 3]. In the intestine, NPC1 L1 and ABCG5/G8 are involved in TICE.[46],[47] TICE is inducible by PCSK9 inhibitors or HMG-CoA reductase inhibitors (statins).[48],[49] In both mice and humans, TICE can be stimulated by a NPC1 L1 inhibitor, ezetimibe, which induces ABCG5/ABCG8 to efflux cholesterol from the intestine to prevent atherosclerosis.[50],[51]

  Bile Acid-Activated Receptors in Atherosclerosis Top

Bile acid synthesis and the EHC of bile acids are regulated by the bile acid-activated nuclear receptor farnesoid X receptor (FXR).[32],[52] FXR plays a central role in the regulation of glucose, lipid, and energy metabolism.[53],[54] FXR is highly expressed in the gastrointestinal tract, acts as a sensor of bile acid levels in hepatocytes and enterocytes, and coordinately regulates transcription of a network of genes in bile acid synthesis, conjugation, and transport. In the liver, activation of FXR by bile acids induces the nuclear receptor small heterodimer partner, which negatively regulates bile acid synthesis by inhibiting CYP7A1 gene transcription [Figure 3].[55],[56] FXR also induces BSEP to stimulate bile acid efflux into bile and inhibits NTCP to suppress bile acid uptake by hepatocytes.[57] In the intestinal ileum, FXR induces an enteroendocrine hormone known as fibroblast growth factor 19 (FGF19) [Figure 3].[58] FGF19 circulates to hepatocytes to activate the FGF receptor 4/β-Klotho complex on the cell membrane, inhibiting CYP7A1 and CYP8B1 gene transcription [Figure 3].[32],[58]

Activation of FXR has been shown to stimulate RCT, increase fecal cholesterol excretion, and reduce pro-inflammatory cytokines to attenuate atherosclerosis.[30],[59],[60],[61] FXR is expressed in vascular smooth muscle and atherosclerotic blood vessels.[62] Accumulation of bile acids has been shown to induce cardiomyopathy and cardiac function by decreasing expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), which is involved in energy metabolism in the heart.[63] It has been reported that activation of FXR contributes to myocardial ischemia-reperfusion injury.[64] Deficiency of FXR impairs bile acid synthesis and increases serum bile acids, cholesterol, TGs, and pro-atherogenic lipoprotein profile in mice.[65] However, activation of FXR reduces ApoAI and ApoCIII expression; thus, it may reduce serum HDL and TGs in humans.[66],[67]

The secondary bile acids LCA and DCA activate G-protein coupled bile acid receptor-1 (Gpbar-1, also known as TGR5) in enteroendocrine L cells to stimulate secretion of glucagon-like peptide 1 (GLP-1), which stimulates insulin secretion in the pancreas to improve insulin sensitivity [Figure 3].[32],[68],[69] TGR5 is widely expressed in most tissues, including the heart. Activation of TGR5 has been shown to improve myocardial function,[70] induce nitric oxide production and reduce monocyte adhesion in vascular endothelial cells,[71] stimulate smooth muscle relaxation,[72] and reduce macrophage inflammation and atherosclerosis.[73],[74] Activation of both FXR and TGR5 protects mice against atherosclerosis.[75]

  Gut Microbiota and Atherosclerosis Top

The role of the gut microbiota in lipid metabolism and atherosclerosis has been implicated.[43],[76],[77],[78],[79],[80],[81] Proinflammatory gut bacteria have been shown to increase systemic inflammation and promote atherosclerosis in mice.[43] Secondary bile acids and lipopolysaccharide (LPS) generated by intestinal bacteria are transported to the heart and liver and cause inflammation. The gut bacteria convert choline (derived from phosphatidylcholine) and L-carnitine to trimethylamine (TMA) by the action of TMA lyases [Figure 4]. TMA is circulated to the liver and converted to trimethylamine-oxide (TMAO) by flavin-containing monooxygenase 3 (FMO3). Serum TMAO levels have been linked to increased cardiovascular events.[82],[83] TMAO impairs RCT, as indicated by increased macrophage cholesterol and oxLDL, CD36 and SR-A1 receptors, and foam-cell formation, to promote atherosclerosis in a gut microbiota-dependent manner.[78] TMAO supplementation in diet suppresses CYP7A1 and CYP27A1 expression, increases hepatic cholesterol, and decreases the total bile acid pool.[78] TMAO also suppresses expression of intestinal NPC1 L1 and ABCG5/ABCG8, thereby reducing intestinal cholesterol absorption.[78]
Figure 4: Interactions of the liver, heart, and intestine in lipid metabolism. The liver-to-heart, liver-tointestine, and intestine-to-heart axes are shown. CYP7A1: cholesterol 7-hydroxylase, TMA: trimethylamine, FXR: farnesoid X receptor, SR-B1: scavenger receptor B1, TMAO: trimethylamine-oxide, VLDL: very low-density lipoprotein, LDL: low-density lipoprotein, RCT: reverse cholesterol transport, TGR5: Takeda G protein receptor 5, EHC: enterohepatic circulation, TMA: trimethylamine, CM: chylomicrons, FGF19: fibroblast growth factor 19, BSH: bile salt hydrolases, DCA: deoxycholic acid, LCA: lithocholic acid, TMA: trimethylamine, GLP-1: glucagon-like peptide 1, TICE: transintestinal cholesterol excretion

