Top

Published in:

Open Access 12-04-2022 | Primary Biliary Cholangitis | Review

Bile acids and their receptors: modulators and therapeutic targets in liver inflammation

Authors: Anna Bertolini, Romina Fiorotto, Mario Strazzabosco

Published in: Seminars in Immunopathology | Issue 4/2022

Abstract

Bile acids participate in the intestinal emulsion, digestion, and absorption of lipids and fat-soluble vitamins. When present in high concentrations, as in cholestatic liver diseases, bile acids can damage cells and cause inflammation. After the discovery of bile acids receptors about two decades ago, bile acids are considered signaling molecules. Besides regulating bile acid, xenobiotic, and nutrient metabolism, bile acids and their receptors have shown immunomodulatory properties and have been proposed as therapeutic targets for inflammatory diseases of the liver. This review focuses on bile acid–related signaling pathways that affect inflammation in the liver and provides an overview of the preclinical and clinical applications of modulators of these pathways for the treatment of cholestatic and autoimmune liver diseases.

De Boer JF, Verkade E, Mulder NL et al (2020) A human-like bile acid pool induced by deletion of hepatic Cyp2c70 modulates effects of FXR activation in mice. J Lipid Res 61:291–305. https://doi.org/10.1194/jlr.RA119000243CrossRefPubMed

Dawson PA, Karpen SJ (2015) Intestinal transport and metabolism of bile acids. J Lipid Res 56:1085–1099. https://doi.org/10.1194/jlr.R054114CrossRefPubMedPubMedCentral

Chiang JYL (2009) Bile acids: regulation of synthesis. J Lipid Res 50:1955–1966. https://doi.org/10.1194/jlr.R900010-JLR200CrossRefPubMedPubMedCentral

Hofmann AF, Hagey LR (2008) Bile acids: chemistry, pathochemistry, biology, pathobiology, and therapeutics. Cell Mol Life Sci 65:2461–2483. https://doi.org/10.1007/s00018-008-7568-6CrossRefPubMed

Heuman DM (1989) Quantitative estimation of the hydrophilic-hydrophobic balance of mixed bile salt solutions. J Lipid Res 30:719–730. https://doi.org/10.1016/S0022-2275(20)38331-0CrossRefPubMed

Attili AF, Angelico M, Cantafora A et al (1986) Bile acid-induced liver toxicity: relation to the hydrophobic-hydrophilic balance of bile acids. Med Hypotheses 19:57–69. https://doi.org/10.1016/0306-9877(86)90137-4CrossRefPubMed

Schölmerich J, Becher M-S, Schmidt K et al (1984) Influence of hydroxylation and conjugation of bile salts on their membrane-damaging properties-studies on isolated hepatocytes and lipid membrane vesicles. Hepatology 4:661–666. https://doi.org/10.1002/hep.1840040416CrossRefPubMed

Galle PR, Theilmann L, Raedsch R et al (1990) Ursodeoxycholate reduces hepatotoxicity of bile salts in primary human hepatocytes. Hepatology 12:486–491. https://doi.org/10.1002/hep.1840120307CrossRefPubMed

Patel T, Bronk SF, Gores GJ (1994) Increases of intracellular magnesium promote glycodeoxycholate-induced apoptosis in rat hepatocytes. J Clin Invest 94:2183–2192. https://doi.org/10.1172/JCI117579CrossRefPubMedPubMedCentral

10.

Fickert P, Wagner M (2017) Biliary bile acids in hepatobiliary injury – what is the link? J Hepatol 67:619–631. https://doi.org/10.1016/j.jhep.2017.04.026CrossRefPubMed

11.

Jansen PLM, Ghallab A, Vartak N et al (2017) The ascending pathophysiology of cholestatic liver disease. Hepatology 65:722–738. https://doi.org/10.1002/hep.28965CrossRefPubMed

12.

Afonso MB, Rodrigues PMP, Simão AL et al (2016) Activation of necroptosis in human and experimental cholestasis. Cell Death Dis 7:e2390–e2390. https://doi.org/10.1038/cddis.2016.280CrossRefPubMedPubMedCentral

13.

Ghallab A, Hofmann U, Sezgin S et al (2019) Bile microinfarcts in cholestasis are initiated by rupture of the apical hepatocyte membrane and cause shunting of bile to sinusoidal blood. Hepatology 69:666–683. https://doi.org/10.1002/hep.30213CrossRefPubMed

14.

