Abstract
The BA-responsive GPCRs S1PR2 and TGR5 are almost ubiquitously expressed in human and rodent tissues. In the liver, S1PR2 is expressed in all cell types, while TGR5 is predominately found in non-parenchymal cells. In contrast to S1PR2, which is mainly activated by conjugated bile acids (BAs), all BAs serve as ligands for TGR5 irrespective of their conjugation state and substitution pattern.
Mice with targeted deletion of either S1PR2 or TGR5 are viable and develop no overt phenotype. In liver injury models, S1PR2 exerts pro-inflammatory and pro-fibrotic effects and thus aggravates liver damage, while TGR5 mediates anti-inflammatory, anti-cholestatic, and anti-fibrotic effects. Thus, inhibitors of S1PR2 signaling and agonists for TGR5 have been employed to attenuate liver injury in rodent models for cholestasis, nonalcoholic steatohepatitis, and fibrosis/cirrhosis.
In biliary epithelial cells, both receptors activate a similar signaling cascade resulting in ERK1/2 phosphorylation and cell proliferation. Overexpression of both S1PR2 and TGR5 was found in human cholangiocarcinoma tissue as well as in CCA cell lines, where stimulation of both GPCRs resulted in transactivation of the epidermal growth factor receptor and triggered cell proliferation as well as increased cell migration and invasiveness.
This chapter will focus on the function of S1PR2 and TGR5 in different liver cell types and summarizes current knowledge on the role of these receptors in liver disease models.
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References
Adada M, Canals D, Hannun YA, Obeid LM (2013) Sphingosine-1-phosphate receptor 2. FEBS J 280(24):6354–6366
Alemi F, Poole DP, Chiu J, Schoonjans K, Cattaruzza F, Grider JR, Bunnett NW, Corvera CU (2013a) The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice. Gastroenterology 144(1):145–154
Alemi F, Kwon E, Poole DP, Lieu T, Lyo V, Cattaruzza F, Cevikbas F, Steinhoff M, Nassini R, Materazzi S, Guerrero-Alba R, Valdez-Morales E, Cottrell GS, Schoonjans K, Geppetti P, Vanner SJ, Bunnett NW, Corvera CU (2013b) The TGR5 receptor mediates bile acid-induced itch and analgesia. J Clin Invest 123(4):1513–1530
Becker S, Reinehr R, Graf D, vom DS, Häussinger D (2007a) Hydrophobic bile salts induce hepatocyte shrinkage via NADPH oxidase activation. Cell Physiol Biochem 19(1–4):89–98
Becker S, Reinehr R, Grether-Beck S, Eberle A, Häussinger D (2007b) Hydrophobic bile salts trigger ceramide formation through endosomal acidification. Biol Chem 388(2):185–196
Beuers U, Hohenester S, de Buy Wenniger LJ, Kremer AE, Jansen PL, Elferink RP (2010) The biliary HCO(3)(-) umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies. Hepatology 52(4):1489–1496
Biagioli M, Carino A, Cipriani S, Francisci D, Marchiano S, Scarpelli P, Sorcini D, Zampella A, Fiorucci S (2017) the bile acid receptor GPBAR1 regulates the M1/M2 phenotype of intestinal macrophages and activation of GPBAR1 rescues mice from murine colitis. J Immunol 199(2):718–733
Blaho VA, Hla T (2014) An update on the biology of sphingosine 1-phosphate receptors. J Lipid Res 55(8):1596–1608
Briere DA, Ruan X, Cheng CC, Siesky AM, Fitch TE, Dominguez C, Sanfeliciano SG, Montero C, Suen CS, Xu Y, Coskun T, Michael MD (2015) Novel small molecule agonist of TGR5 possesses anti-diabetic effects but causes gallbladder filling in mice. PLoS One 10(8):e0136873
Carino A, Marchiano S, Biagioli M, Bucci M, Vellecco V, Brancaleone V, Fiorucci C, Zampella A, Monti MC, Distrutti E, Fiorucci S (2018) Agonism for the bile acid receptor GPBAR1 reverses liver and vascular damage in a mouse model of steatohepatitis. FASEB J. https://doi.org/10.1096/fj.201801373RR
Chavez-Talavera O, Tailleux A, Lefebvre P, Staels B (2017) Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Gastroenterology 152(7):1679–1694.e3
Chen X, Yang D, Shen W, Dong HF, Wang JM, Oppenheim JJ, Howard MZ (2000) Characterization of chenodeoxycholic acid as an endogenous antagonist of the G-coupled formyl peptide receptors. Inflamm Res 49(12):744–755
Chen T, Huang Z, Liu R, Yang J, Hylemon PB, Zhou H (2017) Sphingosine-1 phosphate promotes intestinal epithelial cell proliferation via S1PR2. Front Biosci (Landmark Ed) 22:596–608
Chen T, Lin R, Jin S, Chen R, Xue H, Ye H, Huang Z (2018a) The sphingosine-1-phosphate/sphingosine-1-phosphate receptor 2 axis in intestinal epithelial cells regulates intestinal barrier function during intestinal epithelial cells-CD4+T-cell interactions. Cell Physiol Biochem 48(3):1188–1200