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  Lipid-Lowering Therapies for Treating Atherosclerosis and Familial Hypercholesterolemia Top

Serum bile acid levels vary in individuals, and increased fasting bile acids and serum C4 are correlated with type 2 diabetes (T2D) and ACVD.[84] Disruption of RCT contributes directly to the accumulation of oxidized LDL and fatty foam cells in the endothelium of the aortic wall and to the pathogenesis of atherosclerosis. A study conducted about 50 years ago reported that interruption of the EHC of bile acids by cholestyramine increased ileal excretion of cholesterol and reduced hypercholesterolemia in humans.[85] Cholestyramine reduces serum cholesterol and LDL-cholesterol in T2D.[86] Cholestyramine reduces the bile acid pool to stimulate bile acid synthesis and increases LDLR gene expression to reduce hepatic cholesterol and LDLR-mediated uptake of cholesterol from blood circulation, thereby reducing hypercholesterolemia.[87] Patients with hyperlipoproteinemia treated with cholestyramine had increased bile acid and TG synthesis, whereas those treated with CDCA had reduced bile acid and TG synthesis.[88] Cholestyramine also reduces FGF19 induced by FXR in intestine, thus derepressing CYP7A1 to stimulate bile acid synthesis.[89] Cholestyramine, colestipol, and second generation bile acid binding resins colesevelam and colestimide have been used to treat hypercholesterolemia, cholesterol gallstone disease, and T2D.[90],[91],[92],[93] Cholestyramine significantly reduced atherosclerosis progression in a clinical trial of patients with coronary heart disease.[94] Bile acids may be used to treat atherosclerosis by regulating lipoprotein metabolism. ABCA1, ABCG1, and HDL are potential targets for the treatment of atherosclerosis.[95]

Statins are potent lipid-lowering drugs that inhibit HMG-CoA reductase activity in the de novo cholesterol synthesis pathway, and thus, have been used successfully to reduce the risk of ACVD events in humans. Although statins alone are not sufficient for treating FH, a combination of statins and cholestyramine has been shown to alter lipoprotein profile and lower LDL cholesterol, as well as to safely treat FH.[96],[97],[98] However, statins are not recommended for pregnant women and some patients who are resistant to statins may develop unwanted side effects of muscle pain and liver injury. Drugs designed to increase HDL cholesterol have been further developed for treating FH. Ezetimibe and niacin modestly reduce LDL cholesterol and increase HDL cholesterol. Torcetrapib, a CETP inhibitor, has been shown to effectively increase HDL cholesterol levels and stimulate RCT in mice[99] and humans.[29],[100] However, a clinical trial of torcetrapib for atherosclerosis was withdrawn due to high mortality rate.[101],[102] As an alternative to statins, PCSK9 inhibitors were developed for reducing LDL cholesterol and ACVD risk.[103] PCSK9 inhibitors have been shown to augment circulating LDLRs to hepatocytes to accelerate clearance of LDL. The FDA recently approved two PCSK9 monoclonal antibodies for treating FH. Statins inhibit the synthesis of oxysterols and reduce the activation of LXR by oxysterols in hepatocytes.[104] Activation of LXR specifically in macrophages reduces inflammation and atherosclerosis. Therefore, drugs specifically targeting macrophages may be designed to treat atherosclerosis.[105],[106]

Obeticholic acid (OCA) is a potent bile acid derivative that activates FXR to reduce hepatic lipid synthesis and improve glucose and insulin sensitivity in patients with NAFLD.[37],[107],[108],[109] OCA may also be used to treat atherosclerosis. Activation of FXR represses PCSK9 in human hepatocytes.[110] However, OCA reduces serum ApoAI and HDL cholesterol levels, and may have adverse effects in atherosclerosis.[8],[111],[112]

  Conclusion Top

The liver plays a central role in lipid metabolism and homeostasis by providing TGs and cholesterol to the heart and other tissues. Catabolism of cholesterol to bile acids and biliary cholesterol secretion are the predominant mechanisms to remove excess cholesterol from the body and protect against atherosclerosis. Bile acid signaling via activating FXR in the gut-to-liver axis plays a key role in the regulation of the EHC of bile acids, as well as bile acid synthesis, composition, and pool size, to maintain bile acid homeostasis and regulate whole body lipid homeostasis.[41],[76],[77],[113],[114] The liver, heart, and intestine are linked by lipoproteins, bile acids and gut bacterial metabolites to control bile acid and cholesterol signaling [Figure 4]. The liver-to-heart axis is regulated by normal cholesterol transport to deliver cholesterol to the heart, RCT to transport oxidized cholesterol from macrophages to the liver for catabolism to bile acids, and LDLR-mediated endocytosis to remove excess cholesterol from macrophages and extrahepatic tissues to prevent atherosclerosis. The liver-to-intestine axis is important to bile acid metabolism and to the control of gut bacterial overgrowth to prevent inflammation and injury to the liver and heart. The intestine can directly excrete cholesterol to feces through TICE. The intestine-to-liver axis and intestine-to-heart axis link the gut bacteria metabolite TMA to the liver to form TMAO, which impairs RCT and atherosclerosis. Further study of the impact of the gut microbiota on heart diseases will be important for developing alternate drug therapies to the use of statins for ACVD. Probiotics may be used for ACVD treatment in human patients in the future, as they modify gut microbiota and induce bile acid synthesis and have been shown to protect against NASH and atherosclerosis in mouse models.[115],[116],[117],[118]

Financial support and sponsorship

NIH grants DK44442 and DK58379.

