Role of TGR5 (GPBAR1) in Liver Disease

Abstract

TGR5 (GPBAR1) is a G protein–coupled receptor activated by primary and secondary bile acids, which is expressed in different nonparenchymal cells of the liver, such as sinusoidal endothelial cells, Kupffer cells, cholangiocytes as well as activated hepatic stellate cells. In liver, TGR5 modulates microcirculation, inflammation, regeneration, biliary secretion and proliferation as well as gallbladder filling. Absence of TGR5 renders mice more susceptible toward infectious, inflammatory, metabolic as well as cholestatic liver injuries. It is unknown whether TGR5 plays a role in the pathogenesis of human nonalcoholic steatohepatitis and cholestatic liver diseases such as primary sclerosing cholangitis and primary biliary cholangitis. However, overexpression of TGR5 has been detected in human intra- and extrahepatic cholangiocarcinoma as well as in cystic cholangiocytes, where the receptor promotes cell proliferation, anti-apoptosis as well as cyst growth. While TGR5 agonists may improve various aspects of metabolic, inflammatory, and cholestatic liver diseases, TGR5 inhibitors may attenuate disease progression in polycystic liver disease and cholangiocarcinoma.

Keywords

bile acids - G protein–coupled receptor - steatohepatitis - cholangiopathy - inflammation

