Insulin and Bile Acids in Cholesterol Homeostasis: New Players in Diabetes-Associated Atherosclerosis

HomeCirculationVol. 145, No. 13Insulin and Bile Acids in Cholesterol Homeostasis: New Players in Diabetes-Associated Atherosclerosis Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBInsulin and Bile Acids in Cholesterol Homeostasis: New Players in Diabetes-Associated Atherosclerosis Víctor Cortés, MD, PhD and Robert H. Eckel, MD Víctor CortésVíctor Cortés Correspondence to: Víctor Cortés, MD, PhD, Av Libertador Bernardo O’Higgins 340, Santiago 8330024, Chile. Email E-mail Address: [email protected] https://orcid.org/0000-0002-1658-0965 Department of Nutrition, Diabetes and Metabolism, Pontificia Universidad Católica de Chile, Santiago (V.C.). Search for more papers by this author and Robert H. EckelRobert H. Eckel Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, (R.H.E.). Search for more papers by this author Originally published28 Mar 2022https://doi.org/10.1161/CIRCULATIONAHA.122.058883Circulation. 2022;145:983–986This article is a commentary on the followingInsulin Prevents Hypercholesterolemia by Suppressing 12α-Hydroxylated Bile AcidsArticle, see p 969Cholesterol and bile acids (BAs) have been classically connected in a simple model in which cholesterol is the biosynthetic precursor of BAs and BAs are participants in intestinal cholesterol absorption. Although valid, this model fails to acknowledge the regulatory complexity underlying lipid metabolism. Nowadays, the range of BAs actions has expanded to glucose, fatty acid, triglyceride, and whole-body energy balance. Their implications in pathology go beyond gallbladder disease, reaching obesity, insulin resistance, and cardiovascular disease1.In a further expansion of this research, Semova et al2 describe in this issue of Circulation how in the liver insulin decreases the relative amount of 12α-hydroxylated BAs (12 HBAs), leading to reduced cholesterol absorption. The authors go on to propose that states of insulin deficiency such as type 1 diabetes (T1D) are characterized by increased cholesterol absorption leading to hypercholesterolemia, which could be reversed by the blockade of intestinal cholesterol absorption, for example, with ezetimibe. Although their findings are well substantiated by mechanistic experiments in murine models, their clinical projections require a closer look because, as the authors suggest, they could substantiate an eventual shift for first-line cholesterol-lowering therapy in T1D, from cholesterol synthesis inhibitors (statins) to cholesterol absorption inhibitors (ezetimibe).From a physiological perspective, cholesterol absorption may be considered an excessively complex process for a molecule that is not even a nutrient. In fact, teleologically, it appears more logical for higher mammals to have mechanisms to prevent dietary cholesterol absorption because it can be synthesized by all cells. Moreover, plant sterols are not absorbed but excreted by the intestine by ABCG5/8 (ATP binding cassette proteins G5/G8), preventing sitosterolemia, an atherosclerotic disease caused by sterols tissue deposit.3The answer to this apparent paradox may be the one proposed by Semova et al that cholesterol synthesis is a notoriously complex and energy-demanding process, involving the concerted action of >30 enzymes in the endoplasmic reticulum. Thus, to fit into energy-saving pressures, animals might have adapted to absorb dietary cholesterol at the risk of building up excessive tissue cholesterol over a lifetime. Beyond these putative physiological roles, intestinal cholesterol absorption is an important determinant of circulating cholesterol levels and thus has an impact on cardiovascular health. Although the liver is central in cholesterol homeostasis, being the main site for circulating cholesterol synthesis and responsible for cholesterol elimination by its secretion into the bile, intestinal absorption is also a physiological regulator of the cholesterol body pool.4Because of its extreme hydrophobicity, cholesterol must be solubilized in micelles enriched in BAs and phospholipids to be absorbed. Fractional cholesterol absorption in humans is highly variable, ranging from ≈30% to 80%. In the apical membrane of small intestine enterocytes (mainly proximal jejunum in humans), free cholesterol is bound by NPC1L1 (Niemann-Pick C1-like 1 protein) and internalized by clathrin-AP2-mediated vesicular endocytosis. Cholesterol is then esterified and ultimately transported via lymphatics as chylomicrons. NPC1L1 gene variants explain cholesterol absorption efficiency in humans attributable to differential subcellular localization, recycling, stability, and glycosylation of NPC1L1,5 and NPC1L1 is the molecular target of ezetimibe.6 When mobilized, the hepatic cholesterol pool is incorporated into nascent very-low-density