III. Bile acids and nuclear receptors

2003 ◽  
Vol 284 (3) ◽  
pp. G349-G356 ◽  
Author(s):  
John Y. L. Chiang
Keyword(s):  
Bile Acid ◽  
Cardiovascular Diseases ◽  
Bile Acids ◽  
Nuclear Receptors ◽  
Molecular Mechanisms ◽  
Genetic Manipulation ◽  
Regulatory Genes ◽  
Cholesterol Homeostasis ◽  
Physiological Pathways ◽  
Bile Acid Receptor

Bile acids are physiological detergents that facilitate excretion, absorption, and transport of fats and sterols in the intestine and liver. Recent studies reveal that bile acids also are signaling molecules that activate several nuclear receptors and regulate many physiological pathways and processes to maintain bile acid and cholesterol homeostasis. Mutations of the principal regulatory genes in bile acid biosynthetic pathways have recently been identified in human patients with hepatobiliary and cardiovascular diseases. Genetic manipulation of key regulatory genes and bile acid receptor genes in mice have been obtained. These advances have greatly improved our understanding of the molecular mechanisms underlying complex liver physiology but also raise many questions and controversies to be resolved. These developments will lead to early diagnosis and discovery of drugs for treatment of liver and cardiovascular diseases.

scholarly journals Colesevelam suppresses hepatic glycogenolysis by TGR5-mediated induction of GLP-1 action in DIO mice

2013 ◽  
Vol 304 (4) ◽  
pp. G371-G380 ◽  
Author(s):  
Matthew J. Potthoff ◽  
Austin Potts ◽  
Tianteng He ◽  
João A. G. Duarte ◽  
Ronald Taussig ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Molecular Mechanisms ◽  
Cholesterol Metabolism ◽  
Farnesoid X Receptor ◽  
In Vitro Assays ◽  
Hepatic Glycogen ◽  
Acid Activation ◽  
Acid Receptor ◽  
Bile Acid Receptor

Bile acid sequestrants are nonabsorbable resins designed to treat hypercholesterolemia by preventing ileal uptake of bile acids, thus increasing catabolism of cholesterol into bile acids. However, sequestrants also improve hyperglycemia and hyperinsulinemia through less characterized metabolic and molecular mechanisms. Here, we demonstrate that the bile acid sequestrant, colesevelam, significantly reduced hepatic glucose production by suppressing hepatic glycogenolysis in diet-induced obese mice and that this was partially mediated by activation of the G protein-coupled bile acid receptor TGR5 and glucagon-like peptide-1 (GLP-1) release. A GLP-1 receptor antagonist blocked suppression of hepatic glycogenolysis and blunted but did not eliminate the effect of colesevelam on glycemia. The ability of colesevelam to induce GLP-1, lower glycemia, and spare hepatic glycogen content was compromised in mice lacking TGR5. In vitro assays revealed that bile acid activation of TGR5 initiates a prolonged cAMP signaling cascade and that this signaling was maintained even when the bile acid was complexed to colesevelam. Intestinal TGR5 was most abundantly expressed in the colon, and rectal administration of a colesevelam/bile acid complex was sufficient to induce portal GLP-1 concentration but did not activate the nuclear bile acid receptor farnesoid X receptor (FXR). The beneficial effects of colesevelam on cholesterol metabolism were mediated by FXR and were independent of TGR5/GLP-1. We conclude that colesevelam administration functions through a dual mechanism, which includes TGR5/GLP-1-dependent suppression of hepatic glycogenolysis and FXR-dependent cholesterol reduction.

scholarly journals Role of an mSin3A-Swi/Snf Chromatin Remodeling Complex in the Feedback Repression of Bile Acid Biosynthesis by SHP

2004 ◽  
Vol 24 (17) ◽  
pp. 7707-7719 ◽  
Author(s):  
Jongsook Kim Kemper ◽  
Hwajin Kim ◽  
Ji Miao ◽  
Sonali Bhalla ◽  
Yangjin Bae
Keyword(s):  
Bile Acid ◽  
Nuclear Receptors ◽  
Chromatin Remodeling ◽  
Molecular Mechanisms ◽  
Cholesterol Metabolism ◽  
Direct Interaction ◽  
Dominant Negative ◽  
Cholesterol Homeostasis ◽  
Orphan Receptor ◽  
Interfering Rna

