Role of the G Protein-Coupled Bile Acid Receptor TGR5 in Liver Damage

Digestive Diseases

Volumn 35, Issue 3, 2017, Pages 235-240

  Reich, Maria ^a   Klindt, Caroline ^a   Deutschmann, Kathleen ^a   Spomer, Lina ^a   Häussinger, Dieter ^a   Keitel, Verena ^a  

^a HEINRICH HEINE UNIVERSITY   (Germany)

Author keywords

Bile acid receptor; Cholangiocytes; Cholestasis; G protein coupled receptor; Liver damage

Indexed keywords

CYCLIC AMP; FARNESOID X RECEPTOR; G PROTEIN COUPLED BILE ACID RECEPTOR; G PROTEIN COUPLED RECEPTOR; GLUCAGON LIKE PEPTIDE 1; LIPOPOLYSACCHARIDE; UNCLASSIFIED DRUG; BILE ACID;

ACUTE TOXICITY; APOPTOSIS; ARTICLE; BILE DUCT CARCINOMA; BILE DUCT LIGATION; CELL MIGRATION; CELL PROLIFERATION; CHOLANGIOCYTE; GALLSTONE FORMATION; HUMAN; HYPERTENSION; INFLAMMATION; LIVER FIBROSIS; LIVER INJURY; LIVER REGENERATION; LIVER RESECTION; NONHUMAN; PERFUSION PRESSURE; PRIORITY JOURNAL; RISK FACTOR; AGONISTS; ANIMAL; BIOLOGICAL MODEL; GENETICS; LIVER DISEASE; METABOLISM;

ANIMALS; BILE ACIDS AND SALTS; HUMANS; LIVER DISEASES; MODELS, BIOLOGICAL; RECEPTORS, G-PROTEIN-COUPLED;

EID: 85014730998     PISSN: 02572753     EISSN: 14219875     Source Type: Journal    
DOI: 10.1159/000450917     Document Type: Article

References (43)