Chen T, Reich NW, Bell N, Finn PD, Rodriguez D, Kohler J, Kozuka K, He L, Spencer AG, Charmot D, Navre M, Carreras CW, Koo-McCoy S, Tabora J, Caldwell JS, Jacobs JW, Lewis JG (2018b) Design of gut-restricted thiazolidine agonists of G protein-coupled bile acid receptor 1 (GPBAR1, TGR5). J Med Chem 61(17):7589–7613
Cheng SH, Rich DP, Marshall J, Gregory RJ, Welsh MJ, Smith AE (1991) Phosphorylation of the R domain by cAMP-dependent protein kinase regulates the CFTR chloride channel. Cell 66(5):1027–1036
Cheng K, Khurana S, Chen Y, Kennedy RH, Zimniak P, Raufman JP (2002) Lithocholylcholine, a bile acid/acetylcholine hybrid, is a muscarinic receptor antagonist. J Pharmacol Exp Ther 303(1):29–35
Copple BL, Li T (2016) Pharmacology of bile acid receptors: Evolution of bile acids from simple detergents to complex signaling molecules. Pharmacol Res 104:9–21
de Oliveira MC, Gilglioni EH, de Boer BA, Runge JH, de Waart DR, Salgueiro CL, Ishii-Iwamoto EL, Oude Elferink RP, Gaemers IC (2016) Bile acid receptor agonists INT747 and INT777 decrease oestrogen deficiency-related postmenopausal obesity and hepatic steatosis in mice. Biochim Biophys Acta 1862(11):2054–2062
Deutschmann K, Reich M, Klindt C, Dröge C, Spomer L, Häussinger D, Keitel V (2018) Bile acid receptors in the biliary tree: TGR5 in physiology and disease. Biochim Biophys Acta 1864(4. Pt B):1319–1325
Donepudi AC, Boehme S, Li F, Chiang JY (2017) G-protein-coupled bile acid receptor plays a key role in bile acid metabolism and fasting-induced hepatic steatosis in mice. Hepatology 65(3):813–827
Duan H, Ning M, Chen X, Zou Q, Zhang L, Feng Y, Zhang L, Leng Y, Shen J (2012) Design, synthesis, and antidiabetic activity of 4-phenoxynicotinamide and 4-phenoxypyrimidine-5-carboxamide derivatives as potent and orally efficacious TGR5 agonists. J Med Chem 55(23):10475–10489
Duan H, Ning M, Zou Q, Ye Y, Feng Y, Zhang L, Leng Y, Shen J (2015) Discovery of intestinal targeted TGR5 agonists for the treatment of type 2 diabetes. J Med Chem 58(8):3315–3328
Erice O, Labiano I, Arbelaiz A, Santos-Laso A, Munoz-Garrido P, Jimenez-Aguero R, Olaizola P, Caro-Maldonado A, Martin-Martin N, Carracedo A, Lozano E, Marin JJ, O'Rourke CJ, Andersen JB, Llop J, Gomez-Vallejo V, Padro D, Martin A, Marzioni M, Adorini L, Trauner M, Bujanda L, Perugorria MJ, Banales JM (2018) Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression. Biochim Biophys Acta 1864(4 Pt B):1335–1344
Farrell G, Schattenberg JM, Leclercq I, Yeh MM, Goldin R, Teoh N, Schuppan D (2019) Mouse models of nonalcoholic steatohepatitis: towards optimization of their relevance to human NASH. Hepatology 69(5):2241–2257
Faubion WA, Guicciardi ME, Miyoshi H, Bronk SF, Roberts PJ, Svingen PA, Kaufmann SH, Gores GJ (1999) Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas. J Clin Invest 103(1):137–145
Ferrari C, Macchiarulo A, Costantino G, Pellicciari R (2006) Pharmacophore model for bile acids recognition by the FPR receptor. J Comput Aided Mol Des 20(5):295–303
Finn PD, Rodriguez D, Kohler J, Jiang Z, Wan S, Blanco E, King AJ, Chen T, Bell N, Dragoli D, Jacobs JW, Jain R, Leadbetter M, Siegel M, Carreras CW, Koo-McCoy S, Shaw K, Le C, Vanegas S, Hsu IH, Kozuka K, Okamoto K, Caldwell JS, Lewis JGP (2019) Intestinal TGR5 agonism improves hepatic steatosis and insulin sensitivity in Western diet-fed mice. Am J Physiol Gastrointest Liver Physiol 316(3):G412–G424
Fiorucci S, Zampella A, Cirino G, Bucci M, Distrutti E (2017) Decoding the vasoregulatory activities of bile acid-activated receptors in systemic and portal circulation: role of gaseous mediators. Am J Physiol Heart Circ Physiol 312(1):H21–H32
Gascon-Barre M, Demers C, Mirshahi A, Neron S, Zalzal S, Nanci A (2003) The normal liver harbors the vitamin D nuclear receptor in nonparenchymal and biliary epithelial cells. Hepatology 37(5):1034–1042