• References

• 1 Makishima M, Okamoto AY, Repa JJ. , et al. Identification of a nuclear receptor for bile acids. Science 1999; 284 (5418): 1362-1365
• 2 Parks DJ, Blanchard SG, Bledsoe RK. , et al. Bile acids: natural ligands for an orphan nuclear receptor. Science 1999; 284 (5418): 1365-1368
• 3 Wang H, Chen J, Hollister K, Sowers LC, Forman BM. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 1999; 3 (05) 543-553
• 4 Maruyama T, Miyamoto Y, Nakamura T. , et al. Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun 2002; 298 (05) 714-719
• 5 Kawamata Y, Fujii R, Hosoya M. , et al. A G protein–coupled receptor responsive to bile acids. J Biol Chem 2003; 278 (11) 9435-9440
• 6 Keitel V, Reinehr R, Gatsios P. , et al. The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology 2007; 45 (03) 695-704
• 7 Keitel V, Donner M, Winandy S, Kubitz R, Häussinger D. Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun 2008; 372 (01) 78-84
• 8 Gohlke H, Schmitz B, Sommerfeld A, Reinehr R, Häussinger D. α5 β1-integrins are sensors for tauroursodeoxycholic acid in hepatocytes. Hepatology 2013; 57 (03) 1117-1129
• 9 Deutschmann K, Reich M, Klindt C. , et al. Bile acid receptors in the biliary tree: TGR5 in physiology and disease. Biochim Biophys Acta 2018; 1864 (4 Pt B): 1319-1325
• 10 Copple BL, Li T. Pharmacology of bile acid receptors: Evolution of bile acids from simple detergents to complex signaling molecules. Pharmacol Res 2016; 104: 9-21
• 11 Gascon-Barré M, Demers C, Mirshahi A, Néron S, Zalzal S, Nanci A. The normal liver harbors the vitamin D nuclear receptor in nonparenchymal and biliary epithelial cells. Hepatology 2003; 37 (05) 1034-1042
• 12 Raufman JP, Chen Y, Cheng K, Compadre C, Compadre L, Zimniak P. Selective interaction of bile acids with muscarinic receptors: a case of molecular mimicry. Eur J Pharmacol 2002; 457 (2-3): 77-84
• 13 Staudinger JL, Goodwin B, Jones SA. , et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci U S A 2001; 98 (06) 3369-3374
• 14 Studer E, Zhou X, Zhao R. , et al. Conjugated bile acids activate the sphingosine-1-phosphate receptor 2 in primary rodent hepatocytes. Hepatology 2012; 55 (01) 267-276
• 15 Häussinger D, Reinehr R, Keitel V. Bile acid signaling in the liver and the biliary tree. In: Häussinger D, Keitel V, Kubitz R. , eds. Hepatobiliary Transport in Health and Disease. Berlin, Germany: DeGruyter Publishing; 2012: 85-102
• 16 Forman BM, Goode E, Chen J. , et al. Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 1995; 81 (05) 687-693
• 17 Choi M, Moschetta A, Bookout AL. , et al. Identification of a hormonal basis for gallbladder filling. Nat Med 2006; 12 (11) 1253-1255
• 18 Inagaki T, Choi M, Moschetta A. , et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2005; 2 (04) 217-225
• 19 Kir S, Beddow SA, Samuel VT. , et al. FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. Science 2011; 331 (6024): 1621-1624
• 20 Kliewer SA, Mangelsdorf DJ. Bile acids as hormones: the FXR-FGF15/19 pathway. Dig Dis 2015; 33 (03) 327-331
• 21 Uriarte I, Fernandez-Barrena MG, Monte MJ. , et al. Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice. Gut 2013; 62 (06) 899-910
• 22 Kok T, Hulzebos CV, Wolters H. , et al. Enterohepatic circulation of bile salts in farnesoid X receptor–deficient mice: efficient intestinal bile salt absorption in the absence of ileal bile acid-binding protein. J Biol Chem 2003; 278 (43) 41930-41937
• 23 Modica S, Gadaleta RM, Moschetta A. Deciphering the nuclear bile acid receptor FXR paradigm. Nucl Recept Signal 2010; 8: e005
• 24 Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 2000; 102 (06) 731-744
• 25 Wang YD, Chen WD, Wang M, Yu D, Forman BM, Huang W. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 2008; 48 (05) 1632-1643
• 26 Inagaki T, Moschetta A, Lee YK. , et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci U S A 2006; 103 (10) 3920-3925
• 27 Neuschwander-Tetri BA, Loomba R, Sanyal AJ. , et al; NASH Clinical Research Network. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015; 385 (9972): 956-965
• 28 Nevens F, Andreone P, Mazzella G. , et al; POISE Study Group. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 2016; 375 (07) 631-643
• 29 Harrison SA, Rinella ME, Abdelmalek MF. , et al. NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2018; 391 (10126): 1174-1185
• 30 Sato H, Macchiarulo A, Thomas C. , et al. Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure-activity relationships, and molecular modeling studies. J Med Chem 2008; 51 (06) 1831-1841
• 31 Vassileva G, Hu W, Hoos L. , et al. Gender-dependent effect of Gpbar1 genetic deletion on the metabolic profiles of diet-induced obese mice. J Endocrinol 2010; 205 (03) 225-232
• 32 Keitel V, Häussinger D. Perspective: TGR5 (Gpbar-1) in liver physiology and disease. Clin Res Hepatol Gastroenterol 2012; 36 (05) 412-419
• 33 Keitel V, Reich M, Häussinger D. TGR5: pathogenetic role and/or therapeutic target in fibrosing cholangitis?. Clin Rev Allergy Immunol 2015; 48 (2-3): 218-225
• 34 Maruyama T, Tanaka K, Suzuki J. , et al. Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) in mice. J Endocrinol 2006; 191 (01) 197-205
• 35 Vassileva G, Golovko A, Markowitz L. , et al. Targeted deletion of Gpbar1 protects mice from cholesterol gallstone formation. Biochem J 2006; 398 (03) 423-430
• 36 Reich M, Klindt C, Deutschmann K, Spomer L, Häussinger D, Keitel V. Role of the G protein-coupled bile acid receptor TGR5 in liver damage. Dig Dis 2017; 35 (03) 235-240
• 37 Keitel V, Ullmer C, Häussinger D. The membrane-bound bile acid receptor TGR5 (Gpbar-1) is localized in the primary cilium of cholangiocytes. Biol Chem 2010; 391 (07) 785-789
• 38 Masyuk AI, Huang BQ, Radtke BN. , et al. Ciliary subcellular localization of TGR5 determines the cholangiocyte functional response to bile acid signaling. Am J Physiol Gastrointest Liver Physiol 2013; 304 (11) G1013-G1024
• 39 Reich M, Deutschmann K, Sommerfeld A. , et al. TGR5 is essential for bile acid-dependent cholangiocyte proliferation in vivo and in vitro. Gut 2016; 65 (03) 487-501