Conflicts of interest

There are no conflicts of interest.

  References Top

Lonardo A, Nascimbeni F, Mantovani A, Targher G. Hypertension, diabetes, atherosclerosis and NASH: Cause or consequence? J Hepatol 2018;68:335-52. doi: 10.1016/j.jhep.2017.09.021.  Back to cited text no. 1
Targher G, Byrne CD, Lonardo A, Zoppini G, Barbui C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A meta-analysis. J Hepatol 2016;65:589-600. doi:10.1016/j.jhep.2016.05.013.  Back to cited text no. 2
Ma J, Hwang SJ, Pedley A, Massaro JM, Hoffmann U, Chung RT, et al. Bi-directional analysis between fatty liver and cardiovascular disease risk factors. J Hepatol 2017;66:390-7. doi: 10.1016/j.jhep.2016.09.022.  Back to cited text no. 3
Chimakurthi CR, Rowe IA. Establishing the independence and clinical importance of non-alcoholic fatty liver disease as a risk factor for cardiovascular disease. J Hepatol 2016;65:1265-6. doi:10.1016/j.jhep.2016.06.034.  Back to cited text no. 4
Ginsberg HN, Zhang YL, Hernandez-Ono A. Metabolic syndrome: Focus on dyslipidemia. Obesity 2006;14 Suppl 1:41S-9S. doi: 10.1038/oby.2006.281.  Back to cited text no. 5
Poznyak A, Grechko AV, Poggio P, Myasoedova VA, Alfieri V, Orekhov AN. The diabetes mellitus-atherosclerosis connection: The role of lipid and glucose metabolism and chronic inflammation. Int J Mol Sci 2020;21:(5):1835. doi:10.3390/ijms21051835.  Back to cited text no. 6
Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med 1999;340:115-26. doi: 10.1056/NEJM199901143400207.  Back to cited text no. 7
Sukhorukov VN, Khotina VA, Chegodaev YS, Ivanova E, Sobenin IA, Orekhov AN. Lipid metabolism in macrophages: Focus on atherosclerosis. Biomedicines 2020;8:(8):262. doi:10.3390/biomedicines8080262.  Back to cited text no. 8
Chiang J. Liver physiology: Metabolism and detoxification. Pathobiol Human Dis 2014:1770-82. doi: 10.1016/b978-0-12-386456-7.04202-7.  Back to cited text no. 9
Davis RA, Hui TY. 2000 George lyman duff memorial lecture: Atherosclerosis is a liver disease of the heart. Arterioscler Thromb Vasc Biol 2001;21:887-98. doi: 10.1161/01.atv.21.6.887.  Back to cited text no. 10
Dietschy JM, Turley SD, Spady DK. Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. J Lipid Res 1993;34:1637-59.  Back to cited text no. 11
Chiang JY. Bile acids: Regulation of synthesis. J Lipid Res 2009;50:1955-66. doi:10.1194/jlr.R900010-JLR200.  Back to cited text no. 12
Brown MS, Goldstein JL. The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 1997;89:331-40. doi:10.1016/s0092-8674(00)80213-5.  Back to cited text no. 13
Edwards PA, Tabor D, Kast HR, Venkateswaran A. Regulation of gene expression by SREBP and SCAP. Biochim Biophys Acta 2000;1529:103-13. doi: 10.1016/s1388-1981(00)00140-2.  Back to cited text no. 14
Horton JD, Goldstein JL, Brown MS. SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002;109:1125-31. doi: 10.1172/JCI15593.  Back to cited text no. 15
Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, et al. Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 1997;272:3137-40. doi:10.1074/jbc.272.6.3137.  Back to cited text no. 16
Peet DJ, Janowski BA, Mangelsdorf DJ. The LXRs: A new class of oxysterol receptors. Curr Opin Genet Dev 1998;8:571-5. doi:10.1016/s0959-437x(98)80013-0.  Back to cited text no. 17
Repa JJ, Mangelsdorf DJ. The liver X receptor gene team: Potential new players in atherosclerosis. Nat Med 2002;8:1243-8. doi: 10.1038/nm1102-1243.  Back to cited text no. 18
Tangirala RK, Bischoff ED, Joseph SB, Wagner BL, Walczak R, Laffitte B A, et al. Identification of macrophage liver X receptors as inhibitors of atherosclerosis. Proc Natl Acad Sci U S A 2002;99:11896-901. doi:10.1073/pnas.182199799.  Back to cited text no. 19
Yokode M, Hammer RE, Ishibashi S, Brown MS, Goldstein JL. Diet-induced hypercholesterolemia in mice: Prevention by overexpression of LDL receptors. Science 1990;250:1273-5. doi:10.1126/science.2244210.  Back to cited text no. 20
Goldstein JL, Brown MS. Familial hypercholesterolemia. A genetic regulatory defect in cholesterol metabolism. Am J Med 1975;58:147-50. doi:10.1016/0002-9343(75)90563-x.  Back to cited text no. 21
Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): Liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A 2003;100:928-33. doi: 10.1073/pnas.0335507100.  Back to cited text no. 22
Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003;34:154-6. doi:10.1038/ng1161.  Back to cited text no. 23
Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 2005;37:161-5. doi:10.1038/ng1509.  Back to cited text no. 24
Costet P, Cariou B, Lambert G, Lalanne F, Lardeux B, Jarnoux AL, et al. Hepatic PCSK9 expression is regulated by nutritional status via insulin and sterol regulatory element-binding protein 1c. J Biol Chem 2006;281:6211-8. doi: 10.1074/jbc.M508582200.  Back to cited text no. 25
Lewis GF, Rader DJ. New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ Res 2005;96:1221-32. doi: 10.1161/01.RES.0000170946.56981.5c.  Back to cited text no. 26
Rosenson RS, Brewer HB Jr., Davidson WS, Fayad ZA, Fuster V, Goldstein J, et al. Cholesterol efflux and atheroprotection: Advancing the concept of reverse cholesterol transport. Circulation 2012;125:1905-19. doi:10.1161/CIRCULATIONAHA.111.066589.  Back to cited text no. 27
Yokoyama S. Assembly of high-density lipoprotein. Arterioscler Thromb Vasc Biol. 2006 Jan;26:20-7. doi: 10.1161/01.ATV.0000195789.39418.e8.  Back to cited text no. 28
Catalano G, Julia Z, Frisdal E, Vedie B, Fournier N, Le Goff W, et al. Torcetrapib differentially modulates the biological activities of HDL2 and HDL3 particles in the reverse cholesterol transport pathway. Arterioscler Thromb Vasc Biol 2009;29:268-75. doi:10.1161/ATVBAHA.108.179416.  Back to cited text no. 29
Annema W, Tietge UJ. Role of hepatic lipase and endothelial lipase in high-density lipoprotein-mediated reverse cholesterol transport. Curr Atheroscler Rep 2011;13:257-65. doi:10.1007/s11883-011-0175-2.  Back to cited text no. 30
Chiang JY. Bile acid metabolism and signaling in liver disease and therapy. Liver Res 2017;1:3-9. doi:10.1016/j.livres.2017.05.001.  Back to cited text no. 31
Chiang JY, Ferrell JM. Bile acid receptors FXR and TGR5 signaling in fatty liver diseases and therapy. Am J Physiol Gastrointest Liver Physiol 2020;318:G554-73. doi: 10.1152/ajpgi.00223.2019.  Back to cited text no. 32
Chiang JY, Ferrell JM. Bile acids as metabolic regulators and nutrient sensors. Annu Rev Nutr 2019;39:175-200. doi: 10.1146/annurev-nutr-082018-124344.  Back to cited text no. 33
Kakiyama G, Marques D, Takei H, Nittono H, Erickson S, Fuchs M, et al. Mitochondrial oxysterol biosynthetic pathway gives evidence for CYP7B1 as controller of regulatory oxysterols. J Steroid Biochem Mol Biol 2019;189:36-47. doi: 10.1016/j.jsbmb.2019.01.011.  Back to cited text no. 34
Fu X, Menke JG, Chen Y, Zhou G, MacNaul KL, Wright SD, et al. 27-hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells. J Biol Chem 2001;276:38378-387. doi:10.1074/jbc.M105805200.  Back to cited text no. 35
Björkhem I, Andersson O, Diczfalusy U, Sevastik B, Xiu RJ, Duan C, et al. Atherosclerosis and sterol 27-hydroxylase: Evidence for a role of this enzyme in elimination of cholesterol from human macrophages. Proc Natl Acad Sci U S A 1994;91:8592-6. doi: 10.1073/pnas.91.18.8592.  Back to cited text no. 36
Sayin SI, Wahlström A, Felin J, Jäntti S, Marschall HU, Bamberg K, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 2013;17:225-35. doi:10.1016/j.cmet.2013.01.003.  Back to cited text no. 37
Yao L, Seaton SC, Ndousse-Fetter S, Adhikari AA, DiBenedetto N, Mina AI, et al. A selective gut bacterial bile salt hydrolase alters host metabolism. Elife 2018;7:e37182. doi: 10.7554/eLife.37182.  Back to cited text no. 38
Jones BV, Begley M, Hill C, Gahan CG, Marchesi JR. Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome. Proc Natl Acad Sci U S A 2008;105:13580-5. doi: 10.1073/pnas.0804437105.  Back to cited text no. 39
Labbé A, Ganopolsky JG, Martoni CJ, Prakash S, Jones ML. Bacterial bile metabolising gene abundance in Crohn's, ulcerative colitis and type 2 diabetes metagenomes. PLoS One 2014;9:e115175. doi: 10.1371/journal.pone.0115175.  Back to cited text no. 40
Joyce SA, Gahan CG. The gut microbiota and the metabolic health of the host. Curr Opin Gastroenterol 2014;30:120-7. doi: 10.1097/MOG.0000000000000039.  Back to cited text no. 41
Ridlon JM, Harris SC, Bhowmik S, Kang DJ, Hylemon PB. Consequences of bile salt biotransformations by intestinal bacteria. Gut Microbes 2016;7:22-39. doi:10.1080/19490976.2015.1127483.  Back to cited text no. 42
