Bile acids activated receptors regulate innate immunity

Frontiers in Immunology

Volumn 9, Issue AUG, 2018, Pages

  Fiorucci, Stefano ^a   Biagioli, Michele ^a   Zampella, Angela ^b   Distrutti, Eleonora ^a  

^a UNIVERSITY OF PERUGIA   (Italy)

^b UNIVERSITY OF NAPLES FEDERICO II   (Italy)

Author keywords

Bile acids; Farnesoid X receptor; G protein bile acid receptor 1; Innate immunity; Intestinal microbiota

Indexed keywords

BILE ACID ACTIVATED RECEPTOR; CHOLESTANETRIOL 26 MONOOXYGENASE; CHOLESTEROL 7ALPHA MONOOXYGENASE; CYCLIC AMP DEPENDENT PROTEIN KINASE; CYCLIC AMP RESPONSIVE ELEMENT BINDING PROTEIN; FARNESOID X RECEPTOR; FIBROBLAST GROWTH FACTOR; FIBROBLAST GROWTH FACTOR 19; FIBROBLAST GROWTH FACTOR RECEPTOR 4; G PROTEIN COUPLED BILE ACID RECEPTOR 1; G PROTEIN COUPLED RECEPTOR; GAMMA INTERFERON; GLUCAGON LIKE PEPTIDE 1; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INDUCIBLE NITRIC OXIDE SYNTHASE; INFLAMMASOME; INTERLEUKIN 12; INTERLEUKIN 18; INTERLEUKIN 1BETA; INTERLEUKIN 6; PREGNANE X RECEPTOR; PROTEIN BAD; PROTEIN BAX; PYRUVATE DEHYDROGENASE COMPLEX; RECEPTOR INTERACTING PROTEIN 140; RETINOID X RECEPTOR; SMALL INTERFERING RNA; SODIUM BILE ACID COTRANSPORTER; TUMOR NECROSIS FACTOR; UNCLASSIFIED DRUG; UNINDEXED DRUG; BILE ACID; CELL RECEPTOR; CHOLESTEROL; FARNESOID X-ACTIVATED RECEPTOR; GPBAR1 PROTEIN, HUMAN;

AUTOIMMUNE DISEASE; BILE ACID METABOLISM; CHOLESTEROL METABOLISM; DOWN REGULATION; FEEDBACK SYSTEM; GENE OVEREXPRESSION; GENETIC TRANSCRIPTION; HOST PARASITE INTERACTION; HUMAN; IMMUNOLOGICAL TOLERANCE; INFLAMMATORY BOWEL DISEASE; INNATE IMMUNITY; INTESTINE FLORA; LIVER DISEASE; MICROBIAL COMMUNITY; NONHUMAN; PRIMARY BILIARY CIRRHOSIS; PROTEIN EXPRESSION; REVIEW; TRANSCRIPTION INITIATION; TUMOR MICROENVIRONMENT; UPREGULATION; ANIMAL; HOMEOSTASIS; IMMUNOLOGY; INTESTINE; LIVER; METABOLISM; MICROBIOLOGY; PHYSIOLOGY;

ANIMALS; BILE ACIDS AND SALTS; CHOLESTEROL; GASTROINTESTINAL MICROBIOME; HOMEOSTASIS; HUMANS; IMMUNE TOLERANCE; IMMUNITY, INNATE; INTESTINES; LIVER; RECEPTORS, CYTOPLASMIC AND NUCLEAR; RECEPTORS, G-PROTEIN-COUPLED;

EID: 85051472917     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2018.01853     Document Type: Review

References (113)

1. Zhou L, Sonnenberg GF. Essential immunologic orchestrators of intestinal homeostasis. Sci Immunol (2018) 3(20):eaao1605. doi:10.1126/sciimmunol.aao1605
2. Horst AK, Neumann K, Diehl L, Tiegs G. Modulation of liver tolerance by conventional and nonconventional antigen-presenting cells and regulatory immune cells. Cell Mol Immunol (2016) 13(3):277-92. doi:10.1038/cmi.2015.112
3. Wahlström A, Sayin SI, Marschall HU, Bäckhed F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab (2016) 24(1):41-50. doi:10.1016/j.cmet.2016.05.005
4. Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res (2006) 47(2):241-59. doi:10.1194/jlr. R500013-JLR200
5. Fiorucci S, Distrutti E. Bile acid-activated receptors, intestinal microbiota, and the treatment of metabolic disorders. Trends Mol Med (2015) 21(11):702-14. doi:10.1016/j.molmed.2015.09.001
6. Chiang JY. Bile acids: regulation of synthesis. J Lipid Res (2009) 50(10):1955-66. doi:10.1194/jlr. R900010-JLR200