ABSTRACT The orphan receptor SHP interacts with many nuclear receptors and inhibits their transcriptional activities. SHP is central to feedback repression of cholesterol 7α hydroxylase gene (CYP7A1) expression by bile acids, which is critical for maintaining cholesterol homeostasis. Using CYP7A1 as a model system, we studied the molecular mechanisms of SHP repression at the level of native chromatin. Chromatin immunoprecipitation studies showed that mSin3A and a Swi/Snf complex containing Brm as a central ATPase were recruited to the promoter. This recruitment was associated with chromatin remodeling after bile acid treatment that was blunted by inhibition of the endogenous Swi/Snf function by dominant-negative ATPase mutants. Biochemical studies indicated that SHP was associated with the mSin3A-Swi/Snf complex by direct interaction with Brm and mSin3A through its repression domain. Expression of Brm, but not an ATPase mutant, inhibited CYP7A1 promoter activity and further enhanced SHP-mediated repression. Bile acid-induced recruitment of mSin3A/Brm, chromatin remodeling, and concomitant repression of endogenous CYP7A1 expression were impaired when SHP expression was inhibited by SHP small interfering RNA. Our results suggest that SHP mediates recruitment of mSin3A-Swi/Snf to the CYP7A1 promoter, resulting in chromatin remodeling and gene repression, which may also be a mechanism for the repression by SHP of genes activated by many nuclear receptors. Our study establishes the first link between a Swi/Snf complex and regulation of cholesterol metabolism.

scholarly journals Regulation of Bile Acid and Cholesterol Metabolism by PPARs

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-15 ◽  
Author(s):  
Tiangang Li ◽  
John Y. L. Chiang
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Cholesterol Metabolism ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Cholesterol Homeostasis ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Major Pathway ◽  
Therapeutic Implications

Bile acids are amphipathic molecules synthesized from cholesterol in the liver. Bile acid synthesis is a major pathway for hepatic cholesterol catabolism. Bile acid synthesis generates bile flow which is important for biliary secretion of free cholesterol, endogenous metabolites, and xenobiotics. Bile acids are biological detergents that facilitate intestinal absorption of lipids and fat-soluble vitamins. Recent studies suggest that bile acids are important metabolic regulators of lipid, glucose, and energy homeostasis. Agonists of peroxisome proliferator-activated receptors (PPARα, PPARγ, PPARδ) regulate lipoprotein metabolism, fatty acid oxidation, glucose homeostasis and inflammation, and therefore are used as anti-diabetic drugs for treatment of dyslipidemia and insulin insistence. Recent studies have shown that activation of PPARαalters bile acid synthesis, conjugation, and transport, and also cholesterol synthesis, absorption and reverse cholesterol transport. This review will focus on the roles of PPARs in the regulation of pathways in bile acid and cholesterol homeostasis, and the therapeutic implications of using PPAR agonists for the treatment of metabolic syndrome.

scholarly journals Recent advances in understanding bile acid homeostasis

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2029 ◽  
Author(s):  
John YL Chiang
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Farnesoid X Receptor ◽  
Recent Advances ◽  
Bile Acid Pool Size ◽  
Bile Acid Receptor ◽  
Acid Toxicity ◽  
G Protein Coupled

Bile acids are derived from cholesterol to facilitate intestinal nutrient absorption and biliary secretion of cholesterol. Recent studies have identified bile acids as signaling molecules that activate nuclear farnesoid X receptor (FXR) and membrane G protein-coupled bile acid receptor-1 (Gpbar-1, also known as TGR5) to maintain metabolic homeostasis and protect liver and other tissues and cells from bile acid toxicity. Bile acid homeostasis is regulated by a complex mechanism of feedback and feedforward regulation that is not completely understood. This review will cover recent advances in bile acid signaling and emerging concepts about the classic and alternative bile acid synthesis pathway, bile acid composition and bile acid pool size, and intestinal bile acid signaling and gut microbiome in regulation of bile acid homeostasis.