Brandsma E, Kloosterhuis NJ, Koster M, Dekker DC, Gijbels MJ, van der Velden S, et al. A proinflammatory gut microbiota increases systemic inflammation and accelerates atherosclerosis. Circ Res 2019;124:94-100. doi: 10.1161/CIRCRESAHA.118.313234.  Back to cited text no. 43
Chiang JY, Ferrell JM. Bile acid biology, pathophysiology, and therapeutics. Clin Liver Dis (Hoboken) 2020;15:91-4. doi: 10.1002/cld.861.  Back to cited text no. 44
Voronova V, Sokolov V, Al-Khaifi A, Straniero S, Kumar C, Peskov K, et al. A physiology-based model of bile acid distribution and metabolism under healthy and pathologic conditions in human beings. Cell Mol Gastroenterol Hepatol 2020;10:149-70. doi: 10.1016/j.jcmgh.2020.02.005.  Back to cited text no. 45
Lee MH, Lu K, Hazard S, Yu H, Shulenin S, Hidaka H, et al. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Genet 2001;27:79-83. doi: 10.1038/83799.  Back to cited text no. 46
Patel SB, Graf GA, Temel RE. ABCG5 and ABCG8: More than a defense against xenosterols. J Lipid Res 2018;59:1103-13. doi: 10.1194/jlr.R084244.  Back to cited text no. 47
Temel RE, Brown JM. Biliary and nonbiliary contributions to reverse cholesterol transport. Curr Opin Lipidol 2012;23:85-90. doi: 10.1097/MOL.0b013e3283508c21.  Back to cited text no. 48
Le May C, Berger JM, Lespine A, Pillot B, Prieur X, Letessier E, et al. Transintestinal cholesterol excretion is an active metabolic process modulated by PCSK9 and statin involving ABCB1. Arterioscler Thromb Vasc Biol 2013;33:1484-93. doi: 10.1161/ATVBAHA.112.300263.  Back to cited text no. 49
van der Velde AE, Brufau G, Groen AK. Transintestinal cholesterol efflux. Curr Opin Lipidol 2010;21:167-71. doi: 10.1097/MOL.0b013e3283395e45.  Back to cited text no. 50
Jakulj L, van Dijk TH, de Boer JF, Kootte RS, Schonewille M, Paalvast Y, et al. Transintestinal cholesterol transport is active in mice and humans and controls ezetimibe-induced fecal neutral sterol excretion. Cell Metab 2016;24:783-94. doi:10.1016/j.cmet.2016.10.001.  Back to cited text no. 51
Claudel T, Staels B, Kuipers F. The Farnesoid X receptor: A molecular link between bile acid and lipid and glucose metabolism. Arterioscler Thromb Vasc Biol 2005;25:2020-30. doi: 10.1161/01.ATV.0000178994.21828.a7.  Back to cited text no. 52
Trauner M, Claudel T, Fickert P, Moustafa T, Wagner M. Bile acids as regulators of hepatic lipid and glucose metabolism. Dig Dis 2010;28:220-4. doi:10.1159/000282091.  Back to cited text no. 53
Li T, Chiang JY. Bile acid signaling in metabolic disease and drug therapy. Pharmacol Rev 2014;66:948-83. doi: 10.1124/pr.113.008201.  Back to cited text no. 54
Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB, et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 2000;6:517-26. doi: 10.1016/s1097-2765(00)00051-4.  Back to cited text no. 55
Chiang JY, Kimmel R, Weinberger C, Stroup D. J Biol Chem. 2010;275:10918-24. doi:10.1074/jbc.275.15.10918.  Back to cited text no. 56
Ananthanarayanan M, Balasubramanian N, Makishima M, Mangelsdorf DJ, Suchy FJ. Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J Biol Chem 2001;276:28857-65. doi: 10.1074/jbc.M011610200.  Back to cited text no. 57
Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2005;2:217-25. doi:10.1016/j.cmet.2005.09.001.  Back to cited text no. 58
Bishop-Bailey D. FXR as a novel therapeutic target for vascular disease. Drug News Perspect 2004;17:499-504. doi:10.1358/dnp.2004.17.8.863693.  Back to cited text no. 59
Guo GL, Santamarina-Fojo S, Akiyama TE, Amar MJ, Paigen BJ, Brewer B Jr., et al. Effects of FXR in foam-cell formation and atherosclerosis development. Biochim Biophys Acta 2006;1761:1401-9. doi: 10.1016/j.bbalip.2006.09.018.  Back to cited text no. 60
Hageman J, Herrema H, Groen AK, Kuipers F. A role of the bile salt receptor FXR in atherosclerosis. Arterioscler Thromb Vasc Biol 2010;30:1519-28. doi: 10.1161/ATVBAHA.109.197897.  Back to cited text no. 61
Bishop-Bailey D, Walsh DT, Warner TD. Expression and activation of the farnesoid X receptor in the vasculature. Proc Natl Acad Sci U S A 2004;101:3668-73. doi: 10.1073/pnas.0400046101.  Back to cited text no. 62
Desai MS, Mathur B, Eblimit Z, Vasquez H, Taegtmeyer H, Karpen SJ, et al. Bile acid excess induces cardiomyopathy and metabolic dysfunctions in the heart. Hepatology 2017;65:189-201. doi:10.1002/hep.28890.  Back to cited text no. 63