Godoy P, Hewitt NJ, Albrecht U, Andersen ME, Ansari N, Bhattacharya S, Bode JG, Bolleyn J, Borner C, Bottger J, Braeuning A, Budinsky RA, Burkhardt B, Cameron NR, Camussi G, Cho CS, Choi YJ, Craig Rowlands J, Dahmen U, Damm G, Dirsch O, Donato MT, Dong J, Dooley S, Drasdo D, Eakins R, Ferreira KS, Fonsato V, Fraczek J, Gebhardt R, Gibson A, Glanemann M, Goldring CE, Gomez-Lechon MJ, Groothuis GM, Gustavsson L, Guyot C, Hallifax D, Hammad S, Hayward A, Häussinger D, Hellerbrand C, Hewitt P, Hoehme S, Holzhutter HG, Houston JB, Hrach J, Ito K, Jaeschke H, Keitel V, Kelm JM, Kevin Park B, Kordes C, Kullak-Ublick GA, LeCluyse EL, Lu P, Luebke-Wheeler J, Lutz A, Maltman DJ, Matz-Soja M, McMullen P, Merfort I, Messner S, Meyer C, Mwinyi J, Naisbitt DJ, Nussler AK, Olinga P, Pampaloni F, Pi J, Pluta L, Przyborski SA, Ramachandran A, Rogiers V, Rowe C, Schelcher C, Schmich K, Schwarz M, Singh B, Stelzer EH, Stieger B, Stober R, Sugiyama Y, Tetta C, Thasler WE, Vanhaecke T, Vinken M, Weiss TS, Widera A, Woods CG, Xu JJ, Yarborough KM, Hengstler JG (2013) Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME. Arch Toxicol 87(8):1315–1530
Gohlke H, Schmitz B, Sommerfeld A, Reinehr R, Häussinger D (2013) alpha5 beta1-integrins are sensors for tauroursodeoxycholic acid in hepatocytes. Hepatology 57(3):1117–1129
Graf D, Kurz AK, Fischer R, Reinehr R, Häussinger D (2002) Taurolithocholic acid-3 sulfate induces CD95 trafficking and apoptosis in a c-Jun N-terminal kinase-dependent manner. Gastroenterology 122(5):1411–1427
Guo C, Xie S, Chi Z, Zhang J, Liu Y, Zhang L, Zheng M, Zhang X, Xia D, Ke Y, Lu L, Wang D (2016) Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. Immunity 45(4):802–816
Hait NC, Allegood J, Maceyka M, Strub GM, Harikumar KB, Singh SK, Luo C, Marmorstein R, Kordula T, Milstien S, Spiegel S (2009) Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate. Science 325(5945):1254–1257
Han S, Chiang JY (2009) Mechanism of vitamin D receptor inhibition of cholesterol 7alpha-hydroxylase gene transcription in human hepatocytes. Drug Metab Dispos 37(3):469–478
Haselow K, Bode JG, Wammers M, Ehlting C, Keitel V, Kleinebrecht L, Schupp AK, Häussinger D, Graf D (2013) Bile acids PKA-dependently induce a switch of the IL-10/IL-12 ratio and reduce proinflammatory capability of human macrophages. J Leukoc Biol 94(6):1253–1264
Häussinger D, Keitel V (2017) Dual role of the bile acid receptor Takeda G-protein-coupled receptor 5 for hepatic lipid metabolism in feast and famine. Hepatology 65(3):767–770
Häussinger D, Kurz AK, Wettstein M, Graf D, Vom Dahl S, Schliess F (2003) Involvement of integrins and Src in tauroursodeoxycholate-induced and swelling-induced choleresis. Gastroenterology 124(5):1476–1487
Häussinger D, Reinehr R, Keitel V (2012) Bile acid signaling in the liver and the biliary tree. In: Häussinger D, Keitel V, Kubitz R (eds) Hepatobiliary transport in health and disease. DeGruyter, Berlin, pp 85–102
Hirschfield GM, Karlsen TH, Lindor KD, Adams DH (2013) Primary sclerosing cholangitis. Lancet 382(9904):1587–1599
Hogenauer K, Arista L, Schmiedeberg N, Werner G, Jaksche H, Bouhelal R, Nguyen DG, Bhat BG, Raad L, Rauld C, Carballido JM (2014) 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 57(24):10343–10354
Hohenester S, Gates A, Wimmer R, Beuers U, Anwer MS, Rust C, Webster CR (2010) Phosphatidylinositol-3-kinase p110gamma contributes to bile salt-induced apoptosis in primary rat hepatocytes and human hepatoma cells. J Hepatol 53(5):918–926
Hohenester S, Wenniger LM, Paulusma CC, van Vliet SJ, Jefferson DM, Elferink RP, Beuers U (2012) A biliary HCO3- umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes. Hepatology 55(1):173–183
Hong J, Behar J, Wands J, Resnick M, Wang LJ, DeLellis RA, Lambeth D, Souza RF, Spechler SJ, Cao W (2010) Role of a novel bile acid receptor TGR5 in the development of oesophageal adenocarcinoma. Gut 59(2):170–180
Hou J, Chen Q, Zhang K, Cheng B, Xie G, Wu X, Luo C, Chen L, Liu H, Zhao B, Dai K, Fang X (2015) Sphingosine 1-phosphate receptor 2 signaling suppresses macrophage phagocytosis and impairs host defense against sepsis. Anesthesiology 123(2):409–422
Hov JR, Keitel V, Laerdahl JK, Spomer L, Ellinghaus E, ElSharawy A, Melum E, Boberg KM, Manke T, Balschun T, Schramm C, Bergquist A, Weismuller T, Gotthardt D, Rust C, Henckaerts L, Onnie CM, Weersma RK, Sterneck M, Teufel A, Runz H, Stiehl A, Ponsioen CY, Wijmenga C, Vatn MH, IBSEN Study Group, Stokkers PC, Vermeire S, Mathew CG, Lie BA, Beuers U, Manns MP, Schreiber S, Schrumpf E, Häussinger D, Franke A, Karlsen TH (2010) Mutational characterization of the bile acid receptor TGR5 in primary sclerosing cholangitis. PloS One 5(8):e12403
Hov JR, Keitel V, Schrumpf E, Häussinger D, Karlsen TH (2011) TGR5 sequence variation in primary sclerosing cholangitis. Dig Dis 29(1):78–84