7. Maruyama T, Miyamoto Y, Nakamura T, Tamai Y, Okada H, Sugiyama E, et al. Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun (2002) 298(5):714-9. doi:10.1016/S0006-291X(02)02550-0
8. Vavassori P, Mencarelli A, Renga B, Distrutti E, Fiorucci S. The bile acid receptor FXR is a modulator of intestinal innate immunity. J Immunol (2009) 183(10):6251-61. doi:10.4049/jimmunol.0803978
9. Mencarelli A, Renga B, Migliorati M, Cipriani S, Distrutti E, Santucci L, et al. The bile acid sensor farnesoid X receptor is a modulator of liver immunity in a rodent model of acute hepatitis. J Immunol (2009) 183(10):6657-66. doi:10.4049/jimmunol.0901347
10. Cipriani S, Mencarelli A, Chini MG, Distrutti E, Renga B, Bifulco G, et al. The bile acid receptor GPBAR-1 (TGR5) modulates integrity of intestinal barrier and immune response to experimental colitis. PLoS One (2011) 6(10):e25637. doi:10.1371/journal.pone.0025637
11. Ikegami T, Honda A. Reciprocal interactions between bile acids and gut microbiota in human liver diseases. Hepatol Res (2018) 48(1):15-27. doi:10.1111/hepr.13001
12. Ramírez-Pérez O, Cruz-Ramón V, Chinchilla-López P, Méndez-Sánchez N. The role of the gut microbiota in bile acid metabolism. Ann Hepatol (2017) 16(Suppl 1: s3-105):s15-20. doi:10.5604/01.3001.0010.5494
13. Klaassen CD, Cui JY. Review: mechanisms of how the intestinal microbiota alters the effects of drugs and bile acids. Drug Metab Dispos (2015) 43(10):1505-21. doi:10.1124/dmd.115.065698
14. Trabelsi MS, Daoudi M, Prawitt J, Ducastel S, Touche V, Sayin SI, et al. Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells. Nat Commun (2015) 6:7629. doi:10.1038/ncomms8629
15. Sayin SI, Wahlström A, Felin J, Jäntti S, Marschall HU, Bamberg K, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab (2013) 17(2):225-35. doi:10.1016/j.cmet.2013.01.003
16. Selwyn FP, Csanaky IL, Zhang Y, Klaassen CD. Importance of large intestine in regulating bile acids and glucagon-like peptide-1 in germ-free mice. Drug Metab Dispos (2015) 3(10):1544-56. doi:10.1124/dmd.115.065276
17. Kawamata Y, Fujii R, Hosoya M, Harada M, Yoshida H, Miwa M, et al. A G protein-coupled receptor responsive to bile acids. J Biol Chem (2003) 278(11):9435-40. doi:10.1074/jbc. M209706200
18. Keitel V, Reinehr R, Gatsios P, Rupprecht C, Görg B, Selbach O, et al. The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology (2007) 45(3):695-704. doi:10.1002/hep.21458
19. Renga B, Mencarelli A, Cipriani S, D'Amore C, Carino A, Bruno A, et al. The bile acid sensor FXR is required for immune-regulatory activities of TLR-9 in intestinal inflammation. PLoS One (2013) 8(1):e54472. doi:10.1371/journal.pone.0054472
20. Wildenberg ME, van den Brink GR. FXR activation inhibits inflammation and preserves the intestinal barrier in IBD. Gut (2011) 60(4):432-3. doi:10.1136/gut.2010.233304
21. Chanda D, Park JH, Choi HS. Molecular basis of endocrine regulation by orphan nuclear receptor small heterodimer partner. Endocr J (2008) 55(2):253-68. doi:10.1507/endocrj. K07E-103
22. Fiorucci S, Antonelli E, Rizzo G, Renga B, Mencarelli A, Riccardi L, et al. The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology (2004) 127(5):1497-512. doi:10.1053/j.gastro.2004.08.001