• 40 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 (04) 1421-1432
• 41 Fiorucci S, Zampella A, Cirino G, Bucci M, Distrutti E. Decoding the vasoregulatory activities of bile acid-activated receptors in systemic and portal circulation: role of gaseous mediators. Am J Physiol Heart Circ Physiol 2017; 312 (01) H21-H32
• 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 (11) e0141082
• 43 Renga B, Bucci M, Cipriani S. , et al. Cystathionine γ-lyase, a H₂S-generating enzyme, is a GPBAR1-regulated gene and contributes to vasodilation caused by secondary bile acids. Am J Physiol Heart Circ Physiol 2015; 309 (01) H114-H126
• 44 Kida T, Tsubosaka Y, Hori M, Ozaki H, Murata T. Bile acid receptor TGR5 agonism induces NO production and reduces monocyte adhesion in vascular endothelial cells. Arterioscler Thromb Vasc Biol 2013; 33 (07) 1663-1669
• 45 Pols TW, Nomura M, Harach T. , et al. TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab 2011; 14 (06) 747-757
• 46 Guo C, Xie S, Chi Z. , et al. Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. Immunity 2016; 45 (04) 802-816
• 47 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 (12) 5424-5436
• 48 Perino A, Schoonjans K. TGR5 and immunometabolism: insights from physiology and pharmacology. Trends Pharmacol Sci 2015; 36 (12) 847-857
• 49 Haselow K, Bode JG, Wammers M. , et al. 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 (06) 1253-1264
• 50 Högenauer K, Arista L, Schmiedeberg N. , et al. 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 (24) 10343-10354
• 51 Ichikawa R, Takayama T, Yoneno K. , et al. Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway. Immunology 2012; 136 (02) 153-162
• 52 Keitel V, Häussinger D. TGR5 in cholangiocytes. Curr Opin Gastroenterol 2013; 29 (03) 299-304
• 53 Keitel V, Cupisti K, Ullmer C, Knoefel WT, Kubitz R, Häussinger D. The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology 2009; 50 (03) 861-870
• 54 Duan H, Ning M, Chen X. , et al. 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 (23) 10475-10489
• 55 Li T, Holmstrom SR, Kir S. , et al. The G protein-coupled bile acid receptor, TGR5, stimulates gallbladder filling. Mol Endocrinol 2011; 25 (06) 1066-1071
• 56 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 (04) 1489-1496
• 57 Sawitza I, Kordes C, Götze S, Herebian D, Häussinger D. Bile acids induce hepatic differentiation of mesenchymal stem cells. Sci Rep 2015; 5: 13320
• 58 Tacke F. Targeting hepatic macrophages to treat liver diseases. J Hepatol 2017; 66 (06) 1300-1312
• 59 McMahan RH, Wang XX, Cheng LL. , et al. Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J Biol Chem 2013; 288 (17) 11761-11770
• 60 Thomas C, Gioiello A, Noriega L. , et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 2009; 10 (03) 167-177
• 61 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 (06) 1263-1272
• 62 Chávez-Talavera O, Tailleux A, Lefebvre P, Staels B. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Gastroenterology 2017; 152 (07) 1679-1694.e3
• 63 Franke A, Balschun T, Karlsen TH. , et al; IBSEN study group. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet 2008; 40 (11) 1319-1323
• 64 Karlsen TH, Franke A, Melum E. , et al. Genome-wide association analysis in primary sclerosing cholangitis. Gastroenterology 2010; 138 (03) 1102-1111
• 65 Hov JR, Keitel V, Laerdahl JK. , et al; IBSEN Study Group. Mutational characterization of the bile acid receptor TGR5 in primary sclerosing cholangitis. PLoS One 2010; 5 (08) e12403
• 66 Masyuk TV, Masyuk AI, LaRusso NF. TGR5 in the cholangiociliopathies. Dig Dis 2015; 33 (03) 420-425
• 67 Péan N, Doignon I, Garcin I. , et al. The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice. Hepatology 2013; 58 (04) 1451-1460
• 68 Guest RV, Boulter L, Kendall TJ. , et al. Cell lineage tracing reveals a biliary origin of intrahepatic cholangiocarcinoma. Cancer Res 2014; 74 (04) 1005-1010
• 69 Erice O, Labiano I, Arbelaiz A. , et al. Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression. Biochim Biophys Acta 2018; 1864 (4 Pt B): 1335-1344
• 70 Masyuk TV, Masyuk AI, Lorenzo Pisarello M. , et al. TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate/Gαs signaling. Hepatology 2017; 66 (04) 1197-1218
• 71 Lavoie B, Balemba OB, Godfrey C. , et al. 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
• 72 Briere DA, Ruan X, Cheng CC. , et al. Novel small molecule agonist of TGR5 possesses anti-diabetic effects but causes gallbladder filling in mice. PLoS One 2015; 10 (08) e0136873
• 73 Iwakiri Y, Groszmann RJ. Vascular endothelial dysfunction in cirrhosis. J Hepatol 2007; 46 (05) 927-934
• 74 Iwakiri Y, Shah V, Rockey DC. Vascular pathobiology in chronic liver disease and cirrhosis - current status and future directions. J Hepatol 2014; 61 (04) 912-924
• 75 Schwabl P, Hambruch E, Seeland BA. , et al. The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction. J Hepatol 2017; 66 (04) 724-733
• 76 Alemi F, Kwon E, Poole DP. , et al. The TGR5 receptor mediates bile acid-induced itch and analgesia. J Clin Invest 2013; 123 (04) 1513-1530
• 77 Lieu T, Jayaweera G, Zhao P. , et al. The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice. Gastroenterology 2014; 147 (06) 1417-1428
• 78 Keitel V, Görg B, Bidmon HJ. , et al. The bile acid receptor TGR5 (Gpbar-1) acts as a neurosteroid receptor in brain. Glia 2010; 58 (15) 1794-1805
• 79 Doignon I, Julien B, Serrière-Lanneau V. , et al. Immediate neuroendocrine signaling after partial hepatectomy through acute portal hyperpressure and cholestasis. J Hepatol 2011; 54 (03) 481-488
• 80 Karababa A, Groos-Sahr K, Albrecht U. , et al. Ammonia attenuates LPS-induced upregulation of pro-inflammatory cytokine mRNA in co-cultured astrocytes and microglia. Neurochem Res 2017; 42 (03) 737-749
• 81 McMillin M, Frampton G, Tobin R. , et al. TGR5 signaling reduces neuroinflammation during hepatic encephalopathy. J Neurochem 2015; 135 (03) 565-576
• 82 Fujisaka S, Ussar S, Clish C. , et al. Antibiotic effects on gut microbiota and metabolism are host dependent. J Clin Invest 2016; 126 (12) 4430-4443