The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation
Authors: Thijs W.H. Pols, Lilia G. Noriega, Mitsunori Nomura, Johan Auwerx, Kristina Schoonjans
Journal: Journal of Hepatology (2010)

Bile acids (BAs) are amphipathic molecules that facilitate the uptake of lipids, and their levels fluctuate in the intestine as well as in the blood circulation depending on food intake. Besides their role in dietary lipid absorption, bile acids function as signaling molecules capable to activate specific receptors. These BA receptors are not only important in the regulation of bile acid synthesis and their metabolism, but also regulate glucose homeostasis, lipid metabolism, and energy expenditure. These processes are important in diabetes and other facets of the metabolic syndrome, which represents a considerable increasing health burden. In addition to the function of the nuclear receptor FXRα in regulating local effects in the organs of the enterohepatic axis, increasing evidence points to a crucial role of the G-protein coupled receptor (GPCR) TGR5 in mediating systemic actions of BAs. Here we discuss the current knowledge on BA receptors, with a strong focus on the cell membrane receptor TGR5, which emerges as a valuable target for intervention in metabolic diseases. Bile acids (BAs) are amphipathic molecules that facilitate the uptake of lipids, and their levels fluctuate in the intestine as well as in the blood circulation depending on food intake. Besides their role in dietary lipid absorption, bile acids function as signaling molecules capable to activate specific receptors. These BA receptors are not only important in the regulation of bile acid synthesis and their metabolism, but also regulate glucose homeostasis, lipid metabolism, and energy expenditure. These processes are important in diabetes and other facets of the metabolic syndrome, which represents a considerable increasing health burden. In addition to the function of the nuclear receptor FXRα in regulating local effects in the organs of the enterohepatic axis, increasing evidence points to a crucial role of the G-protein coupled receptor (GPCR) TGR5 in mediating systemic actions of BAs. Here we discuss the current knowledge on BA receptors, with a strong focus on the cell membrane receptor TGR5, which emerges as a valuable target for intervention in metabolic diseases. Bile acids (BAs) are a component of bile, which also contains phosphatidylcholine, bilirubin, and cholesterol as main constituents. An important physiological role of BAs is to facilitate the uptake of lipids together with the fat-soluble vitamins A, D, E, and K from the intestine. BAs facilitate these absorptive processes through their detergent properties, which allow the emulsification of lipids [[1]Russell D.W. Fifty years of advances in bile acid synthesis and metabolism.J Lipid Res. 2009; 50: S120-S125Crossref PubMed Scopus (190) Google Scholar]. 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It should be noted that relative high concentrations of LCA (ranging from 30 to 100 μM) are needed to induce activation of VDR and PXR, which could raise questions about the physiological relevance of the direct regulation of their activity by BAs. BAs also modulate kinase-signaling pathways, such as the JNK pathway, which has been demonstrated to be involved in the downregulation of CYP7A1 [[47]Gupta S. Stravitz R.T. Dent P. Hylemon P.B. Down-regulation of cholesterol 7alpha-hydroxylase (CYP7A1) gene expression by bile acids in primary rat hepatocytes is mediated by the c-Jun N-terminal kinase pathway.J Biol Chem. 2001; 276: 15816-15822Crossref PubMed Scopus (261) Google Scholar]. Another study has coupled JNK activation indirectly to BAs as the mechanism of the FGF19-FGFR4 signaling pathway to suppress CYP7A1 [[48]Holt J.A. Luo G. Billin A.N. Bisi J. McNeill Y.Y. 