A new life for bile acids
Authors: Peter L.M. Jansen
Journal: Journal of Hepatology (2010)

COMMENTARY ON: TGR5-mediated bile acid sensing controls glucose homeostasis.Thomas C, Gioiello A, Noriega L, Strehle A, Oury J, Rizzo G, Macchiarulo A, Yamamoto H, Mataki C, Pruzanski M, Pellicciari R, Auwerx J, Schoonjans K. Cell Metab 2009;10(3):167–177.Copyright (2009), with permission from Elsevier.Abstract: TGR5 is a G protein-coupled receptor expressed in brown adipose tissue and muscle, where its activation by bile acids triggers an increase in energy expenditure and attenuates diet-induced obesity. Using a combination of pharmacological and genetic gain- and loss-of-function studies in vivo, we show here that TGR5 signaling induces intestinal glucagon-like peptide-1 (GLP-1) release, leading to improved liver and pancreatic function and enhanced glucose tolerance in obese mice. In addition, we show that the induction of GLP-1 release in enteroendocrine cells by 6α-ethyl-23(S)-methyl-cholic acid (EMCA, INT-777), a specific TGR5 agonist, is linked to an increase of the intracellular ATP/ADP ratio and a subsequent rise in intracellular calcium mobilization. Altogether, these data show that the TGR5 signaling pathway is critical in regulating intestinal GLP-1 secretion in vivo, and suggest that pharmacological targeting of TGR5 may constitute a promising incretin-based strategy for the treatment of diabesity and associated metabolic disorders. COMMENTARY ON: TGR5-mediated bile acid sensing controls glucose homeostasis. Thomas C, Gioiello A, Noriega L, Strehle A, Oury J, Rizzo G, Macchiarulo A, Yamamoto H, Mataki C, Pruzanski M, Pellicciari R, Auwerx J, Schoonjans K. Cell Metab 2009;10(3):167–177. Copyright (2009), with permission from Elsevier. Abstract: TGR5 is a G protein-coupled receptor expressed in brown adipose tissue and muscle, where its activation by bile acids triggers an increase in energy expenditure and attenuates diet-induced obesity. Using a combination of pharmacological and genetic gain- and loss-of-function studies in vivo, we show here that TGR5 signaling induces intestinal glucagon-like peptide-1 (GLP-1) release, leading to improved liver and pancreatic function and enhanced glucose tolerance in obese mice. In addition, we show that the induction of GLP-1 release in enteroendocrine cells by 6α-ethyl-23(S)-methyl-cholic acid (EMCA, INT-777), a specific TGR5 agonist, is linked to an increase of the intracellular ATP/ADP ratio and a subsequent rise in intracellular calcium mobilization. Altogether, these data show that the TGR5 signaling pathway is critical in regulating intestinal GLP-1 secretion in vivo, and suggest that pharmacological targeting of TGR5 may constitute a promising incretin-based strategy for the treatment of diabesity and associated metabolic disorders. "The room is empty; this must be a bile acid meeting"– quote by eminent hepatologist. Bile acids have long been considered as nothing more than emulsifiers of lipids. As such, bile acids could excite few hepatologists. However, it now appears that bile acids have important and intriguing signalling functions and researchers from many corners including the industry have come to see what is going on. The story begins in the early 1980s when Bert O'Malley, Ron Evans, Pierre Chambon, and others first purified and later cloned a number of hormone receptors [1Hughes M.R. Compton J.G. Schrader W.T. O'Malley B.W. 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Not only FXR but also the pregnane X-receptor (PXR), the constitutive androstane receptor (CAR), and the vitamin D receptor (VDR) are activated by primary (FXR) and secondary bile acids (PXR, CAR, VDR) with effects on the expression of enzymes of the cytochrome P-450 family (CYP3A4, CYP2B6, CYP2C9), UDP-glucuronosyltransferase (UGT 1A1), glutathionetransferase (GSTA1/A2), ABC transporters (ABCB11, ABCG2, MDR1, MRP2, MRP3, MRP4), and other transport proteins such as the organic anionic transport proteins OATP1B1, OATP1B3, OATP2B1, and the organic solute transporter OSTα/β [17Staudinger J.L. Goodwin B. Jones S.A. et al.The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.Proc Natl Acad Sci USA. 2001; 98: 3369-3374Crossref PubMed Scopus (1163) Google Scholar, 18Makishima M. Lu T.T. Xie W. et al.Vitamin D receptor as an intestinal bile acid sensor.Science. 2002; 296: 1313-1316Crossref PubMed Scopus (995) Google Scholar, 19Kohle C. Bock K.W. 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The GPCRs are membrane surface receptors that are activated by external ligands [[22]Takeda S. Kadowaki S. Haga T. Takaesu H. Mitaku S. Identification of G protein-coupled receptor genes from the human genome sequence.FEBS Lett. 2002; 520: 97-101Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar]. GPCRs are members of a very large protein superfamily. These proteins are evolutionarily well conserved and comprise 40–50 taste and 500–1000 odorant receptors, including receptors for pheromones. Maruymama and Kawamata discovered that bile acids activate a member of the GPCR family [23Maruyama T. Miyamoto Y. Nakamura T. et al.Identification of membrane-type receptor for bile acids (M-BAR).Biochem Biophys Res Commun. 