Pu J, Yuan A, Shan P, Gao E, Wang X, Wang Y, et al. Cardiomyocyte-expressed farnesoid-X-receptor is a novel apoptosis mediator and contributes to myocardial ischaemia/reperfusion injury. Eur Heart J 2013;34:1834-45. doi: 10.1093/eurheartj/ehs011.  Back to cited text no. 64
Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 2000;102:731-44. doi: 10.1016/s0092-8674(00)00062-3.  Back to cited text no. 65
Claudel T, Sturm E, Duez H, Torra IP, Sirvent A, Kosykh V, et al. Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element. J Clin Invest 2002;109:961-71. doi:10.1172/JCI14505.  Back to cited text no. 66
Claudel T, Inoue Y, Barbier O, Duran-Sandoval D, Kosykh V, Fruchart J, et al. Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression. Gastroenterology 2003;125:544-55. doi:10.1016/s0016-5085(03)00896-5.  Back to cited text no. 67
Maruyama T, Tanaka K, Suzuki J, Miyoshi H, Harada N, Nakamura T, et al. Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) in mice. J Endocrinol 2006;191:197-205. doi:10.1677/joe.1.06546.  Back to cited text no. 68
Katsuma S, Hirasawa A, Tsujimoto G. Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem Biophys Res Commun 2005;329:386-90. doi: 10.1016/j.bbrc.2005.01.139.  Back to cited text no. 69
Eblimit Z, Thevananther S, Karpen SJ, Taegtmeyer H, Moore DD, Adorini L, et al. TGR5 activation induces cytoprotective changes in the heart and improves myocardial adaptability to physiologic, inotropic, and pressure-induced stress in mice. Cardiovasc Ther 2018;36:e12462. doi: 10.1111/1755-5922.12462.  Back to cited text no. 70
Kida T, Tsubosaka Y, Hori M, Ozaki H, Murata T. Bile acid receptor TGR5 agonism induces NO production and reduces monocyte adhesion in vascular endothelial cells. Arterioscler Thromb Vasc Biol 2013;33:1663-9. doi: 10.1161/ATVBAHA.113.301565.  Back to cited text no. 71
Rajagopal S, Kumar DP, Mahavadi S, Bhattacharya S, Zhou R, Corvera CU, et al. Activation of G protein-coupled bile acid receptor, TGR5, induces smooth muscle relaxation via both Epac- and PKA-mediated inhibition of RhoA/Rho kinase pathway. Am J Physiol Gastrointest Liver Physiol 2013;304:G527-35. doi: 10.1152/ajpgi.00388.2012.  Back to cited text no. 72
Pols TW, Nomura M, Harach T, Lo Sasso G, Oosterveer MH, Thomas C, et al. TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab 2011;14:747-57. doi: 10.1016/j.cmet.2011.11.006.  Back to cited text no. 73
Li J, Cheng R, Wan H. Overexpression of TGR5 alleviates myocardial ischemia/reperfusion injury via AKT/GSK-3β mediated inflammation and mitochondrial pathway. Biosci Rep 2020;40:BSR20193482. doi: 10.1042/BSR20193482.  Back to cited text no. 74
Miyazaki-Anzai S, Masuda M, Levi M, Keenan AL, Miyazaki M. Dual activation of the bile acid nuclear receptor FXR and G-protein-coupled receptor TGR5 protects mice against atherosclerosis. PLoS One 2014;9:e108270. doi: 10.1371/journal.pone.0108270.  Back to cited text no. 75
Zhang L, Xie C, Nichols RG, Chan SH, Jiang C, Hao R, et al. Farnesoid X receptor signaling shapes the gut microbiota and controls hepatic lipid metabolism. mSystems 2016;1:e00070-16. doi: 10.1128/mSystems.00070-16.  Back to cited text no. 76
Ikegami T, Honda A. Reciprocal interactions between bile acids and gut microbiota in human liver diseases. Hepatol Res 2018;48:15-27. doi: 10.1111/hepr.13001.  Back to cited text no. 77
Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013;19:576-85. doi: 10.1038/nm.3145.  Back to cited text no. 78
Ma J, Li H. The role of gut microbiota in atherosclerosis and hypertension. Front Pharmacol 2018;9:1082. doi: 10.3389/fphar.2018.01082.  Back to cited text no. 79
Valdes AM, Walter J, Segal E, Spector TD. Role of the gut microbiota in nutrition and health. BMJ 2018;361:k2179. doi:10.1136/bmj.k2179.  Back to cited text no. 80
Lau K, Srivatsav V, Rizwan A, Nashed A, Liu R, Shen R, et al. Bridging the gap between gut microbial dysbiosis and cardiovascular diseases. Nutrients 2017;9:(8),859. doi: 10.3390/nu9080859.  Back to cited text no. 81
Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011;472:57-63. doi: 10.1038/nature09922.  Back to cited text no. 82
Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 2013;368:1575-84. doi: 10.1056/NEJMoa1109400.  Back to cited text no. 83
