Bile acid receptor: Introduction

Bile acids

Bile acids are acidic sterols primarily synthesised from cholesterol in the liver and are major components of bile, which has a classical role of enhancing fat absorption from the intestine. They are stored in the gall bladder until secretion to the duodenum where they have a well established role in solubilization and absorption of dietary lipids and lipid soluble vitamins. Following absorption from the intestine, bile acids are returned via the portal blood to the liver to maintain cholesterol homeostasis. In humans, the principal bile acids include primary bile acids, cholic and chenodeoxycholic acid and secondary bile acids, deoxycholic and lithocholic acid.

Bile acids also function as signalling molecules by modulating transcription of genes for enzymes and transport proteins modulating their own and cholesterol homeostasis. They do this by activating nuclear hormone receptors, such as the farnesoid X receptor. Recently, bile acids have been shown to have a role in a second independent signalling pathway, by activating a G protein-coupled receptor, originally called BG37 or M-BAR [12] or TGR5 [7] by the two different groups making this discovery. Previous names also include GPCR19, GPR131 and MGC40597. The function of these receptors is beginning to emerge [6,8,14,19-21] and the role of bile acids in endocrine function [5], dyslipidemia and related disorders [2-3], liver and hepatic diseases [10] and metabolism [9,15,17-18] has been reviewed.

Receptor Structure

The sequence of the bile acid receptor is distinct from other known receptors in the G protein-coupled receptor superfamily, displaying less than 30% sequence similarity to the most closely related receptors, human EDG-1, EDG-6 and EDG-8 (sphingosine-1-phosphate receptors) [7]. Amino acid sequences have been predicted from genes encoding bile receptors from a number of species. There is a high level of conservation of amino acids compared to human, which is shown in parentheses: rat (82%), mouse (83%), cow (86%) and rabbit (90%) [7].

Receptor distribution

Using RT-PCR, mRNA encoding the receptor were high in human, cow and rabbit but very low in rat and mouse. In human tissues, receptor mRNA was mainly detected in peripheral tissues particularly placenta, spleen and lung with lower levels were found in various other tissues including lung and fetal liver [7]. Levels in the brain were low by RT-PCR [7] or undetectable by the less sensitive Northern analysis [12]. High levels of receptor mRNA were detected in specific cells, CD14 positive monocytes [7], cell lines derived from intestinal enteroendocrine cells (NCI-H716, STC-1 and GLUTag) [12] and sinusoidal endothelial cells from the liver [21].


Gastrointestinal tract
Consistent with the presence of receptor mRNA in murine enteroendocrine cell line (STC-1) derived from the intestine, bile acids caused glucagon-like peptide-1 (GLP-1) secretion in a concentration-dependent manner with a corresponding increase in cAMP in vitro. RNA interference experiments reduced expression of the receptor resulting in decreased secretion of GLP-1. In agreement, transient transfection of STC-1 cells with an expression plasmid containing the bile acid receptor significantly enhanced GLP-1 secretion [6]. Bile acids have been implicated in gastrointestinal tract cell carcinogenesis, share properties with tumour promoters in that both affect signal transduction pathways responsible for cell proliferation and apoptosis. The bile acid receptor has been proposed as mediating activation of epidermal growth factor receptor and mitogen-activated protein kinases in gastric carcinoma cells [21].

Sinusoidal endothelial cells in the liver are also exposed to high concentration of bile acids from the enterohepatic circulation. Immunohistochemistry using an antisera directed to the C-terminus of the rat bile acid receptor revealed expression of the protein to the sinusoidal endothelial cells but not endothelial cells of the portal or central veins. Bile salts increased cAMP in isolated sinusoidal endothelial cells SEC and induced mRNA expression of endothelial NO synthase (eNOS), a cAMP-dependent gene and induced NO production in liver slices, suggesting the receptor may regulate haemodynamics in the liver [8].

Energy homeostasis
Watanabe et al [19] have recently shown that administration of bile acids (cholic acid) increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin in mice fed a high fat diet. Animals were less obese and glucose levels better regulated than controls. Intriguingly, in lean mice cholic acid had no effect on body weight or feeding. This novel metabolic effect of bile acids was mediated by increasing energy expenditure by burning more fat and was dependent on induction of the cAMP-dependent thyroid hormone activating enzyme type 2, iodothyronine deiodinase (D2) which converts the precursor of thyroid hormone, thyroxine (T3) into the active triiodothyronamine (T3). Treatment of the most important tissues regulating energy homeostatsis in mice (brown adipocytes) or humans (skeletal myocytes) with bile acids increases D2 activity and oxygen consumption. These effects are independent of the nuclear receptor (FXRα), and instead are mediated by increased cAMP production that stems from the binding of GPCR bile acid receptor. The authors propose that the bile acid-D2 signalling pathway is a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.