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The total GPCR family comprises over 800 receptors, which are divided into three subgroups [[53]Pierce K.L. Premont R.T. Lefkowitz R.J. Seven-transmembrane receptors.Nat Rev Mol Cell Biol. 2002; 3: 639-650Crossref PubMed Scopus (1866) Google Scholar]. There are currently three known GPCRs whose activities are modulated by BAs. Based on their sequence homology, these BA-modulated GPCRs are classified in the class A or rhodopsin-like receptor class, which represents the largest subgroup of GPCRs. BAs are able to modulate the activity of the muscarinic receptors (also designated as acetylcholine receptors) [54Raufman J.P. Zimniak P. Bartoszko-Malik A. Lithocholyltaurine interacts with cholinergic receptors on dispersed chief cells from guinea pig stomach.Am J Physiol. 1998; 274: G997-G1004PubMed Google Scholar, 55Raufman J.P. Chen Y. Zimniak P. Cheng K. 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The relevance has not been analyzed so far in humans. The GPCR that has been most studied in relation to BAs is TGR5, also known as M-BAR, GPBAR, or GPR131. This cell-surface BA receptor was discovered in 2002 [[61]Maruyama T. Miyamoto Y. Nakamura T. Tamai Y. Okada H. Sugiyama E. et al.Identification of membrane-type receptor for bile acids (M-BAR).Biochem Biophys Res Commun. 2002; 298: 714-719Crossref PubMed Scopus (572) Google Scholar], and first characterized in 2003 [[62]Kawamata Y. Fujii R. Hosoya M. Harada M. Yoshida H. Miwa M. et al.A G protein-coupled receptor responsive to bile acids.J Biol Chem. 2003; 278: 9435-9440Crossref PubMed Scopus (860) Google Scholar]. TGR5 is encoded by a single-exon gene, and its conservation among several vertebrate species underlines the relevance of this GPCR in vertebrate physiology [[61]Maruyama T. Miyamoto Y. Nakamura T. Tamai Y. Okada H. 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Miwa M. et al.A G protein-coupled receptor responsive to bile acids.J Biol Chem. 2003; 278: 9435-9440Crossref PubMed Scopus (860) Google Scholar]. Human and mouse TGR5 show basically the same affinity for the different BAs, although certain synthetic TGR5 agonists reveal a large difference between mouse and human TGR5 with regard to their efficacy to activate the receptor [[63]Herbert M.R. Siegel D.L. Staszewski L. Cayanan C. Banerjee U. Dhamija S. et al.Synthesis and SAR of 2-aryl-3-aminomethylquinolines as agonists of the bile acid receptor TGR5.Bioorg Med Chem Lett. 2010; 20: 5718-5721Crossref PubMed Scopus (41) Google Scholar]. TGR5 is expressed in many different organs and cells with varying degrees of expression. For example, high expression levels of TGR5 have been detected in gallbladder epithelium [64Vassileva G. Golovko A. Markowitz L. Abbondanzo S.J. Zeng M. Yang S. et al.Targeted deletion of Gpbar1 protects mice from cholesterol gallstone formation.Biochem J. 2006; 398: 423-430Crossref PubMed Scopus (179) Google Scholar, 65Keitel V. Cupisti K. Ullmer C. Knoefel W.T. Kubitz R. Haussinger D. The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders.Hepatology. 2009; 50: 861-870Crossref PubMed Scopus (179) Google Scholar] and in the intestine, mainly in the ileum and colon [61Maruyama T. Miyamoto Y. Nakamura T. Tamai Y. Okada H. Sugiyama E. et al.Identification of membrane-type receptor for bile acids (M-BAR).Biochem Biophys Res Commun. 2002; 298: 714-719Crossref PubMed Scopus (572) Google Scholar, 66Maruyama 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: 197-205Crossref PubMed Scopus (173) Google Scholar]. TGR5 was also highly expressed in human monocytes as compared to other human leukocyte subsets examined [[62]Kawamata Y. Fujii R. Hosoya M. Harada M. Yoshida H. Miwa M. et al.A G protein-coupled receptor responsive to bile acids.J Biol Chem. 2003; 278: 9435-9440Crossref PubMed Scopus (860) Google Scholar]. In line with these findings, rabbit spleen and rabbit alveolar macrophages were also found to express relatively high levels of TGR5 versus other tissues [[62]Kawamata Y. Fujii R. Hosoya M. Harada M. Yoshida H. Miwa M. et al.A G protein-coupled receptor responsive to bile acids.J Biol Chem. 2003; 278: 9435-9440Crossref PubMed Scopus (860) Google Scholar]. TGR5 is detected in several liver cells, including rat liver sinusoidal endothelial cells, as well as in rat Kupffer cells, resident macrophages of the liver [67Keitel V. Reinehr R. Gatsios P. Rupprecht C. Gorg B. 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