lipoprotein, secreted into the bile through ABCG5/G8, or enzymatically converted into BAs.7Multiple enzymes in the endoplasmic reticulum, mitochondria, cytosol, and peroxisomes of hepatocytes are involved in the conversion of cholesterol into cholic acid (CA) and chenodeoxycholic acid, the 2 major primary BAs in humans, and CA and muricholic acid in rodents. In the distal ileum, 95% of BAs are reabsorbed to the portal circulation and returned to the liver. The remaining primary BAs reach the large intestine to be converted into the secondary BAs deoxycholic and lithocholic acids (derived from CA and chenodeoxycholic acid, respectively) by colonic bacteria.1Cholesterol 7-α hydroxylase (CYP7A1) catalyzes the rate-limiting reaction in the classical BA synthesis pathway. CYP7A1 transcription is positively and negatively regulated by nuclear receptors liver X receptor and farnesoid X receptor, respectively. Liver X receptor is activated by oxysterols, whereas farnesoid X receptor is activated by primary BAs, mainly CA. In addition, in enterocytes, farnesoid X receptor increases fibroblast growth factor (FGF) 15/19, which circulates to the liver to lower CYP7A1 transcription and thus decrease BA synthesis rate (Figure). This enterohepatic transcriptional network ensures a stable BA pool size of 2 to 4 g in humans.1Download figureDownload PowerPointFigure. Cholesterol regulation by BAs and insulin in the liver and small intestine and its changes in T1D. In the physiological state (left), hepatic cholesterol is mobilized to very-low-density lipoprotein secretion (not shown), direct secretion into the bile by ABCG5/G8 (ATP binding cassette proteins G5/G8; not shown), or biotransformation into bile acids (BAs). A small amount is also converted into oxysterols, which are the ligands for the nuclear receptor liver X receptor (LXR). A decrease in cholesterol concentration in the endoplasmic reticulum membrane leads to activation of SREBP2 (sterol regulatory element-binding protein 2) to maintain hepatic and whole-body cholesterol balance. BAs are synthesized by classic and alternative pathways, controlled by cholesterol 7-α hydroxylase (CYP7A1) and cytochrome P450c27 (CYP27) activities, respectively. CYP7A1 is transcriptionally regulated by LXR and farnesoid X receptor (FXR), activated by oxysterols and BAs, respectively. Insulin signaling determines AKT-mediated FoxO1; phosphorylation also regulates CYP8B1, which catalyzes the formation of cholic acid (CA) and thus controls the ratio between CA and chenodeoxycholic acid (CDCA). In the intestine, CA activates FXR, resulting in the transcriptional activation of fibroblast growth factor (FGF) 15/19, which reaches the liver via portal circulation and inhibits CYP7A1 transcription, closing a negative feedback loop. Increased levels of luminal CA lead to the formation of more hydrophobic intestinal micelles that favor intestinal cholesterol absorption via NPC1L1 (Niemann-Pick C1-like 1 protein). In the intestine, insulin likely promotes cholesterol absorption by scavenger receptor class B type I (SR-BI), thus opposing the actions of insulin in the liver, which prevents cholesterol absorption by BAs modifications. Absolute insulin-deficient action that occurs in type 1 diabetes (T1D; right) leads to overactivation of FoxO1, elevated gluconeogenesis, and excessive production of CA in the liver. In the intestine, increased CA/CDCA ratio favors cholesterol absorption, which ultimately leads to higher circulating low-density lipoprotein cholesterol and increased atherosclerosis risk. The findings of Semova et al2 are highlighted in blue. IR indicates insulin resistance.Another key regulatory point in the BA pathway is catalyzed by sterol 12α-hydroxylase, also known as CYP8B1, generating 12 HBA. The ratio of 12 HBA to non-12 HBA (in humans, this is essentially the ratio of CA to chenodeoxycholic acid) is a determinant of cholesterol absorption efficiency in the intestine.8 BA synthesis is also subjected to circadian and nutritional cycles. CYP7A1 gene expression and BA synthesis peak during the day in humans and during the night in rodents, and fasting decreases CYP7A1 gene expression but increases CYP8B1 levels.9 It is notable that hepatic cholesterol and BA synthetic activities are asynchronous because cholesterol synthesis peaks at 4 am in humans.10 Therefore, insulin signaling could be the underlying link between feeding and cholesterol and BA cycles.On feeding, insulin signaling in the liver leads to AKT-dependent phosphorylation and nuclear exclusion of the transcription factor Forkhead box O1 (FoxO1). This results in the inactivation of gluconeogenesis but also in the reduction of CYP8B1 at the transcriptional level, leading to decreased 12 HBA/non-12 HBA ratio and thus lowering intestinal cholesterol absorption rates. Small changes in cholesterol