23. Yang Z, Koehler AN, Wang L. A novel small molecule activator of nuclear receptor SHP inhibits HCC cell migration via suppressing Ccl2. Mol Cancer Ther (2016) 15(10):2294-301. doi:10.1158/1535-7163.MCT-16-0153
24. Zhang Y, Liu C, Barbier O, Smalling R, Tsuchiya H, Lee S, et al. Bcl2 is a critical regulator of bile acid homeostasis by dictating Shp and lncRNA H19 function. Sci Rep (2016) 6:20559. doi:10.1038/srep20559
25. Song Y, Liu C, Liu X, Trottier J, Beaudoin M, Zhang L, et al. H19 promotes cholestatic liver fibrosis by preventing ZEB1-mediated inhibition of epithelial cell adhesion molecule. Hepatology (2017) 66(4):1183-96. doi:10.1002/hep.29209
26. Biagioli M, Carino A, Cipriani S, Francisci D, Marchianò S, Scarpelli P, et al. The bile acid receptor GPBAR1 regulates the M1/M2 phenotype of intestinal macrophages and activation of GPBAR1 rescues mice from murine colitis. J Immunol (2017) 199(2):718-33. doi:10.4049/jimmunol.1700183
27. Haselow K, Bode JG, Wammers M, Ehlting C, Keitel V, Kleinebrecht L, 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(6):1253-64. doi:10.1189/jlb.0812396
28. Pols TW, Nomura M, Harach T, Lo Sasso G, Oosterveer MH, Thomas C, et al. TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab (2011) 14(6):747-57. doi:10.1016/j.cmet.2011.11.006
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(12):5424-36. doi:10.1172/JCI76289
30. 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(6):1263-72. doi:10.1016/j.jhep.2010.12.004
31. Gadaleta RM, van Erpecum KJ, Oldenburg B, Willemsen EC, Renooij W, Murzilli S, et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut (2011) 60(4):463-72. doi:10.1136/gut.2010.212159
32. Massafra V, Ijssennagger N, Plantinga M, Milona A, Ramos Pittol JM, Boes M, et al. Splenic dendritic cell involvement in FXR-mediated amelioration of DSS colitis. Biochim Biophys Acta (2016) 1862(2):166-73. doi:10.1016/j.bbadis.2015.11.001
33. Ichikawa R, Takayama T, Yoneno K, Kamada N, Kitazume MT, Higuchi H, et al. Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway. Immunology (2012) 136(2):153-62. doi:10.1111/j.1365-2567.2012.03554.x
34. LamkanfiM, Dixit VM. Mechanisms and functions of inflammasomes. Cell (2014) 157(5):1013-22. doi:10.1016/j.cell.2014.04.007
35. Guo C, Xie S, Chi Z, Zhang J, Liu Y, Zhang L, et al. Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. Immunity (2016) 45(4):802-16. doi:10.1016/j.immuni.2016.09.008
36. Hao H, Cao L, Jiang C, Che Y, Zhang S, Takahashi S, et al. Farnesoid X receptor regulation of the NLRP3 inflammasome underlies cholestasis-associated sepsis. Cell Metab (2017) 25(4):856-67.e5. doi:10.1016/j.cmet.2017.03.007
37. Liu HM, Liao JF, Lee TY. Farnesoid X receptor agonist GW4064 ameliorates lipopolysaccharide-induced ileocolitis through TLR4/MyD88 pathway related mitochondrial dysfunction in mice. Biochem Biophys Res Commun (2017) 490(3):841-8. doi:10.1016/j.bbrc.2017.06.129
38. Cai SY, Ouyang X, Chen Y, Soroka CJ, Wang J, Mennone A, et al. Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response. JCI Insight (2017) 2(5):e90780. doi:10.1172/jci.insight.90780
