The bile acid receptor (GPBA) responds to bile acids produced during the liver metabolism of cholesterol. Selective agonists are promising drugs for the treatment of metabolic disorders, such as type II diabetes, obesity and atherosclerosis.

The triterpenoid natural product betulinic acid has also been reported to inhibit inflammatory signalling through the NFκB pathway [8]. Disruption of GPBA expression is reported to protect from cholesterol gallstone formation [10]. A new series of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides have been reported as highly potent agonists [4].

* Key recommended reading is highlighted with an asterisk

* Duboc H, Taché Y, Hofmann AF. (2014) The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig Liver Dis, 46 (4): 302-12. [PMID:24411485]

Fiorucci S, Cipriani S, Baldelli F, Mencarelli A. (2010) Bile acid-activated receptors in the treatment of dyslipidemia and related disorders. Prog Lipid Res, 49 (2): 171-85. [PMID:19932133]

Fiorucci S, Mencarelli A, Palladino G, Cipriani S. (2009) Bile-acid-activated receptors: targeting TGR5 and farnesoid-X-receptor in lipid and glucose disorders. Trends Pharmacol Sci, 30 (11): 570-80. [PMID:19758712]

Keitel V, Häussinger D. (2012) Perspective: TGR5 (Gpbar-1) in liver physiology and disease. Clin Res Hepatol Gastroenterol, 36 (5): 412-9. [PMID:22521118]

* Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. (2009) Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev, 89 (1): 147-91. [PMID:19126757]

Li T, Chiang JY. (2012) Bile Acid signaling in liver metabolism and diseases. J Lipids, 2012: 754067. [PMID:21991404]

* Lieu T, Jayaweera G, Bunnett NW. (2014) GPBA: a GPCR for bile acids and an emerging therapeutic target for disorders of digestion and sensation. Br J Pharmacol, 171 (5): 1156-66. [PMID:24111923]

Nguyen A, Bouscarel B. (2008) Bile acids and signal transduction: role in glucose homeostasis. Cell Signal, 20 (12): 2180-97. [PMID:18634871]

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]

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]

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]

* van Nierop FS, Scheltema MJ, Eggink HM, Pols TW, Sonne DP, Knop FK, Soeters MR. (2017) Clinical relevance of the bile acid receptor TGR5 in metabolism. Lancet Diabetes Endocrinol, 5 (3): 224-233. [PMID:27639537]

1. Baxter JD, Webb P. (2006) Metabolism: bile acids heat things up. Nature, 439: 402-403. [PMID:16437098]

2. Genet C, Strehle A, Schmidt C, Boudjelal G, Lobstein A, Schoonjans K, Souchet M, Auwerx J, Saladin R, Wagner A. (2010) Structure-activity relationship study of betulinic acid, a novel and selective TGR5 agonist, and its synthetic derivatives: potential impact in diabetes. J Med Chem, 53 (1): 178-90. [PMID:19911773]

3. Kawamata Y, Fujii R, Hosoya M, Harada M, Yoshida H, Miwa M, Fukusumi S, Habata Y, Itoh T, Shintani Y, Hinuma S, Fujisawa Y, Fujino M. (2003) A G protein-coupled receptor responsive to bile acids. J Biol Chem, 278: 9435-9440. [PMID:12524422]

4. 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]

5. 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]

6. 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]

7. Sato H, Genet C, Strehle A, Thomas C, Lobstein A, Wagner A, Mioskowski C, Auwerx J, Saladin R. (2007) Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaea. Biochem Biophys Res Commun, 362 (4): 793-8. [PMID:17825251]

8. Takada Y, Aggarwal BB. (2003) Betulinic acid suppresses carcinogen-induced NF-kappa B activation through inhibition of I kappa B alpha kinase and p65 phosphorylation: abrogation of cyclooxygenase-2 and matrix metalloprotease-9. J Immunol, 171 (6): 3278-86. [PMID:12960358]

9. Takeda S, Kadowaki S, Haga T, Takaesu H, Mitaku S. (2002) Identification of G protein-coupled receptor genes from the human genome sequence. FEBS Lett, 520 (1-3): 97-101. [PMID:12044878]

10. Vassileva G, Golovko A, Markowitz L, Abbondanzo SJ, Zeng M, Yang S, Hoos L, Tetzloff G, Levitan D, Murgolo NJ et al.. (2006) Targeted deletion of Gpbar1 protects mice from cholesterol gallstone formation. Biochem J, 398 (3): 423-30. [PMID:16724960]

11. 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]

Subcommittee members: Anthony P. Davenport (Chairperson) Experimental Medicine and Immunotherapeutics University of Cambridge Addenbrooke’s Hospital Cambridge UK Tom I. Bonner Special Volunteer Office of Science Director NIMH Bethesda MD USA Janet J. Maguire Experimental Medicine and Immunotherapeutics University of Cambridge Addenbrooke’s Hospital Cambridge UK

Other contributors: Rebecca Hills (Past curator) Edward Rosser (Past curator)