Howard M, Jiang X, Stolz DB, Hill WG, Johnson JA, Watkins SC, Frizzell RA, Bruton CM, Robbins PD, Weisz OA (2000) Forskolin-induced apical membrane insertion of virally expressed, epitope-tagged CFTR in polarized MDCK cells. Am J Physiol Cell Physiol 279(2):C375–C382
Hughes JE, Srinivasan S, Lynch KR, Proia RL, Ferdek P, Hedrick CC (2008) Sphingosine-1-phosphate induces an antiinflammatory phenotype in macrophages. Circ Res 102(8):950–958
Ichikawa R, Takayama T, Yoneno K, Kamada N, Kitazume MT, Higuchi H, Matsuoka K, Watanabe M, Itoh H, Kanai T, Hisamatsu T, Hibi T (2012) Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway. Immunology 136(2):153–162
Ikeda H, Nagashima K, Yanase M, Tomiya T, Arai M, Inoue Y, Tejima K, Nishikawa T, Watanabe N, Omata M, Fujiwara K (2004) Sphingosine 1-phosphate enhances portal pressure in isolated perfused liver via S1P2 with Rho activation. Biochem Biophys Res Commun 320(3):754–759
Ikeda H, Watanabe N, Ishii I, Shimosawa T, Kume Y, Tomiya T, Inoue Y, Nishikawa T, Ohtomo N, Tanoue Y, Iitsuka S, Fujita R, Omata M, Chun J, Yatomi Y (2009) Sphingosine 1-phosphate regulates regeneration and fibrosis after liver injury via sphingosine 1-phosphate receptor 2. J Lipid Res 50(3):556–564
Iracheta-Vellve A, Calenda CD, Petrasek J, Ambade A, Kodys K, Adorini L, Szabo G (2018) FXR and TGR5 agonists ameliorate liver injury, steatosis, and inflammation after binge or prolonged alcohol feeding in mice. Hepatol Commun 2(11):1379–1391
Ishii I, Friedman B, Ye X, Kawamura S, McGiffert C, Contos JJ, Kingsbury MA, Zhang G, Brown JH, Chun J (2001) Selective loss of sphingosine 1-phosphate signaling with no obvious phenotypic abnormality in mice lacking its G protein-coupled receptor, LP(B3)/EDG-3. J Biol Chem 276(36):33697–33704
Isomoto H, Mott JL, Kobayashi S, Werneburg NW, Bronk SF, Haan S, Gores GJ (2007) Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing. Gastroenterology 132(1):384–396
Iwakiri Y, Groszmann RJ (2007) Vascular endothelial dysfunction in cirrhosis. J Hepatol 46(5):927–934
Iwakiri Y, Shah V, Rockey DC (2014) Vascular pathobiology in chronic liver disease and cirrhosis - current status and future directions. J Hepatol 61(4):912–924
Kageyama Y, Ikeda H, Watanabe N, Nagamine M, Kusumoto Y, Yashiro M, Satoh Y, Shimosawa T, Shinozaki K, Tomiya T, Inoue Y, Nishikawa T, Ohtomo N, Tanoue Y, Yokota H, Koyama T, Ishimaru K, Okamoto Y, Takuwa Y, Koike K, Yatomi Y (2012) Antagonism of sphingosine 1-phosphate receptor 2 causes a selective reduction of portal vein pressure in bile duct-ligated rodents. Hepatology 56(4):1427–1438
Karababa A, Groos-Sahr K, Albrecht U, Keitel V, Shafigullina A, Görg B, Häussinger D (2017) Ammonia attenuates LPS-induced upregulation of pro-inflammatory cytokine mRNA in co-cultured astrocytes and microglia. Neurochem Res 42(3):737–749
Karimian G, Buist-Homan M, Schmidt M, Tietge UJ, de Boer JF, Klappe K, Kok JW, Combettes L, Tordjmann T, Faber KN, Moshage H (2013) Sphingosine kinase-1 inhibition protects primary rat hepatocytes against bile salt-induced apoptosis. Biochim Biophys Acta 1832(12):1922–1929
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(11):9435–9440
Keitel V, Häussinger D (2011) TGR5 in the biliary tree. Dig Dis 29(1):45–47
Keitel V, Häussinger D (2012) Perspective: TGR5 (Gpbar-1) in liver physiology and disease. Clin Res Hepatol Gastroenterol 36(5):412–419
Keitel V, Häussinger D (2013) TGR5 in cholangiocytes. Curr Opin Gastroenterol 29(3):299–304
Keitel V, Häussinger D (2018) Role of TGR5 (GPBAR1) in liver disease. Semin Liver Dis 38(4):333–339
Keitel V, Reinehr R, Gatsios P, Rupprecht C, Görg B, Selbach O, Häussinger D, Kubitz R (2007) The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology 45(3):695–704
Keitel V, Kubitz R, Häussinger D (2008a) Endocrine and paracrine role of bile acids. World J Gastroenterol: WJG 14(37):5620–5629
Keitel V, Donner M, Winandy S, Kubitz R, Häussinger D (2008b) Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun 372(1):78–84
Keitel V, Cupisti K, Ullmer C, Knoefel WT, Kubitz R, Häussinger D (2009) The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology 50(3):861–870
Keitel V, Görg B, Bidmon HJ, Zemtsova I, Spomer L, Zilles K, Häussinger D (2010a) The bile acid receptor TGR5 (Gpbar-1) acts as a neurosteroid receptor in brain. Glia 58(15):1794–1805
Keitel V, Ullmer C, Häussinger D (2010b) The membrane-bound bile acid receptor TGR5 (Gpbar-1) is localized in the primary cilium of cholangiocytes. Biol Chem 391(7):785–789