39. Yang CS, Kim JJ, Kim TS, Lee PY, Kim SY, Lee HM, et al. Small heterodimer partner interacts with NLRP3 and negatively regulates activation of the NLRP3 inflammasome. Nat Commun (2015) 6:6115. doi:10.1038/ncomms7115
40. Gong Z, Zhou J, Zhao S, Tian C, Wang P, Xu C, et al. Chenodeoxycholic acid activates NLRP3 inflammasome and contributes to cholestatic liver fibrosis. Oncotarget (2016) 7(51):83951-63. doi:10.18632/oncotarget.13796
41. 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(6):731-44. doi:10.1016/S0092-8674(00)00062-3
42. Vassileva G, Golovko A, Markowitz L, Abbondanzo SJ, Zeng M, Yang S, et al. Targeted deletion of Gpbar1 protects mice from cholesterol gallstone formation. Biochem J (2006) 398(3):423-30. doi:10.1042/BJ20060537
43. Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature (2012) 489(7415):220-30. doi:10.1038/nature11550
44. Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature (2012) 486(7402):207-14. doi:10.1038/nature11234
45. Wright EK, Kamm MA, Teo SM, Inouye M, Wagner J, Kirkwood CD. Recent advances in characterizing the gastrointestinal microbiome in Crohn's disease: a systematic review. Inflamm Bowel Dis (2015) 21(6):1219-28. doi:10.1097/MIB.0000000000000382
46. Duboc H, Rajca S, Rainteau D, Benarous D, Maubert MA, Quervain E, et al. Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases. Gut (2013) 62(4):531-9. doi:10.1136/gutjnl-2012-302578
47. Jones BV, Begley M, Hill C, Gahan CG, Marchesi JR. Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome. Proc Natl Acad Sci U S A (2008) 105(36):13580-5. doi:10.1073/pnas.0804437105
48. Pols TWH, Puchner T, Korkmaz HI, Vos M, Soeters MR, de Vries CJM. Lithocholic acid controls adaptive immune responses by inhibition of Th1 activation through the Vitamin D receptor. PLoS One (2017) 12(5):e0176715. doi:10.1371/journal.pone.0176715
49. Degirolamo C, Rainaldi S, Bovenga F, Murzilli S, Moschetta A. Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the Fxr-Fgf15 axis in mice. Cell Rep (2014) 7(1):12-8. doi:10.1016/j.celrep.2014.02.032
50. Coskun M, Vermeire S, Nielsen OH. Novel targeted therapies for inflammatory bowel disease. Trends Pharmacol Sci (2017) 38(2):127-42. doi:10.1016/j.tips.2016.10.014
51. Zundler S, Neurath MF. Novel insights into the mechanisms of gut homing and antiadhesion therapies in inflammatory bowel diseases. Inflamm Bowel Dis (2017) 23(4):617-27. doi:10.1097/MIB.0000000000001067
52. Rivollier A, He J, Kole A, Valatas V, Kelsall BL. Inflammation switches the differentiation program of Ly6Chi monocytes from antiinflammatory macrophages to inflammatory dendritic cells in the colon. J Exp Med (2012) 209(1):139-55. doi:10.1084/jem.20101387
53. López-Cotarelo P, Gómez-Moreira C, Criado-García O, Sánchez L, Rodríguez-Fernández JL. Beyond chemoattraction: multifunctionality of chemokine receptors in leukocytes. Trends Immunol (2017) 38(12):927-41. doi:10.1016/j.it.2017.08.004
54. Fiorucci S, Biagioli M, Distrutti E. Immunephenotype predicts response to Vedolizumab: integrating clinical and biochemical biomarkers in the treatment of inflammatory bowel diseases. Dig Dis Sci (2018). doi:10.1007/s10620-018-5039-y