1. 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: A G protein-coupled receptor responsive to bile acids. J Biol Chem 2003; 278: 9435-9440.
2. Maruyama T, Miyamoto Y, Nakamura T, Tamai Y, Okada H, Sugiyama E, Nakamura T, Itadani H, Tanaka K: Identification of membranetype receptor for bile acids (M-BAR). Biochem Biophys Res Commun 2002; 298: 714-719.
3. Maruyama T, Tanaka K, Suzuki J, Miyoshi H, Harada N, Nakamura T, Miyamoto Y, Kanatani A, Tamai Y: Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbar1/MBar) in mice. J Endocrinol 2006; 191: 197-205.
4. Vassileva G, Golovko A, Markowitz L, Abbondanzo SJ, Zeng M, Yang S, Hoos L, Tetzloff G, Levitan D, Murgolo NJ, Keane K, Davis HR Jr, Hedrick J, Gustafson EL: Targeted deletion of Gpbar1 protects mice from cholesterol gallstone formation. Biochem J 2006; 398: 423-430.
5. Briere DA, Ruan X, Cheng CC, Siesky AM, Fitch TE, Dominguez C, Sanfeliciano SG, Montero C, Suen CS, Xu Y, Coskun T, Michael MD: Novel small molecule agonist of TGR5 possesses anti-diabetic effects but causes gallbladder filling in mice. PLoS One 2015; 10:e0136873.
6. Keitel V, Cupisti K, Ullmer C, Knoefel WT, Kubitz R, Haussinger D: The membranebound bile acid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology 2009; 50: 861-870.
7. Gertzen CG, Spomer L, Smits SH, Haussinger D, Keitel V, Gohlke H: Mutational mapping of the transmembrane binding site of the Gprotein coupled receptor TGR5 and binding mode prediction of TGR5 agonists. Eur J Med Chem 2015; 104: 57-72.
8. Keitel V, Gorg B, Bidmon HJ, Zemtsova I, Spomer L, Zilles K, Haussinger D: The bile acid receptor TGR5 (Gpbar-1) acts as a neurosteroid receptor in brain. Glia 2010; 58: 1794-1805.
9. Keitel V, Spomer L, Marin JJ, Williamson C, Geenes V, Kubitz R, Haussinger D, Macias RI: Effect of maternal cholestasis on TGR5 expression in human and rat placenta at term. Placenta 2013; 34: 810-816.
10. Sato H, Macchiarulo A, Thomas C, Gioiello A, Une M, Hofmann AF, Saladin R, Schoonjans K, Pellicciari R, Auwerx J: Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure-activity relationships, and molecular modeling studies. J Med Chem 2008; 51: 1831-1841.
11. Keitel V, Haussinger D: Perspective: TGR5 (Gpbar-1) in liver physiology and disease. Clin Res Hepatol Gastroenterol 2012; 36: 412-419.
12. Keitel V, Donner M, Winandy S, Kubitz R, Haussinger D: Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun 2008; 372: 78-84.
13. Keitel V, Haussinger D: TGR5 in cholangiocytes. Curr Opin Gastroenterol 2013; 29: 299-304.
14. Keitel V, Reich M, Haussinger D: TGR5: pathogenetic role and/or therapeutic target in fibrosing cholangitis? Clin Rev Allergy Immunol 2015; 48: 218-225.
15. Keitel V, Reinehr R, Gatsios P, Rupprecht C, Gorg B, Selbach O, Haussinger D, Kubitz R: The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology 2007; 45: 695-704.
16. Keitel V, Ullmer C, Haussinger D: The membrane-bound bile acid receptor TGR5 (Gpbar-1) is localized in the primary cilium of cholangiocytes. Biol Chem 2010; 391: 785-789.
17. Masyuk AI, Huang BQ, Radtke BN, Gajdos GB, Splinter PL, Masyuk TV, Gradilone SA, LaRusso NF: Ciliary subcellular localization of TGR5 determines the cholangiocyte functional response to bile acid signaling. Am J Physiol Gastrointest Liver Physiol 2013; 304: G1013-G1024.
18. Masyuk TV, Masyuk AI, LaRusso NF: TGR5 in the cholangiociliopathies. Dig Dis 2015; 33: 420-425.
19. Wang YD, Chen WD, Yu D, Forman BM, Huang W: The G-protein-coupled bile acid receptor, Gpbar1 (TGR5), negatively regulates hepatic inflammatory response through antagonizing nuclear factor κ light-chain enhancer of activated B cells (NF-κB) in mice. Hepatology 2011; 54: 1421-1432.
20. Reich M, Deutschmann K, Sommerfeld A, Klindt C, Kluge S, Kubitz R, Ullmer C, Knoefel WT, Herebian D, Mayatepek E, Haussinger D, Keitel V: TGR5 is essential for bile aciddependent cholangiocyte proliferation in vivo and in vitro. Gut 2016; 65: 487-501.
21. Li T, Holmstrom SR, Kir S, Umetani M, Schmidt DR, Kliewer SA, Mangelsdorf DJ: The G protein-coupled bile acid receptor, TGR5, stimulates gallbladder filling. Mol Endocrinol 2011; 25: 1066-1071.
22. Lavoie B, Balemba OB, Godfrey C, Watson CA, Vassileva G, Corvera CU, Nelson MT, Mawe GM: Hydrophobic bile salts inhibit gallbladder smooth muscle function via stimulation of GPBAR1 receptors and activation of KATP channels. J Physiol 2010; 588(pt 17): 3295-3305.
23. Duan H, Ning M, Chen X, Zou Q, Zhang L, Feng Y, Zhang L, Leng Y, Shen J: Design, synthesis, and antidiabetic activity of 4-phenoxynicotinamide and 4-phenoxypyrimidine-5-carboxamide derivatives as potent and orally efficacious TGR5 agonists. J Med Chem 2012; 55: 10475-10489.