The actions of bile acids mediated via this receptor can be distinguished from nuclear receptor activity by ligand specificity and cAMP response. Selective agonists (23-alkyl-substituted and 6,23-alkyl-disubstituted derivatives of chenodeoxycholic acid) have been reported with selectivity for the bile acid receptor (EC50 = 3.68 µM) over farnesoid X nuclear hormone receptor [14]. Since activation of the receptor increases energy expenditure [19] and stimulates GLP-1 secretion 3 synthetic agonists could reduce obesity and improve glucose homeostasis. Sato et al. [16] screened a collection of natural occurring bile acids, bile acid derivatives, and some steroid hormones to generate structure activity relationships of for the receptor, leading to the discovery of 6α-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777), as a potent and selective agonist [13]. A series of 3-aryl-4-isoxazolecarboxamides were also identified as small molecule agonists, which demonstrated improved GLP-1 secretion in vivo [1]. Genet et al. [4] identified from a screen of naturally occurring triterpenoids betulinic, oleanolic , and ursolic acid which exhibited selective agonist activity. We describe here the biological screening of a collection of agonists against the G protein-coupled receptor TGR5, known to be activated by bile acids and which mediates some important cell functions. A new series of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides have been reported as highly potent agonists [11].


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11. Londregan AT, Piotrowski DW, Futatsugi K, Warmus JS, Boehm M, Carpino PA, Chin JE, Janssen AM, Roush NS, Buxton J et al.. (2013) Discovery of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides as potent agonists of TGR5 via sequential combinatorial libraries. Bioorg Med Chem Lett, 23 (5): 1407-11. [PMID:23337601]

12. Maruyama T, Miyamoto Y, Nakamura T, Tamai Y, Okada H, Sugiyama E, Nakamura T, Itadani H, Tanaka K. (2002) Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun, 298 (5): 714-9. [PMID:12419312]

13. Pellicciari R, Gioiello A, Macchiarulo A, Thomas C, Rosatelli E, Natalini B, Sardella R, Pruzanski M, Roda A, Pastorini E et al.. (2009) 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, 52 (24): 7958-61. [PMID:20014870]

14. Pellicciari R, Sato H, Gioiello A, Costantino G, Macchiarulo A, Sadeghpour BM, Giorgi G, Schoonjans K, Auwerx J. (2007) Nongenomic actions of bile acids. Synthesis and preliminary characterization of 23- and 6,23-alkyl-substituted bile acid derivatives as selective modulators for the G-protein coupled receptor TGR5. J Med Chem, 50 (18): 4265-8. [PMID:17685603]

15. Pols TW, Noriega LG, Nomura M, Auwerx J, Schoonjans K. (2011) The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation. J Hepatol, 54 (6): 1263-72. [PMID:21145931]

16. Sato H, Macchiarulo A, Thomas C, Gioiello A, Une M, Hofmann AF, Saladin R, Schoonjans K, Pellicciari R, Auwerx J. (2008) Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure-activity relationships, and molecular modeling studies. J Med Chem, 51 (6): 1831-41. [PMID:18307294]

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18. Tiwari A, Maiti P. (2009) TGR5: an emerging bile acid G-protein-coupled receptor target for the potential treatment of metabolic disorders. Drug Discov Today, 14 (9-10): 523-30. [PMID:19429513]

19. Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, Messaddeq N, Harney JW, Ezaki O, Kodama T et al.. (2006) Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature, 439 (7075): 484-9. [PMID:16400329]

20. Yang JI, Yoon JH, Myung SJ, Gwak GY, Kim W, Chung GE, Lee SH, Lee SM, Kim CY, Lee HS. (2007) Bile acid-induced TGR5-dependent c-Jun-N terminal kinase activation leads to enhanced caspase 8 activation in hepatocytes. Biochem Biophys Res Commun, 361: 156-161. [PMID:17659258]

21. Yasuda H, Hirata S, Inoue K, Mashima H, Ohnishi H, Yoshiba M. (2007) Involvement of membrane-type bile acid receptor M-BAR/TGR5 in bile acid-induced activation of epidermal growth factor receptor and mitogen-activated protein kinases in gastric carcinoma cells. Biochem Biophys Res Commun, 354 (1): 154-9. [PMID:17214962]

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