55. 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(7):1663-9. doi:10.1161/ATVBAHA.113.301565
56. Yoneno K, Hisamatsu T, Shimamura K, Kamada N, Ichikawa R, Kitazume MT, et al. TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease. Immunology (2013) 139(1):19-29. doi:10.1111/imm.12045
57. Lleo A, Marzorati S, Anaya JM, Gershwin ME. Primary biliary cholangitis: a comprehensive overview. Hepatol Int (2017) 11(6):485-99. doi:10.1007/s12072-017-9830-1
58. Liu JZ, Almarri MA, Gaffney DJ, Mells GF, Jostins L, Cordell HJ, et al. Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis. Nat Genet (2012) 44(10):1137-41. doi:10.1038/ng.2395
59. Lleo A, Liao J, Invernizzi P, Zhao M, Bernuzzi F, Ma L, et al. Immunoglobulin M levels inversely correlate with CD40 ligand promoter methylation in patients with primary biliary cirrhosis. Hepatology (2012) 55(1):153-60. doi:10.1002/hep.24630
60. Lal G, Zhang N, van der Touw W, Ding Y, Ju W, Bottinger EP, et al. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol (2009) 182(1):259-73. doi:10.4049/jimmunol.182.1.259
61. Sawalha AH. Epigenetics and T-cell immunity. Autoimmunity (2008) 41(4):245-52. doi:10.1080/08916930802024145
62. Lleo A, Selmi C, Invernizzi P, Podda M, Coppel RL, Mackay IR, et al. Apotopes and the biliary specificity of primary biliary cirrhosis. Hepatology (2009) 49(3):871-9. doi:10.1002/hep.22736
63. Poupon R, Chazouillères O, Poupon RE. Chronic cholestatic diseases. J Hepatol (2000) 32(1 Suppl):129-40. doi:10.1016/S0168-8278(00)80421-3
64. Amaral JD, Viana RJ, Ramalho RM, Steer CJ, Rodrigues CM. Bile acids: regulation of apoptosis by ursodeoxycholic acid. J Lipid Res (2009) 50(9):1721-34. doi:10.1194/jlr. R900011-JLR200
65. Li S, Zhao Y, He X, Kim TH, Kuharsky DK, Rabinowich H, et al. Relief of extrinsic pathway inhibition by the Bid-dependent mitochondrial release of Smac in Fas-mediated hepatocyte apoptosis. J Biol Chem (2002) 277(30):26912-20. doi:10.1074/jbc. M200726200
66. Qiao L, Studer E, Leach K, McKinstry R, Gupta S, Decker R, et al. Deoxycholic acid (DCA) causes ligand-independent activation of epidermal growth factor receptor (EGFR) and FAS receptor in primary hepatocytes: inhibition of EGFR/mitogen activated protein kinase-signaling module enhances DCA-induced apoptosis. Mol Biol Cell (2001) 12(9):2629-45. doi:10.1091/mbc.12.9.2629
67. Gujral JS, Liu J, Farhood A, Hinson JA, Jaeschke H. Functional importance of ICAM-1 in the mechanism of neutrophil-induced liver injury in bile duct-ligated mice. Am J Physiol Gastrointest Liver Physiol (2004) 286(3):G499-507. doi:10.1152/ajpgi.00318.2003
68. Ohtsuka M, Miyazaki M, Kubosawa H, Kondo Y, Ito H, Shimizu H, et al. Role of neutrophils in sinusoidal endothelial cell injury after extensive hepatectomy in cholestatic rats. J Gastroenterol Hepatol (2000) 15(8):880-6. doi:10.1046/j.1440-1746.2000.02224.x
69. Gujjral JS, Farhood A, Bajt ML, Jaeschke H. Neutrophils aggravate acute liver injury during obstructive cholestasis in bile duct-ligated mice. Hepatology (2003) 38(2):355-63. doi:10.1053/jhep.2003.50341