Steiner C, Othman A, Saely CH, Rein P, Drexel H, von Eckardstein A, et al. Bile acid metabolites in serum: Intraindividual variation and associations with coronary heart disease, metabolic syndrome and diabetes mellitus. PLoS One 2011;6:e25006. doi: 10.1371/journal.pone.0025006.  Back to cited text no. 84
Grundy SM, Ahrens EH Jr., Salen G. Interruption of the enterohepatic circulation of bile acids in man: Comparative effects of cholestyramine and ileal exclusion on cholesterol metabolism. J Lab Clin Med 1971;78:94-121. doi.10.1161/01.cir.46.1.95.  Back to cited text no. 85
Garg A, Grundy SM. Cholestyramine therapy for dyslipidemia in non-insulin-dependent diabetes mellitus. A short-term, double-blind, crossover trial. Ann Intern Med 1994;121:416-22. doi:10.7326/0003-4819-121-6-199409150-00004.  Back to cited text no. 86
Nakahara M, Fujii H, Maloney PR, Shimizu M, Sato R. Bile acids enhance low density lipoprotein receptor gene expression via a MAPK cascade-mediated stabilization of mRNA. J Biol Chem 2002;277:37229-34. doi:10.1074/jbc.M206749200.  Back to cited text no. 87
Angelin B, Einarsson K, Hellström K, Leijd B. Effects of cholestyramine and chenodeoxycholic acid on the metabolism of endogenous triglyceride in hyperlipoproteinemia. J Lipid Res 1978;19:1017-24.  Back to cited text no. 88
Kuipers F, Stroeve JH, Caron S, Staels B. Bile acids, farnesoid X receptor, atherosclerosis and metabolic control. Curr Opin Lipidol 2007;18:289-97. doi: 10.1097/MOL.0b013e3281338d08.  Back to cited text no. 89
Portincasa P, Di Ciaula A, Palmieri VO, Baldassarre G, Palasciano G. Enhancement of gallbladder emptying in gallstone patients after oral cholestyramine. Am J Gastroenterol 1994;89:909-14.  Back to cited text no. 90
Fonseca VA, Handelsman Y, Staels B. Colesevelam lowers glucose and lipid levels in type 2 diabetes: The clinical evidence. Diabetes Obes Metab 2010;12:384-92. doi: 10.1111/j.1463-1326.2009.01181.x.  Back to cited text no. 91
Hansen M, Sonne DP, Mikkelsen KH, Gluud LL, Vilsbøll T, Knop FK. Bile acid sequestrants for glycemic control in patients with type 2 diabetes: A systematic review with meta-analysis of randomized controlled trials. J Diab Complicat 2017;31:918-27. doi: 10.1016/j.jdiacomp.2017.01.011.  Back to cited text no. 92
Staels B. A review of bile acid sequestrants: Potential mechanism(s) for glucose-lowering effects in type 2 diabetes mellitus. Postgrad Med 2009;121:25-30. doi: 10.3810/pgm.2009.05.suppl53.290.  Back to cited text no. 93
Watts GF, Lewis B, Brunt JN, Lewis ES, Coltart DJ, Smith LD, et al. Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas' Atherosclerosis Regression Study (STARS) Lancet 1992;339:563-9. doi: 10.1016/0140-6736(92)90863-x.  Back to cited text no. 94
Tall AR, Yvan-Charvet L, Terasaka N, Pagler T, Wang N. HDL, ABC transporters, and cholesterol efflux: Implications for the treatment of atherosclerosis. Cell Metab 2008;7:365-75. doi: 10.1016/j.cmet.2008.03.001.  Back to cited text no. 95
Bard JM, Parra HJ, Douste-Blazy P, Fruchart JC. Effect of pravastatin, an HMG CoA reductase inhibitor, and cholestyramine, a bile acid sequestrant, on lipoprotein particles defined by their apolipoprotein composition. Metabolism 1990;39:269-73. doi: 10.1016/0026-0495(90)90046-f.  Back to cited text no. 96
Hoogerbrugge N, Mol MJ, Van Dormaal JJ, Rustemeijer C, Muls E, Stalenhoef AF, et al. The efficacy and safety of pravastatin, compared to and in combination with bile acid binding resins, in familial hypercholesterolaemia. J Intern Med 1990;228:261-6. doi: 10.1111/j.1365-2796.1990.tb00229.x.  Back to cited text no. 97
Alder M, Bavishi A, Zumpf K, Peterson J, Stone NJ. A meta-analysis assessing additional LDL-C reduction from addition of a bile acid sequestrant to statin therapy. Am J Med 2020;133:1322-7. doi:10.1016/j.amjmed.2020.03.056.  Back to cited text no. 98
Briand F, Thieblemont Q, André A, Ouguerram K, Sulpice T. CETP inhibitor torcetrapib promotes reverse cholesterol transport in obese insulin-resistant CETP-ApoB100 transgenic mice. Clin Transl Sci 2011;4:414-20. doi:10.1111/j.1752-8062.2011.00344.x.  Back to cited text no. 99
Clark RW, Sutfin TA, Ruggeri RB, Willauer AT, Sugarman ED, Magnus-Aryitey G, et al. Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: An initial multidose study of torcetrapib. Arterioscler Thromb Vasc Biol 2004;24:490-7. doi:10.1161/01.ATV.0000118278.21719.17.  Back to cited text no. 100