24. Pols TW, Noriega LG, Nomura M, Auwerx J, Schoonjans K: The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation. J Hepatol 2011; 54: 1263-1272.
25. Donepudi AC, Boehme S, Li F, Chiang JY: Gprotein-coupled bile acid receptor plays a key role in bile acid metabolism and fasting-induced hepatic steatosis in mice. Hepatology 2016, Epub ahead of print.
26. Sayin SI, Wahlstrom A, Felin J, Jantti S, Marschall HU, Bamberg K, Angelin B, Hyotylainen T, OreŜič M, Backhed F: 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.
27. Maurer KJ, Carey MC, Fox JG: Roles of infection, inflammation, and the immune system in cholesterol gallstone formation. Gastroenterology 2009; 136: 425-440.
28. Haselow K, Bode JG, Wammers M, Ehlting C, Keitel V, Kleinebrecht L, Schupp AK, Haussinger D, Graf D: Bile acids PKA-dependently induce a switch of the IL-10/IL-12 ratio and reduce proinflammatory capability of human macrophages. J Leukoc Biol 2013; 94: 1253-1264.
29. Perino A, Pols TW, Nomura M, Stein S, Pellicciari R, Schoonjans K: TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation. J Clin Invest 2014; 124: 5424-5436.
30. Pols TW, Nomura M, Harach T, Lo Sasso G, Oosterveer MH, Thomas C, Rizzo G, Gioiello A, Adorini L, Pellicciari R, Auwerx J, Schoonjans K: TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab 2011; 14: 747-757.
31. Hogenauer K, Arista L, Schmiedeberg N, Werner G, Jaksche H, Bouhelal R, Nguyen DG, Bhat BG, Raad L, Rauld C, Carballido JM: G-protein-coupled bile acid receptor 1 (GPBAR1, TGR5) agonists reduce the production of proinflammatory cytokines and stabilize the alternative macrophage phenotype. J Med Chem 2014; 57: 10343-10354.
32. Ichikawa R, Takayama T, Yoneno K, Kamada N, Kitazume MT, Higuchi H, Matsuoka K, Watanabe M, Itoh H, Kanai T, Hisamatsu T, Hibi T: Bile acids induce monocyte differentiation toward interleukin-12 hypoproducing dendritic cells via a TGR5-dependent pathway. Immunology 2012; 136: 153-162.
33. Pean N, Doignon I, Garcin I, Besnard A, Julien B, Liu B, Branchereau S, Spraul A, Guettier C, Humbert L, Schoonjans K, Rainteau D, Tordjmann T: The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice. Hepatology 2013; 58: 1451-1460.
34. 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: TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 2009; 10: 167-177.
35. Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, Messaddeq N, Harney JW, Ezaki O, Kodama T, Schoonjans K, Bianco AC, Auwerx J: Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006; 439: 484-489.
36. Duan H, Ning M, Zou Q, Ye Y, Feng Y, Zhang L, Leng Y, Shen J: Discovery of intestinal targeted TGR5 agonists for the treatment of type 2 diabetes. J Med Chem 2015; 58: 3315-3328.
37. Pellicciari R, Gioiello A, Macchiarulo A, Thomas C, Rosatelli E, Natalini B, Sardella R, Pruzanski M, Roda A, Pastorini E, Schoonjans K, Auwerx J: 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: 7958-7961.
38. Ullmer C, Alvarez Sanchez R, Sprecher U, Raab S, Mattei P, Dehmlow H, Sewing S, Iglesias A, Beauchamp J, Conde-Knape K: Systemic bile acid sensing by G protein-coupled bile acid receptor 1 (GPBAR1) promotes PYY and GLP-1 release. Br J Pharmacol 2013; 169: 671-684.
39. Phillips DP, Gao W, Yang Y, Zhang G, Lerario IK, Lau TL, Jiang J, Wang X, Nguyen DG, Bhat BG, Trotter C, Sullivan H, Welzel G, Landry J, Chen Y, Joseph SB, Li C, Gordon WP, Richmond W, Johnson K, Bretz A, Bursulaya B, Pan S, McNamara P, Seidel HM: Discovery of trifluoromethyl(pyrimidin-2-yl) azetidine-2-carboxamides as potent, orally bioavailable TGR5 (GPBAR1) agonists: structure-activity relationships, lead optimization, and chronic in vivo efficacy. J Med Chem 2014; 57: 3263-3282.
40. Perino A, Schoonjans K: TGR5 and immunometabolism: insights from physiology and pharmacology. Trends Pharmacol Sci 2015; 36: 847-857.
41. McMahan RH, Wang XX, Cheng LL, Krisko T, Smith M, El Kasmi K, Pruzanski M, Adorini L, Golden-Mason L, Levi M, Rosen HR: Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J Biol Chem 2013; 288: 11761-11770.
42. Renga B, Cipriani S, Carino A, Simonetti M, Zampella A, Fiorucci S: Reversal of endothelial dysfunction by GPBAR1 agonism in portal hypertension involves a AKT/FOXOA1 dependent regulation of H2S generation and endothelin-1. PLoS One 2015; 10:e0141082.
43. Beuers U, Hohenester S, de Buy Wenniger LJ, Kremer AE, Jansen PL, Elferink RP: The biliary HCO(3)(-) umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies. Hepatology 2010; 52: 1489-1496.