Keitel V, Reich M, Häussinger D (2015) TGR5: pathogenetic role and/or therapeutic target in fibrosing cholangitis? Clin Rev Allergy Immunol 48(2–3):218–225
Kono M, Belyantseva IA, Skoura A, Frolenkov GI, Starost MF, Dreier JL, Lidington D, Bolz SS, Friedman TB, Hla T, Proia RL (2007) Deafness and stria vascularis defects in S1P2 receptor-null mice. J Biol Chem 282(14):10690–10696
Kwong E, Li Y, Hylemon PB, Zhou H (2015) Bile acids and sphingosine-1-phosphate receptor 2 in hepatic lipid metabolism. Acta Pharm Sin B 5(2):151–157
Lavoie B, Balemba OB, Godfrey C, Watson CA, Vassileva G, Corvera CU, Nelson MT, Mawe GM (2010) Hydrophobic bile salts inhibit gallbladder smooth muscle function via stimulation of GPBAR1 receptors and activation of KATP channels. J Physiol 588. (Pt 17:3295–3305
Li C, Zheng S, You H, Liu X, Lin M, Yang L, Li L (2011a) Sphingosine 1-phosphate (S1P)/S1P receptors are involved in human liver fibrosis by action on hepatic myofibroblasts motility. J Hepatol 54(6):1205–1213
Li T, Holmstrom SR, Kir S, Umetani M, Schmidt DR, Kliewer SA, Mangelsdorf DJ (2011b) The G protein-coupled bile acid receptor, TGR5, stimulates gallbladder filling. Mol Endocrinol 25(6):1066–1071
Li S, Qiu M, Kong Y, Zhao X, Choi HJ, Reich M, Bunkelman BH, Liu Q, Hu S, Han M, Xie H, Rosenberg AZ, Keitel V, Kwon TH, Levi M, Li C, Wang W (2018) Bile acid G protein-coupled membrane receptor TGR5 modulates aquaporin 2-mediated water homeostasis. J Am Soc Nephrol 29(11):2658–2670
Lieu T, Jayaweera G, Zhao P, Poole DP, Jensen D, Grace M, McIntyre P, Bron R, Wilson YM, Krappitz M, Haerteis S, Korbmacher C, Steinhoff MS, Nassini R, Materazzi S, Geppetti P, Corvera CU, Bunnett NW (2014) The bile acid receptor TGR5 activates the trpa1 channel to induce itch in mice. Gastroenterology 147(6):1417–1428
Liu X, Yue S, Li C, Yang L, You H, Li L (2011) Essential roles of sphingosine 1-phosphate receptor types 1 and 3 in human hepatic stellate cells motility and activation. J Cell Physiol 226(9):2370–2377
Liu W, Lan T, Xie X, Huang K, Peng J, Huang J, Shen X, Liu P, Huang H (2012) S1P2 receptor mediates sphingosine-1-phosphate-induced fibronectin expression via MAPK signaling pathway in mesangial cells under high glucose condition. Exp Cell Res 318(8):936–943
Liu R, Zhao R, Zhou X, Liang X, Campbell DJ, Zhang X, Zhang L, Shi R, Wang G, Pandak WM, Sirica AE, Hylemon PB, Zhou H (2014) Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2. Hepatology 60(3):908–918
Liu R, Li X, Qiang X, Luo L, Hylemon PB, Jiang Z, Zhang L, Zhou H (2015) Taurocholate induces cyclooxygenase-2 expression via the sphingosine 1-phosphate receptor 2 in a human cholangiocarcinoma cell line. J Biol Chem 290(52):30988–31002
Lorenz JN, Arend LJ, Robitz R, Paul RJ, MacLennan AJ (2007) Vascular dysfunction in S1P2 sphingosine 1-phosphate receptor knockout mice. Am J Physiol Regul Integr Comp Physiol 292(1):R440–R446
MacLennan AJ, Carney PR, Zhu WJ, Chaves AH, Garcia J, Grimes JR, Anderson KJ, Roper SN, Lee N (2001) An essential role for the H218/AGR16/Edg-5/LP(B2) sphingosine 1-phosphate receptor in neuronal excitability. Eur J Neurosci 14(2):203–209
Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ, Shan B (1999) Identification of a nuclear receptor for bile acids. Science 284(5418):1362–1365
Maroni L, Alpini G, Marzioni M (2014) Cholangiocarcinoma development: the resurgence of bile acids. Hepatology 60(3):795–797
Martin RE, Bissantz C, Gavelle O, Kuratli C, Dehmlow H, Richter HG, Obst Sander U, Erickson SD, Kim K, Pietranico-Cole SL, Alvarez-Sanchez R, Ullmer C (2013) 2-Phenoxy-nicotinamides are potent agonists at the bile acid receptor GPBAR1 (TGR5). ChemMedChem 8(4):569–576
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):714–719
Maruyama T, Tanaka K, Suzuki J, Miyoshi H, Harada N, Nakamura T, Miyamoto Y, Kanatani A, Tamai Y (2006) Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) in mice. J Endocrinol 191(1):197–205
Masyuk AI, Huang BQ, Radtke BN, Gajdos GB, Splinter PL, Masyuk TV, Gradilone SA, LaRusso NF (2013) Ciliary subcellular localization of TGR5 determines the cholangiocyte functional response to bile acid signaling. Am J Physiol Gastrointest Liver Physiol 304(11):G1013–G1024
Masyuk TV, Masyuk AI, LaRusso NF (2015) TGR5 in the cholangiociliopathies. Dig Dis 33(3):420–425
Masyuk TV, Masyuk AI, Lorenzo Pisarello M, Howard BN, Huang BQ, Lee PY, Fung X, Sergienko E, Ardecky RJ, Chung TDY, Pinkerton AB, LaRusso NF (2017) TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate/Galphas signaling. Hepatology 66(4):1197–1218