scholarly journals Downregulation of CTRP-3 by Weight Loss In Vivo and by Bile Acids and Incretins in Adipocytes In Vitro

2020 ◽  
Vol 21 (21) ◽  
pp. 8168
Author(s):  
Andreas Schmid ◽  
Jonas Gehl ◽  
Miriam Thomalla ◽  
Alexandra Hochberg ◽  
Anja Kreiß ◽  
...  
Keyword(s):  
Weight Loss ◽  
Bile Acid ◽  
Bile Acids ◽  
Serum Levels ◽  
Receptor Expression ◽  
Low Calorie Diet ◽  
Calorie Diet ◽  
Bile Acid Receptor

The adipokine CTRP-3 (C1q/TNF-related protein-3) exerts anti-inflammatory and anti-diabetic effects. Its regulation in obesity and during weight loss is unknown. Serum and adipose tissue (AT) samples were obtained from patients (n = 179) undergoing bariatric surgery (BS). Moreover, patients (n = 131) participating in a low-calorie diet (LCD) program were studied. CTRP 3 levels were quantified by ELISA and mRNA expression was analyzed in AT and in 3T3-L1 adipocytes treated with bile acids and incretins. There was a persistent downregulation of CTRP-3 serum levels during weight loss. CTRP-3 expression was higher in subcutaneous than in visceral AT and serum levels of CTRP-3 were positively related to AT expression levels. A rapid decrease of circulating CTRP-3 was observed immediately upon BS, suggesting weight loss-independent regulatory mechanisms. Adipocytes CTRP-3 expression was inhibited by primary bile acid species and GLP 1. Adipocyte-specific CTRP-3 deficiency increased bile acid receptor expression. Circulating CTRP-3 levels are downregulated during weight loss, with a considerable decline occurring immediately upon BS. Mechanisms dependent and independent of weight loss cause the post-surgical decline of CTRP-3. The data strongly argue for regulatory interrelations of CTRP-3 with bile acids and incretin system.

Sa1444 Bile Acids Cause Relaxation of Human Gallbladder Through G Protein-Coupled Bile Acid Receptor

2012 ◽  
Vol 142 (5) ◽  
pp. S-307
Author(s):  
Ming-Che Lee ◽  
Ying-Chin Yang ◽  
Yen-Cheng Chen ◽  
Shih-Che Huang
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
G Protein ◽  
Human Gallbladder ◽  
Acid Receptor ◽  
Bile Acid Receptor ◽  
G Protein Coupled

scholarly journals Deoxycholic Acid Could Induce Apoptosis and Trigger Gastric Carcinogenesis on Gastric Epithelial Cells by Quantitative Proteomic Analysis

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Yanyan Shi ◽  
Ying Wei ◽  
Ting Zhang ◽  
Jing Zhang ◽  
Ye Wang ◽  
...  
Keyword(s):  
Bile Acid ◽  
Gastric Mucosa ◽  
Bile Acids ◽  
Molecular Mechanisms ◽  
Deoxycholic Acid ◽  
Bile Reflux ◽  
Epithelial Cell Line ◽  
Gastric Mucosal Lesions ◽  
Tandem Mass Spectrometric ◽  
String Programs

Background.Pathologic duodenogastric reflux can induce or aggravate gastritis because of the presence of bile acids. Bile reflux has been generally considered to be associated with intestinal metaplasia and gastric cancer. However, the pathogenic mechanisms of the effects of bile acids on gastric mucosa are still unknown.Methods.To explore the mechanisms by which bile acids induce gastric mucosal lesions, we examined cell apoptosis in the gastric epithelial cell line GES-1 and investigated the changes in protein profiles of GES-1 cells in response to a bile acid deoxycholic acid using a proteomics approach. Changes in the profiles of the differently expressed proteins were analyzed using the DAVID and STRING programs.Results.We found apoptosis was significantly induced in GES-1 cells by deoxycholic acid. Using liquid chromatographic/tandem mass spectrometric (LC-MS/MS) methods, 134 upregulated proteins and 214 downregulated proteins were identified in the bile acid treated GES-1 cells. Bioinformatics analysis revealed the interactions and signaling networks of these differentially expressed proteins.Conclusion.These findings may improve the understanding of the molecular mechanisms underlying the pathogenicity of bile acids on gastric mucosa.