70. Allen K, Jaeschke H, Copple BL. Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis. Am J Pathol (2011) 178(1):175-86. doi:10.1016/j.ajpath.2010.11.026
71. Dahm LJ, Roth RA. Differential effects of lithocholate on rat neutrophil activation. J Leukoc Biol (1990) 47(6):551-60. doi:10.1002/jlb.47.6.551
72. Brien KM, Allen KM, Rockwell CE, Towery K, Luyendyk JP, Copple BL. IL-17A synergistically enhances bile acid-induced inflammation during obstructive cholestasis. Am J Pathol (2013) 183(5):1498-507. doi:10.1016/j.ajpath.2013.07.019
73. Bleier JI, Katz SC, Chaudhry UI, Pillarisetty VG, Kingham TP III, Shah AB, et al. Biliary obstruction selectively expands and activates liver myeloid dendritic cells. J Immunol (2006) 176(12):7189-95. doi:10.4049/jimmunol.176.12.7189
74. Halilbasic E, Claudel T, Trauner M. Bile acid transporters and regulatory nuclear receptors in the liver and beyond. J Hepatol (2013) 58(1):155-68. doi:10.1016/j.jhep.2012.08.002
75. Wang L, Lee YK, Bundman D, Han Y, Thevananther S, Kim CS, et al. Redundant pathways for negative feedback regulation of bile acid production. Dev Cell (2002) 2(6):721-31. doi:10.1016/S1534-5807(02)00187-9
76. Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab (2005) 2(4):217-25. doi:10.1016/j.cmet.2005.09.001
77. Ananthanarayanan M, Balasubramanian N, Makishima M, Mangelsdorf DJ, Suchy FJ. Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J Biol Chem (2001) 276(31):28857-65. doi:10.1074/jbc. M011610200
78. Kast HR, Goodwin B, Tarr PT, Jones SA, Anisfeld AM, Stoltz CM, et al. Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. J Biol Chem (2002) 277(4):2908-15. doi:10.1074/jbc. M109326200
79. Ballatori N, Christian WV, Lee JY, Dawson PA, Soroka CJ, Boyer JL, et al. OSTa-OSTβ: a major basolateral bile acid and steroid transporter in human intestinal, renal, and biliary epithelia. Hepatology (2005) 42(6):1270-9. doi:10.1002/hep.20961
80. Jung D, Mangelsdorf DJ, Meyer UA. Pregnane x receptor is a target of farnesoid x receptor. J Biol Chem (2006) 281(28):19081-91. doi:10.1074/jbc. M600116200
81. Renga B, Migliorati M, Mencarelli A, Cipriani S, D'Amore C, Distrutti E, et al. Farnesoid X receptor suppresses constitutive androstane receptor activity at the multidrug resistance protein-4 promoter. Biochim Biophys Acta (2011) 1809(3):157-65. doi:10.1016/j.bbagrm.2011.01.008
82. Perez MJ, Briz O. Bile-acid-induced cell injury and protection. World J Gastroenterol (2009) 15(14):1677-89. doi:10.3748/wjg.15.1677
83. Poupon R. Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: an overview of their mechanisms of action. Clin Res Hepatol Gastroenterol (2012) 36(Suppl 1):S3-12. doi:10.1016/S2210-7401(12)70015-3
84. Dilger K, Hohenester S, Winkler-Budenhofer U, Bastiaansen BA, Schaap FG, Rust C, et al. Effect of ursodeoxycholic acid on bile acid profiles and intestinal detoxification machinery in primary biliary cirrhosis and health. J Hepatol (2012) 57(1):133-40. doi:10.1016/j.jhep.2012.02.014
85. Yoshikawa M, Tsujii T, Matsumura K, Yamao J, Matsumura Y, Kubo R, et al. Immunomodulatory effects of ursodeoxycholic acid on immune responses. Hepatology (1992) 16(2):358-64. doi:10.1002/hep.1840160213
