Bile acids play a critical role in the regulation of glucose, lipid and energy metabolisms by activating the nuclear bile acid receptor farnesoid X receptor (FXR) and membrane G protein-coupled bile acid receptor-1 (aka takeda G protein couple receptor 5, TGR5) signaling. Paradoxical roles of FXR in the regulation of glucose and lipid metabolism and metabolic disorder have been reported recently. The activation or inhibition of intestinal FXR signaling has been shown to improve insulin and glucose sensitivity and energy metabolism to prevent diabetes, obesity and non-alcoholic fatty liver disease (NAFLD). TGR5 has an anti-inflammatory function in the intestine and stimulates glucagon-like peptide-1 (GLP-1) secretion in the intestine to stimulate insulin secretion from the pancreas. The role of TGR5 in metabolism and metabolic regulation is not clear and warrants further study. FXR and TGR5 are co-expressed in the ileum and colon. These 2 bile acid-activated receptors may cooperate to stimulate GLP-1 secretion and improve hepatic metabolism. FXR and TGR5 dual agonists may have therapeutic potential for treating diabetes and NAFLD.

1.
Li T, Chiang JY: Bile acid signaling in metabolic disease and drug therapy. Pharmacol Rev 2014;66:948-983.
2.
Chiang JY: Bile acids: regulation of synthesis. J Lipid Res 2009;50:1955-1966.
3.
Inagaki T, et al: Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci U S A 2006;103:3920-3925.
4.
Jones BV, et al: Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome. Proc Natl Acad Sci U S A 2008;105:13580-13585.
5.
Aron-Wisnewsky J, et al: Gut microbiota and non-alcoholic fatty liver disease: new insights. Clin Microbiol Infect 2013;19:338-348.
6.
Kakiyama G, et al: Modulation of the fecal bile acid profile by gut microbiota in cirrhosis. J Hepatol 2013;58:949-955.
7.
Joyce SA, Gahan CG: The gut microbiota and the metabolic health of the host. Curr Opin Gastroenterol 2014;30:120-7.
8.
Ridlon JM, et al: Bile acids and the gut microbiome. Curr Opin Gastroenterol 2014;30:332-338.
9.
Chiang JY, Miller WF, Lin GM: Regulation of cholesterol 7 alpha-hydroxylase in the liver. Purification of cholesterol 7 alpha-hydroxylase and the immunochemical evidence for the induction of cholesterol 7 alpha-hydroxylase by cholestyramine and circadian rhythm. J Biol Chem 1990;265:3889-3897.
10.
Ferrell JM, Chiang JY: Circadian rhythms in liver metabolism and disease. Acta Pharm Sin B 2015;5:113-122.
11.
Galman C, Angelin B, Rudling M: Bile acid synthesis in humans has a rapid diurnal variation that is asynchronous with cholesterol synthesis. Gastroenterology 2005;129:1445-1453.
12.
Lundasen T, et al: Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man. J Intern Med 2006;260:530-536.
13.
Asher G, Schibler U: Crosstalk between components of circadian and metabolic cycles in mammals. Cell Metab 2011;13:125-137.
14.
Vollmers C, et al: Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression. Proc Natl Acad Sci U S A 2009;106:21453-21458.
15.
Hatori M, et al: Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metab 2012;15:848-860.
16.
Pathak P, Li T, Chiang JY: Retinoic acid-related orphan receptor α regulates diurnal rhythm and fasting induction of sterol 12α-hydroxylase in bile acid synthesis. J Biol Chem 2013;288:37154-37165.
17.
Ferrell JM, Chiang JY: Short-term circadian disruption impairs bile acid and lipid homeostasis in mice. Cell Mol Gastroenterol Hepatol 2015;1:664-677.
18.
Watanabe M, et al: Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest 2004;113:1408-1418.
19.
Zhang Y, et al: Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci U S A 2006;103:1006-1011.
20.
Prawitt J, et al: Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity. Diabetes 2011;60:1861-1871.
21.
Watanabe M, et al: Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure. J Biol Chem 2011;286:26913-26920.
22.
Li F, et al: Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat Commun 2013;4:2384.
23.
Jiang C, et al: Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest 2015;125:386-402.
24.
Jiang C, et al: Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat Commun 2015;6:10166.
25.
Fang S, et al: Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 2015;21:159-165.
26.
Maruyama T, et al: Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun 2002;298:714-719.
27.
Kawamata Y, et al: A G protein-coupled receptor responsive to bile acids. J Biol Chem 2003;278:9435-9440.
28.
Keitel V, et al: Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun 2008;372:78-84.
29.
Keitel V, et al: The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology 2007;45:695-704.
30.
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;329:386-390.
31.
Thomas C, et al: TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 2009;10:167-177.
32.
Mojsov S, et al: Preproglucagon gene expression in pancreas and intestine diversifies at the level of post-translational processing. J Biol Chem 1986;261:11880-11889.
33.
Ding X, et al: Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology 2006;43:173-181.
34.
Watanabe M, et al: Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006;439:484-489.
35.
Sayin SI, 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;17:225-235.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.