McMahan RH, Wang XX, Cheng LL, Krisko T, Smith M, El Kasmi K, Pruzanski M, Adorini L, Golden-Mason L, Levi M, Rosen HR (2013) Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J Biol Chem 288(17):11761–11770
McMillin M, Frampton G, Grant S, Khan S, Diocares J, Petrescu A, Wyatt A, Kain J, Jefferson B, DeMorrow S (2017) Bile acid-mediated sphingosine-1-phosphate receptor 2 signaling promotes neuroinflammation during hepatic encephalopathy in mice. Front Cell Neurosci 11:191
Meng H, Lee VM (2009) Differential expression of sphingosine-1-phosphate receptors 1-5 in the developing nervous system. Dev Dyn 238(2):487–500
Nagahashi M, Takabe K, Liu R, Peng K, Wang X, Wang Y, Hait NC, Wang X, Allegood JC, Yamada A, Aoyagi T, Liang J, Pandak WM, Spiegel S, Hylemon PB, Zhou H (2015) Conjugated bile acid-activated S1P receptor 2 is a key regulator of sphingosine kinase 2 and hepatic gene expression. Hepatology 61(4):1216–1226
Nagahashi M, Yuza K, Hirose Y, Nakajima M, Ramanathan R, Hait NC, Hylemon PB, Zhou H, Takabe K, Wakai T (2016) The roles of bile acids and sphingosine-1-phosphate signaling in the hepatobiliary diseases. J Lipid Res 57(9):1636–1643
Park J, Tadlock L, Gores GJ, Patel T (1999) Inhibition of interleukin 6-mediated mitogen-activated protein kinase activation attenuates growth of a cholangiocarcinoma cell line. Hepatology 30(5):1128–1133
Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, Willson TM, Zavacki AM, Moore DD, Lehmann JM (1999) Bile acids: natural ligands for an orphan nuclear receptor. Science 284(5418):1365–1368
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 (2013) The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice. Hepatology 58(4):1451–1460
Perino A, Schoonjans K (2015) TGR5 and immunometabolism: insights from physiology and pharmacology. Trends Pharmacol Sci 36(12):847–857
Perino A, Pols TW, Nomura M, Stein S, Pellicciari R, Schoonjans K (2014) TGR5 reduces macrophage migration through mTOR-induced C/EBPbeta differential translation. J Clin Invest 124(12):5424–5436
Pols TW, Noriega LG, Nomura M, Auwerx J, Schoonjans K (2011a) The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation. J Hepatol 54(6):1263–1272
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 (2011b) TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab 14(6):747–757
Poole DP, Godfrey C, Cattaruzza F, Cottrell GS, Kirkland JG, Pelayo JC, Bunnett NW, Corvera CU (2010) Expression and function of the bile acid receptor GpBAR1 (TGR5) in the murine enteric nervous system. Neurogastroenterol Motil 22(7):814–825. e227–8
Rajagopal S, Kumar DP, Mahavadi S, Bhattacharya S, Zhou R, Corvera CU, Bunnett NW, Grider JR, Murthy KS (2013) Activation of G protein-coupled bile acid receptor, TGR5, induces smooth muscle relaxation via both Epac- and PKA-mediated inhibition of RhoA/Rho kinase pathway. Am J Physiol Gastrointest Liver Physiol 304(5):G527–G535
Raufman JP, Chen Y, Cheng K, Compadre C, Compadre L, Zimniak P (2002a) Selective interaction of bile acids with muscarinic receptors: a case of molecular mimicry. Eur J Pharmacol 457(2–3):77–84
Raufman JP, Chen Y, Zimniak P, Cheng K (2002b) Deoxycholic acid conjugates are muscarinic cholinergic receptor antagonists. Pharmacology 65(4):215–221
Reich M, Deutschmann K, Sommerfeld A, Klindt C, Kluge S, Kubitz R, Ullmer C, Knoefel WT, Herebian D, Mayatepek E, Häussinger D, Keitel V (2016) TGR5 is essential for bile acid-dependent cholangiocyte proliferation in vivo and in vitro. Gut 65(3):487–501
Reich M, Klindt C, Deutschmann K, Spomer L, Häussinger D, Keitel V (2017) Role of the G protein-coupled bile acid receptor TGR5 in liver damage. Dig Dis 35(3):235–240
Reinehr R, Fischer R, Häussinger D (2002) Regulation of endothelin-A receptor sensitivity by cyclic adenosine monophosphate in rat hepatic stellate cells. Hepatology 36(4 Pt 1):861–873
Reinehr R, Graf D, Häussinger D (2003) Bile salt-induced hepatocyte apoptosis involves epidermal growth factor receptor-dependent CD95 tyrosine phosphorylation. Gastroenterology 125(3):839–853
Reinehr R, Becker S, Wettstein M, Häussinger D (2004) Involvement of the Src family kinase yes in bile salt-induced apoptosis. Gastroenterology 127(5):1540–1557
Reinehr R, Becker S, Keitel V, Eberle A, Grether-Beck S, Häussinger D (2005) Bile salt-induced apoptosis involves NADPH oxidase isoform activation. Gastroenterology 129(6):2009–2031