2002; 298: 714-719Crossref PubMed Scopus (754) Google Scholar, 24Kawamata Y. Fujii R. Hosoya M. et al.A G protein-coupled receptor responsive to bile acids.J Biol Chem. 2003; 278: 9435-9440Crossref PubMed Scopus (1156) Google Scholar]. This member was first called M-BAR or BG37 but now has adopted the name TGR5. TGR5 is expressed in placenta, spleen, lung, mammary gland, stomach, small intestine, colon, adipose tissue, liver, adrenal glands, kidney, skeletal muscle, and pituitary gland. Taurolithocholic acid, lithocholic acid, and deoxycholic acid have the greatest affinity for the receptor followed by chenodeoxycholic acid, cholic acid, and ursodeoxycholic acid. In a seminal paper in 2006 by the Auwerx group, it was shown that activation of TGR5 in brown adipocytes and human skeletal myocytes stimulates the thyroid hormone activating enzyme type 2 iodothyronine deiodinase in a cyclic-AMP-dependent way [[25]Watanabe M. Houten S.M. Mataki C. et al.Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation.Nature. 2006; 439: 484-489Crossref PubMed Scopus (1642) Google Scholar]. This stimulates mitochondrial activity and oxygen consumption and therefore energy expenditure. Recently, in 2009, the same group reported that TGR5 plays a critical role in the release of glucagon-like peptide-1, a hormone that controls glucose homeostasis [[26]Thomas C. Gioiello A. Noriega L. et al.TGR5-mediated bile acid sensing controls glucose homeostasis.Cell Metab. 2009; 10: 167-177Abstract Full Text Full Text PDF PubMed Scopus (1302) Google Scholar]. GLP-1 stimulates insulin production and secretion in pancreas beta cells and inhibits glucagon secretion. TGR5 research was greatly helped by the development of potent and selective agonists like the cholic acid derivative, 6α-ethyl-23(S)-methyl-cholic acid (INT-777) by Pellicciari [[27]Pellicciari R. Gioiello A. Macchiarulo A. et al.Discovery of 6alpha-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a potent and selective agonist for the TGR5 receptor, a novel target for diabesity.J Med Chem. 2009; 52: 7958-7961Crossref PubMed Scopus (206) Google Scholar]. This agent, that has no FXR activity, stimulates cAMP production, increases oxygen consumption, increases the ATP/ADP ratio, and activates cytochrome c oxidase in enteroendocrine L cells. Furthermore, INT-777 increases intracellular calcium levels and stimulates GLP-1 release. These effects disappear when TGR5 is knocked out by siRNA. Thomas et al. show that insulin sensitivity in TGR5 knock-out mice on a high fat diet (HFD) is abnormal while in TGR5-transgenic mice on HFD, glucose tolerance and insulin sensitivity is restored. Pancreas islets in wild-type and TGR5−/− mice on HFD, look hypertrophic and insulin-depleted while in TGR5-transgenic mice on HFD, the islets look normal and insulin-rich. This may be related to GLP-1 secretion, which is reduced in TGR5−/− and increased in TGR5-transgenic mice. These effects could be reproduced in pharmacologic intervention studies. Weight gain, liver fat mass and elevated transaminases were attenuated in mice on HFD receiving INT-777. INT-777 caused an increase in energy expenditure as measured by increased oxygen consumption, increased mitochondrial enzymes, and increased deiodinase gene expression and restored insulin sensitivity [[26]Thomas C. Gioiello A. Noriega L. et al.TGR5-mediated bile acid sensing controls glucose homeostasis.Cell Metab. 2009; 10: 167-177Abstract Full Text Full Text PDF PubMed Scopus (1302) Google Scholar]. These elegant studies show that activation of the bile acid receptor TGR5 has a profound and important effect on glucose homeostasis. In another recent study the Auwerx group extended these observations to humans. In this new study Patti et al. provide suggestive evidence that the improvement of glucose metabolism in obese patients after gastric bypass surgery may be due to slightly elevated bile acid levels, which may stimulate TGR5 [[28]Patti M.E. Houten S.M. Bianco A.C. et al.Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism.Obesity (Silver Spring). 2009; 17: 1671-1677Crossref PubMed Scopus (454) Google Scholar]. For hepatologists these studies are food for thought. Although metabolism in mice and men shows considerable differences (see for instance Schaap et al. [[29]Schaap F.G. van der Gaag N.A. Gouma D.J. Jansen P.L. High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis.Hepatology. 2009; 49: 1228-1235Crossref PubMed Scopus (221) Google Scholar]) one may ask if disturbances of bile acid signalling may contribute to the aetiology of non-alcoholic fatty liver disease. Would TGR5 agonists be helpful in the treatment of NAFLD or NASH? Perhaps yes, but the effect of INT-777 on thyroid metabolism may also be reason for concern as it may induce a state of (mild?) hyperthyroidism. What happens to cholestatic liver disease when bile acids are elevated? Would that lead to stimulation of TGR5 and an overstimulation of energy expenditure? Does this perhaps explain the weight loss often seen in these patients? Traditionally, this has been attributed to a lack of bile acids in the intestine for digestion of fat but the work of Johan Auwerx suggests an alternative view. Elevated bile acid levels may cause overstimulation of metabolism. Thus, treatment with ursodeoxycholic acid and/or bile acid sequestering agents may improve metabolism and counteract anorexia by lowering serum levels of primary bile acids in patients with cholestatic liver disease. The Authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.