scholarly journals Bile acid detoxifying enzymes limit susceptibility to liver fibrosis in female SHRSP5/Dmcr rats fed with a high-fat-cholesterol diet

2017 ◽  
Author(s):  
Husna Yetti ◽  
Hisao Naito ◽  
Yuan Yuan ◽  
Xiaofang Jia ◽  
Yumi Hayashi ◽  
...  
Keyword(s):  
Bile Acid ◽  
Nuclear Receptors ◽  
Molecular Mechanisms ◽  
Pregnane X Receptor ◽  
Mature Female ◽  
Farnesoid X Receptor ◽  
Detoxification Enzymes ◽  
Cytochrome P450 Enzymes ◽  
High Fat ◽  
Expression Levels

During middle age, women are less susceptible to nonalcoholic steatohepatitis (NASH) than men. Thus, we investigated the underlying molecular mechanisms behind these sexual differences using an established rat model of NASH. Mature female and male stroke-prone spontaneously hypertensive 5/Dmcr rats were fed control or high-fat-cholesterol (HFC) diets for 2, 8, and 14 weeks. Although HFC-induced hepatic fibrosis was markedly less severe in females than in males, only minor gender differences were observed in expression levels of cytochrome P450 enzymes (CYP)7A1, CYP8B1 CYP27A1, and CYP7B1, and multidrug resistance-associated protein 3, and bile salt export pump, which are involved in fibrosis-related bile acid (BA) kinetics. However, the BA detoxification-related enzymes UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) 2A1, and the nuclear receptors constitutive androstene receptor (CAR) and pregnane X receptor (PXR), were strongly suppressed in HFC fed males, and were only slightly changed in HFC-diet fed females. Expression levels of the farnesoid X receptor and its small heterodimer partner were similarly regulated in a gender-dependent fashion following HFC feeding. Hence, the pronounced female resistance to HFC-induced liver damage likely reflects sustained expression of the nuclear receptors CAR and PXR and the BA detoxification enzymes UGT and SULT.

scholarly journals Structural basis of bile acid receptor activation and Gs coupling

2020 ◽  
Author(s):  
Fan Yang ◽  
Chunyou Mao ◽  
Lulu Guo ◽  
Jingyu Lin ◽  
Qianqian Ming ◽  
...  
Keyword(s):  
Bile Acid ◽  
Ligand Binding ◽  
Bile Acids ◽  
G Protein ◽  
Binding Pocket ◽  
Receptor Activation ◽  
Structural Features ◽  
Ligand Binding Pocket ◽  
Bile Acid Receptor ◽  
Key Residues

AbstractG protein-coupled bile acid receptor (GPBAR) is a membrane receptor that senses bile acids to regulate diverse functions through Gs activation. Here, we report the cryo-EM structures of GPBAR–Gs complexes stabilized by either high-affinity P395 or the semisynthesized bile acid derivative INT-777 at 3-Å resolution. These structures revealed a large oval-shaped ligand pocket with several sporadic polar groups to accommodate the amphipathic cholic core of bile acids. A fingerprint of key residues recognizing diverse bile acids in the orthosteric site, a putative second bile acid binding site with allosteric properties and structural features contributing to bias property were identified through structural analysis and mutagenesis studies. Moreover, structural comparison of GPBAR with other GPCRs uncovered an atypical mode of receptor activation and G-protein– coupling, featuring a different set of key residues connecting the ligand binding pocket to the Gs coupling site, and a specific interaction motif localized in intracellular loop 3. Overall, our study not only provides unique structural features of GPBAR in bile acid recognition, allosteric effects and biased signaling, but also suggests that distinct allosteric connecting mechanisms between the ligand binding pocket and the G protein binding site exist in the GPCR superfamily.

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