Renga B, Bucci M, Cipriani S, Carino A, Monti MC, Zampella A, Gargiulo A, d’Emmanuele di Villa Bianca R, Distrutti E, Fiorucci S (2015a) Cystathionine gamma-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 309(1):H114–H126
Renga B, Cipriani S, Carino A, Simonetti M, Zampella A, Fiorucci S (2015b) Reversal of endothelial dysfunction by GPBAR1 agonism in portal hypertension involves a AKT/FOXOA1 dependent regulation of H2S generation and endothelin-1. PLoS One 10(11):e0141082
Roth JD, Feigh M, Veidal SS, Fensholdt LK, Rigbolt KT, Hansen HH, Chen LC, Petitjean M, Friley W, Vrang N, Jelsing J, Young M (2018) INT-767 improves histopathological features in a diet-induced ob/ob mouse model of biopsy-confirmed non-alcoholic steatohepatitis. World J Gastroenterol 24(2):195–210
Sanchez T, Skoura A, Wu MT, Casserly B, Harrington EO, Hla T (2007) Induction of vascular permeability by the sphingosine-1-phosphate receptor-2 (S1P2R) and its downstream effectors ROCK and PTEN. Arterioscler Thromb Vasc Biol 27(6):1312–1318
Santos-Cortez RL, Faridi R, Rehman AU, Lee K, Ansar M, Wang X, Morell RJ, Isaacson R, Belyantseva IA, Dai H, Acharya A, Qaiser TA, Muhammad D, Ali RA, Shams S, Hassan MJ, Shahzad S, Raza SI, Bashir ZE, Smith JD, Nickerson DA, Bamshad MJ, University of Washington Center for Mendelian Genomics, Riazuddin S, Ahmad W, Friedman TB, Leal SM (2016) Autosomal-recessive hearing impairment due to rare missense variants within S1PR2. Am J Hum Genet 98(2):331–338
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):1831–1841
Sato M, Ikeda H, Uranbileg B, Kurano M, Saigusa D, Aoki J, Maki H, Kudo H, Hasegawa K, Kokudo N, Yatomi Y (2016) Sphingosine kinase-1, S1P transporter spinster homolog 2 and S1P2 mRNA expressions are increased in liver with advanced fibrosis in human. Sci Rep 6:32119
Sawitza I, Kordes C, Götze S, Herebian D, Häussinger D (2015) Bile acids induce hepatic differentiation of mesenchymal stem cells. Sci Rep 5:13320
Sheikh Abdul Kadir SH, Miragoli M, Abu-Hayyeh S, Moshkov AV, Xie Q, Keitel V, Nikolaev VO, Williamson C, Gorelik J (2010) Bile acid-induced arrhythmia is mediated by muscarinic M2 receptors in neonatal rat cardiomyocytes. PLoS One 5(3):e9689
Sodeman T, Bronk SF, Roberts PJ, Miyoshi H, Gores GJ (2000) Bile salts mediate hepatocyte apoptosis by increasing cell surface trafficking of Fas. Am J Physiol Gastrointest Liver Physiol 278(6):G992–G999
Sommerfeld A, Reinehr R, Häussinger D (2015) Tauroursodeoxycholate protects rat hepatocytes from bile acid-induced apoptosis via beta1-integrin- and protein kinase A-dependent mechanisms. Cell Physiol Biochem 36(3):866–883
Soroka CJ, Assis DN, Alrabadi LS, Roberts S, Cusack L, Jaffe AB, Boyer JL (2018) Bile-derived organoids from patients with primary sclerosing cholangitis recapitulate their inflammatory immune profile. Hepatology. https://doi.org/10.1002/hep.30470
Staudinger JL, Goodwin B, Jones SA, Hawkins-Brown D, MacKenzie KI, LaTour A, Liu Y, Klaassen CD, Brown KK, Reinhard J, Willson TM, Koller BH, Kliewer SA (2001) The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl AcadSciUSA 98(6):3369–3374
Studer E, Zhou X, Zhao R, Wang Y, Takabe K, Nagahashi M, Pandak WM, Dent P, Spiegel S, Shi R, Xu W, Liu X, Bohdan P, Zhang L, Zhou H, Hylemon PB (2012) Conjugated bile acids activate the sphingosine-1-phosphate receptor 2 in primary rodent hepatocytes. Hepatology 55(1):267–276
Tacke F (2017) Targeting hepatic macrophages to treat liver diseases. J Hepatol 66(6):1300–1312
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 (2009) TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 10(3):167–177
Tietz PS, Marinelli RA, Chen XM, Huang B, Cohn J, Kole J, McNiven MA, Alper S, LaRusso NF (2003) Agonist-induced coordinated trafficking of functionally related transport proteins for water and ions in cholangiocytes. J Biol Chem 278(22):20413–20419
Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson A, Kampf C, Sjostedt E, Asplund A, Olsson I, Edlund K, Lundberg E, Navani S, Szigyarto CA, Odeberg J, Djureinovic D, Takanen JO, Hober S, Alm T, Edqvist PH, Berling H, Tegel H, Mulder J, Rockberg J, Nilsson P, Schwenk JM, Hamsten M, von Feilitzen K, Forsberg M, Persson L, Johansson F, Zwahlen M, von Heijne G, Nielsen J, Ponten F (2015) Proteomics. Tissue-based map of the human proteome. Science 347(6220):1260419
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 (2006) Targeted deletion of Gpbar1 protects mice from cholesterol gallstone formation. Biochem J 398(3):423–430