concentration in the endoplasmic reticulum of hepatocytes are sensed by the Insig/SCAP (SREBP cleavage-activating protein)/SREBP2 (sterol regulatory element-binding protein 2) system, turning the cholesterol synthesis machinery on restoring hepatocyte (and whole-body) cholesterol balance (Figure). This model is congruent with the finding of increased hepatic and circulating cholesterol in hepatocyte-specific FoxO1-deficient mice.11 Direct evidence of the role of 12 HBAs in atherosclerosis is provided by the observation that CYP8B1 gene deletion in apolipoprotein E–deficient mice decreases blood total cholesterol ≈40% to 50% and the extent of aortic atherosclerosis by 50% compared with pure apolipoprotein E–deficient mice.12Semova et al show that hepatocyte-specific insulin receptor-deficient mice (LIRKO) develop the opposite phenotype to FoxO1 hepatic deficiency, that is, increased CYP8B1 levels, attributable to derepressed FoxO1 transcriptional activity and thus increased 12 HBA contribution to the BA pool. This leads to lower hepatic cholesterol synthesis rates attributable to increased cholesterol intestinal absorption and ultimately higher circulating cholesterol. Two experimental systems closer to T1D (streptozotocin and Akita mice) showed that whole-body insulin deficiency essentially replicates the effects of hepatic insulin receptor deficiency on cholesterol metabolism and that either CYP8B1 knockdown or ezetimibe was sufficient to revert hypercholesterolemia in these animals (Figure). The authors also evaluated cholesterol status in a small cohort of patients with T1D, confirming increased cholesterol absorption using a stable isotope method and lower cholesterol synthesis rates by quantifying lathosterol in blood. As expected, ezetimibe ameliorated these parameters in this cohort of patients.2From a clinical perspective, macrovascular disease continues to be a major burden for patients with diabetes, and cholesterol-lowering therapy has been shown to decrease both events and mortality.13 It is important to note that although most prospective evidence derives from studies in patients with type 2 diabetes, small clinical trials and observational evidence support the efficacy and safety of cholesterol-lowering therapy in patients with T1D.14 After lifestyle modifications, inhibition of cholesterol synthesis with statins is the first-line approach to decrease low-density lipoprotein cholesterol in patients with or without diabetes. Addition of or replacement with second-line drugs such as ezetimibe is reserved for cases of inability to reach low-density lipoprotein cholesterol target levels.15 The observation of increased intestinal cholesterol absorption rates in patients with T1D provides pathophysiological support for the use of ezetimibe but does not imply that this drug should be elevated to first-line therapy and replace statins. The reason is that data to demonstrate the benefit of ezetimibe-to reduce cardiovascular events in patients with T1D are lacking.Last, the article by Semova et al offers the opportunity to give a closer look at the concept of personalized medicine. Medicine in some ways has always been personalized in the sense that physicians have looked for the best and safest integral treatment for each individual patient. The current use of the concept is focused on the individualized design of therapeutic plans based on the biological (and we add psychological, cultural, and economic) particularities of individual patients. Although market-driven personalized medicine initiatives are grounded mostly on genetic testing and artificial intelligence–based recommendations, Semova et al show that complex pathophysiological considerations must be added to reach the goal of truly personalized medicine.Article InformationSources of FundingThis work was funded by Fondecyt 1181214 and 1221146 to V.C.Disclosures None.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 985.https://www.ahajournals.org/journal/circCorrespondence to: Víctor Cortés, MD, PhD, Av Libertador Bernardo O’Higgins 340, Santiago 8330024, Chile. Email [email protected]clReferences1. Cortés VA, Barrera F, Nervi F. 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Lipid management for cardiovascular risk reduction in type 1 diabetes.Curr Opin Endocrinol Diabetes Obes. 2020; 27:207–214. doi: 10.1097/MED.0000000000000551CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesInsulin Prevents Hypercholesterolemia by Suppressing 12α-Hydroxylated Bile AcidsIvana Semova, et al. Circulation. 2022;145:969-982 March 29, 2022Vol 145, Issue 13 Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.058883PMID: 35344404 Originally publishedMarch 28, 2022 KeywordsatherosclerosischolesterolinsulinEditorialsbile aciddiabetesPDF download Advertisement SubjectsBasic Science ResearchLipids and CholesterolMetabolism