Verma N, Figueredo VM. HDL cholesterol: All hope is not lost after the torcetrapib setback-emerging therapeutic strategies on the horizon. Am J Ther 2014;21:222-32. doi: 10.1097/MJT.0b013e318249a1b5.  Back to cited text no. 101
Howes LG, Kostner K. The withdrawal of torcetrapib from drug development: Implications for the future of drugs that alter HDL metabolism. Expert Opin Investig Drugs 2007;16:1509-16. doi: 10.1517/13543784.16.10.1509.  Back to cited text no. 102
Toth S, Pella D, Fedacko J. Vaccines targeting PSCK9 for the treatment of hyperlipidemia. Cardiol Ther 2020;9:323-32. doi: 10.1007/s40119-020-00191-6.  Back to cited text no. 103
Wong J, Quinn CM, Brown AJ. Statins inhibit synthesis of an oxysterol ligand for the liver x receptor in human macrophages with consequences for cholesterol flux. Arterioscler Thromb Vasc Biol 2004;24:2365-71. doi: 10.1161/01.ATV.0000148707.93054.7d.  Back to cited text no. 104
Joseph SB, Tontonoz P. LXRs: New therapeutic targets in atherosclerosis? Curr Opin Pharmacol 2003;3:192-7. doi: 10.1016/s1471-4892(03)00009-2.  Back to cited text no. 105
Brown AJ, Jessup W. Oxysterols and atherosclerosis. Atherosclerosis 1999;142:1-28. doi: 10.1016/S0021-9150(98)00196-8.  Back to cited text no. 106
Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): A multicentre, randomised, placebo-controlled trial. Lancet 2015;385:956-65. doi: 10.1016/S0140-6736(14)61933-4  Back to cited text no. 107
Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013;145:574-82.e1. doi:10.1053/j.gastro.2013.05.042.  Back to cited text no. 108
Sun L, Xie C, Wang G, Wu Y, Wu Q, Wang X, et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat Med 2018;24:1919-29. doi: 10.1038/s41591-018-0222-4.  Back to cited text no. 109
Langhi C, Le May C, Kourimate S, Caron S, Staels B, Krempf M, et al. Activation of the farnesoid X receptor represses PCSK9 expression in human hepatocytes. FEBS Lett 2008;582:949-55. doi:10.1016/j.febslet.2008.02.038.  Back to cited text no. 110
Pencek R, Marmon T, Roth JD, Liberman A, Hooshmand-Rad R, Young MA. Effects of obeticholic acid on lipoprotein metabolism in healthy volunteers. Diabetes Obes Metab 2016;18:936-40. doi:10.1111/dom.12681.  Back to cited text no. 111
Gutierrez A, Ratliff EP, Andres AM, Huang X, McKeehan WL, Davis RA. Bile acids decrease hepatic paraoxonase 1 expression and plasma high-density lipoprotein levels via FXR-mediated signaling of FGFR4. Arterioscler Thromb Vasc Biol 2006;26:301-6. doi: 10.1161/01.ATV.0000195793.73118.b4.  Back to cited text no. 112
Ohtani N, Kawada N. Role of the gut-liver axis in liver inflammation, fibrosis, and cancer: A special focus on the gut microbiota relationship. Hepatol Commun 2019;3:456-70. doi: 10.1002/hep4.1331.  Back to cited text no. 113
Pathak P, Xie C, Nichols RG, Ferrell JM, Boehme S, Krausz KW, et al. Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology 2018;68:1574-88. doi:10.1002/hep.29857.  Back to cited text no. 114
Brandi G, De Lorenzo S, Candela M, Pantaleo MA, Bellentani S, Tovoli F, et al. Microbiota, NASH, HCC and the potential role of probiotics. Carcinogenesis 2017;38:231-40. doi: 10.1093/carcin/bgx007.  Back to cited text no. 115
Degirolamo C, Rainaldi S, Bovenga F, Murzilli S, Moschetta A. Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the Fxr-Fgf15 axis in mice. Cell Rep 2014;7:12-8. doi:10.1016/j.celrep.2014.02.032.  Back to cited text no. 116
Michael DR, Davies TS, Moss JW, Calvente DL, Ramji DP, Marchesi JR, et al. The anti-cholesterolaemic effect of a consortium of probiotics: An acute study in C57BL/6J mice. Sci Rep 2017;7:2883. doi: 10.1038/s41598-017-02889-5.  Back to cited text no. 117
Mencarelli A, Cipriani S, Renga B, Bruno A, D'Amore C, Distrutti E, et al. VSL#3 resets insulin signaling and protects against NASH and atherosclerosis in a model of genetic dyslipidemia and intestinal inflammation. PLoS One 2012;7:e45425. doi: 10.1371/journal.pone.0045425.  Back to cited text no. 118


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]


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Cholesterol Meta...
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Bile Acid Synthesis
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