Velazquez-Villegas LA, Perino A, Lemos V, Zietak M, Nomura M, Pols TWH, Schoonjans K (2018) TGR5 signalling promotes mitochondrial fission and beige remodelling of white adipose tissue. Nat Commun 9(1):245
Wammers M, Schupp AK, Bode JG, Ehlting C, Wolf S, Deenen R, Köhrer K, Häussinger D, Graf D (2018) Reprogramming of pro-inflammatory human macrophages to an anti-inflammatory phenotype by bile acids. Sci Rep 8(1):255
Wang H, Chen J, Hollister K, Sowers LC, Forman BM (1999) Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 3(5):543–553
Wang YD, Chen WD, Yu D, Forman BM, Huang W (2011) The G-protein-coupled bile acid receptor, Gpbar1 (TGR5), negatively regulates hepatic inflammatory response through antagonizing nuclear factor kappa light-chain enhancer of activated B cells (NF-kappaB) in mice. Hepatology 54(4):1421–1432
Wang C, Mao J, Redfield S, Mo Y, Lage JM, Zhou X (2014) Systemic distribution, subcellular localization and differential expression of sphingosine-1-phosphate receptors in benign and malignant human tissues. Exp Mol Pathol 97(2):259–265
Wang XX, Edelstein MH, Gafter U, Qiu L, Luo Y, Dobrinskikh E, Lucia S, Adorini L, D'Agati VD, Levi J, Rosenberg A, Kopp JB, Gius DR, Saleem MA, Levi M (2016) G protein-coupled bile acid receptor TGR5 activation inhibits kidney disease in obesity and diabetes. J Am Soc Nephrol 27(5):1362–1378
Wang Y, Aoki H, Yang J, Peng K, Liu R, Li X, Qiang X, Sun L, Gurley EC, Lai G, Zhang L, Liang G, Nagahashi M, Takabe K, Pandak WM, Hylemon PB, Zhou H (2017) The role of sphingosine 1-phosphate receptor 2 in bile-acid-induced cholangiocyte proliferation and cholestasis-induced liver injury in mice. Hepatology 65(6):2005–2018
Ward JB, Mroz MS, Keely SJ (2013) The bile acid receptor, TGR5, regulates basal and cholinergic-induced secretory responses in rat colon. Neurogastroenterol Motil 25(8):708–711
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 (2006) Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439(7075):484–489
Welzel TM, Graubard BI, El-Serag HB, Shaib YH, Hsing AW, Davila JA, McGlynn KA (2007) Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case-control study. Clin Gastroenterol Hepatol 5(10):1221–1228
Williams MJ, Clouston AD, Forbes SJ (2014) Links between hepatic fibrosis, ductular reaction, and progenitor cell expansion. Gastroenterology 146(2):349–356
Wu T (2005) Cyclooxygenase-2 and prostaglandin signaling in cholangiocarcinoma. Biochim Biophys Acta 1755(2):135–150
Xie W, Radominska-Pandya A, Shi Y, Simon CM, Nelson MC, Ong ES, Waxman DJ, Evans RM (2001) An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids. Proc Natl Acad Sci U S A 98(6):3375–3380
Xu W, Lu C, Zhang F, Shao J, Zheng S (2016) Dihydroartemisinin restricts hepatic stellate cell contraction via an FXR-S1PR2-dependent mechanism. IUBMB Life 68(5):376–387
Yang H, Li TW, Peng J, Tang X, Ko KS, Xia M, Aller MA (2011) A mouse model of cholestasis-associated cholangiocarcinoma and transcription factors involved in progression. Gastroenterology 141(1):378–388. 388.e1–4
Yang L, Han Z, Tian L, Mai P, Zhang Y, Wang L, Li L (2015) Sphingosine 1-phosphate receptor 2 and 3 mediate bone marrow-derived monocyte/macrophage motility in cholestatic liver injury in mice. Sci Rep 5:13423
Yang J, Yang L, Tian L, Ji X, Yang L, Li L (2018) Sphingosine 1-phosphate (S1P)/S1P receptor2/3 axis promotes inflammatory M1 polarization of bone marrow-derived monocyte/macrophage via G(alpha)i/o/PI3K/JNK pathway. Cell Physiol Biochem 49(5):1677–1693
Zhang G, Yang L, Kim GS, Ryan K, Lu S, O'Donnell RK, Spokes K, Shapiro N, Aird WC, Kluk MJ, Yano K, Sanchez T (2013) Critical role of sphingosine-1-phosphate receptor 2 (S1PR2) in acute vascular inflammation. Blood 122(3):443–455
Zhou H, Hylemon PB (2014) Bile acids are nutrient signaling hormones. Steroids 86:62–68
Acknowledgment
Our studies reported herein were supported by DFG through SFB974 “Communication and systems relevance in liver damage and regeneration.”
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Keitel, V., Stindt, J., Häussinger, D. (2019). Bile Acid-Activated Receptors: GPBAR1 (TGR5) and Other G Protein-Coupled Receptors. In: Fiorucci, S., Distrutti, E. (eds) Bile Acids and Their Receptors. Handbook of Experimental Pharmacology, vol 256. Springer, Cham. https://doi.org/10.1007/164_2019_230
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