86. Kowdley KV, Luketic V, Chapman R, Hirschfield GM, Poupon R, Schramm C, et al. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology (2018) 67(5):1890-902. doi:10.1002/hep.29569
87. Sombetzki M, Fuchs CD, Fickert P, österreicher CH, Mueller M, Claudel T, et al. 24-nor-ursodeoxycholic acid ameliorates inflammatory response and liver fibrosis in a murine model of hepatic schistosomiasis. J Hepatol (2015) 62(4):871-8. doi:10.1016/j.jhep.2014.11.020
88. Fiorucci S, Distrutti E, Ricci P, Giuliano V, Donini A, Baldelli F. Targeting FXR in cholestasis: hype or hope? Expert Opin Ther Targets (2014) 18(12):1449-59. doi:10.1517/14728222.2014.956087
89. Sepe V, Renga B, Festa C, D'Amore C, Masullo D, Cipriani S, et al. Modification on ursodeoxycholic acid (UDCA) scaffold. Discovery of bile acid derivatives as selective agonists of cell-surface G-protein coupled bile acid receptor 1 (GP-BAR1). J Med Chem (2014) 57(18):7687-701. doi:10.1021/jm500889f
90. Pellicciari R, Fiorucci S, Camaioni E, Clerici C, Costantino G, Maloney PR, et al. 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem (2002) 45(17):3569-72. doi:10.1021/jm025529g
91. Fiorucci S, Cipriani S, Mencarelli A, Renga B, Distrutti E, Baldelli F. Counter-regulatory role of bile acid activated receptors in immunity and inflammation. Curr Mol Med (2010) 10(6):579-95. doi:10.2174/1566524011009060579
92. Fiorucci S, Clerici C, Antonelli E, Orlandi S, Goodwin B, Sadeghpour BM, et al. Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis. J Pharmacol Exp Ther (2005) 313(2):604-12. doi:10.1124/jpet.104.079665
93. FDA Adds Boxed Warning to Highlight Correct Dosing of Ocaliva (obeticholic acid) for Patients with a Rare Chronic Liver Disease. (2018). Available from: https://www.fda.gov/Drugs/DrugSafety/ucm594941.htm
94. Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol (2018) 15(1):11-20. doi:10.1038/nrgastro.2017.109
95. Younossi ZM, Loomba R, Rinella ME, Bugianesi E, Marchesini G, Neuschwander-Tetri BA, et al. Current and future therapeutic regimens for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Hepatology (2017) 68(1):361-71. doi:10.1002/hep.29724
96. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet (2015) 385(9972):956-65. doi:10.1016/S0140-6736(14)61933-4
97. Ratziu V, Sanyal AJ, MacConell L, Shringarpure R, Marmon T, Shapiro D, et al. Regenerate: a phase 3, double blind, randomized, placebo-controlled multicenter study of obeticholic acid therapy for nonalcoholic steatohepatitis. J Hepatol (2016) 64(2):S294-5. doi:10.1016/S0168-8278(16)00372-X
98. Gege C, Kinzel O, Steeneck C, Schulz A, Kremoser C. Knocking on FXR's door: the 'hammerhead'-structure series of FXR agonists-amphiphilic isoxazoles with potent in vitro and in vivo activities. Curr Top Med Chem (2014) 14:2143-58. doi:10.2174/1568026614666141112094430
99. Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Participants With Nonalcoholic Steatohepatitis (NASH). ClinicalTrials.gov Identifier: NCT02854605. Available from: https://clinicaltrials.gov/ct2/show/NCT02854605
100. Lou G, Ma X, Fu X, Meng Z, Zhang W, Wang YD, et al. GPBAR1/TGR5 mediates bile acid-induced cytokine expression in Kupffer cells. PLoS One (2014) 9(4):e93567. doi:10.1371/journal.pone.0093567
101. McMahan RH, Wang XX, Cheng LL, Krisko T, Smith M, El Kasmi K, et al. Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J Biol Chem (2013) 288(17):11761-70. doi:10.1074/jbc. M112.446575
102. Carino A, Cipriani S, Marchianò S, Biagioli M, Scarpelli P, Zampella A, et al. Gpbar1 agonism promotes a Pgc-1a-dependent browning of white adipose tissue and energy expenditure and reverses diet-induced steatohepatitis in mice. Sci Rep (2017) 7(1):13689. doi:10.1038/s41598-017-13102-y
103. Carino A, Cipriani S, Marchianò S, Biagioli M, Santorelli C, Donini A, et al. BAR502, a dual FXR and GPBAR1 agonist, promotes browning of white adipose tissue and reverses liver steatosis and fibrosis. Sci Rep (2017) 7:42801. doi:10.1038/srep42801
104. Högenauer K, Arista L, Schmiedeberg N, Werner G, Jaksche H, Bouhelal R, 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):10343-54. doi:10.1021/jm501052c
105. Wieland A, Frank DN, Harnke B, Bambha K. Systematic review: microbial dysbiosis and nonalcoholic fatty liver disease. Aliment Pharmacol Ther (2015) 42:1051-63. doi:10.1111/apt.13376
106. Loomba R, Seguritan V, Li W, Long T, Klitgord N, Bhatt A, et al. Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease. Cell Metab (2017) 25:1054-62.e5. doi:10.1016/j.cmet.2017.04.001
107. García-Lezana T, Raurell I, Bravo M, Torres-Arauz M, Salcedo MT, Santiago A, et al. Restoration of a healthy intestinal microbiota normalizes portal hypertension in a rat model of nonalcoholic steatohepatitis. Hepatology (2018) 67:1485-98. doi:10.1002/hep.29646
108. Zhou D, Pan Q, Shen F, Cao HX, Ding WJ, Chen YW, et al. Total fecal microbiota transplantation alleviates high-fat diet-induced steatohepatitis in mice via beneficial regulation of gut microbiota. Sci Rep (2017) 7(1):1529. doi:10.1038/s41598-017-01751-y
109. Lewis ND, Patnaude LA, Pelletier J, Souza DJ, Lukas SM, King FJ, et al. A GPBAR1 (TGR5) small molecule agonist shows specific inhibitory effects on myeloid cell activation in vitro and reduces experimental autoimmune encephalitis (EAE) in vivo. PLoS One (2014) 9(6):e100883. doi:10.1371/journal.pone.0100883
110. Yanguas-Casás N, Barreda-Manso MA, Nieto-Sampedro M, Romero-Ramírez L. TUDCA: an agonist of the bile acid receptor GPBAR1/TGR5 with anti-inflammatory effects in microglial cells. J Cell Physiol (2017) 232(8):2231-45. doi:10.1002/jcp.25742
111. Ho PP, Steinman L. Obeticholic acid, a synthetic bile acid agonist of the farnesoid X receptor, attenuates experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A (2016) 113(6):1600-5. doi:10.1073/pnas.1524890113
112. Wang XX, Edelstein MH, Gafter U, Qiu L, Luo Y, Dobrinskikh E, et al. G protein-coupled bile acid receptor TGR5 activation inhibits kidney disease in obesity and diabetes. J Am Soc Nephrol (2016) 27(5):1362-78. doi:10.1681/ASN.2014121271
113. Wang XX, Luo Y, Wang D, Adorini L, Pruzanski M, Dobrinskikh E, et al. A dual agonist of farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5, INT-767, reverses age-related kidney disease in mice. J Biol Chem (2017) 92(29):12018-24. doi:10.1074/jbc. C117.794982