Allen K, Jaeschke H, Copple BL (2011) Bile acids induce inflammatory genes in hepatocytes. Am J Pathol 178:175–186. https://doi.org/10.1016/j.ajpath.2010.11.026CrossRefPubMedPubMedCentral

15.

Zhang Y, Hong J, Rockwell CE et al (2012) Effect of bile duct ligation on bile acid composition in mouse serum and liver. Liver Int 32:58–69. https://doi.org/10.1111/j.1478-3231.2011.02662.xCrossRefPubMed

16.

Cai S-Y, Ouyang X, Chen Y et al (2017) Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response. JCI Insight 2:1–13. https://doi.org/10.1172/jci.insight.90780CrossRef

17.

Cai S-Y, Yu D, Soroka CJ et al (2021) Hepatic NFAT signaling regulates the expression of inflammatory cytokines in cholestasis. J Hepatol 74:550–559. https://doi.org/10.1016/j.jhep.2020.09.035CrossRefPubMed

18.

Gujral JS, Liu J, Farhood A et al (2004) Functional importance of ICAM-1 in the mechanism of neutrophil-induced liver injury in bile duct-ligated mice. Am J Physiol Liver Physiol 286:G499–G507. https://doi.org/10.1152/ajpgi.00318.2003CrossRef

19.

Zou T-T, Zhu Y, Wan C-M, Liao Q (2021) Clinical features of sodium-taurocholate cotransporting polypeptide deficiency in pediatric patients case series and literature review. Transl Pediatr 10:1045–1054. https://doi.org/10.21037/tp-20-360CrossRefPubMedPubMedCentral

20.

Slijepcevic D, Kaufman C, Wichers CGK et al (2015) Impaired uptake of conjugated bile acids and hepatitis b virus pres1-binding in na + -taurocholate cotransporting polypeptide knockout mice. Hepatology 62:207–219. https://doi.org/10.1002/hep.27694CrossRefPubMed

21.

Felzen A, Verkade HJ (2021) The spectrum of progressive familial intrahepatic cholestasis diseases: update on pathophysiology and emerging treatments. Eur J Med Genet 64:104317. https://doi.org/10.1016/j.ejmg.2021.104317CrossRefPubMed

22.

Svegliati-Baroni G, Ridolfi F, Hannivoort R et al (2005) Bile acids induce hepatic stellate cell proliferation via activation of the epidermal growth factor receptor. Gastroenterology 128:1042–1055. https://doi.org/10.1053/j.gastro.2005.01.007CrossRefPubMed

23.

Strazzabosco M, Joplin R, Zsembery A et al (1997) Na(+)-dependent and -independent Cl-/HCO3- exchange mediate cellular HCO3- transport in cultured human intrahepatic bile duct cells. Hepatology 25:976–985. https://doi.org/10.1002/hep.510250431CrossRefPubMed

24.

Hohenester S, de Buy M, Wenniger L, Paulusma CC et al (2012) A biliary HCO 3 − umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes. Hepatology 55:173–183. https://doi.org/10.1002/hep.24691CrossRefPubMed

25.

Xia X, Francis H, Glaser S et al (2006) Bile acid interactions with cholangiocytes. World J Gastroenterol 12:3553–3563. https://doi.org/10.3748/wjg.v12.i22.3553CrossRefPubMedPubMedCentral

26.

Smit JJM, Groen K, Mel CAAM et al (1993) Homozygous disruption of the murine MDR2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell 75:451–462. https://doi.org/10.1016/0092-8674(93)90380-9CrossRefPubMed

27.

Fickert P, Fuchsbichler A, Wagner M et al (2004) Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 127:261–274. https://doi.org/10.1053/j.gastro.2004.04.009CrossRefPubMed

28.

Harada K, Chiba M, Okamura A et al (2011) Monocyte chemoattractant protein-1 derived from biliary innate immunity contributes to hepatic fibrogenesis. J Clin Pathol 64:660–665. https://doi.org/10.1136/jclinpath-2011-200040CrossRefPubMed

29.

Yokoyama T, Komori A, Nakamura M et al (2006) Human intrahepatic biliary epithelial cells function in innate immunity by producing IL-6 and IL-8 via the TLR4-NF-kappaB and -MAPK signaling pathways. Liver Int 26:467–476. https://doi.org/10.1111/j.1478-3231.2006.01254.xCrossRefPubMed

30.

Strazzabosco M, Fiorotto R, Cadamuro M et al (2018) Pathophysiologic implications of innate immunity and autoinflammation in the biliary epithelium. Biochim Biophys Acta - Mol Basis Dis 1864:1374–1379. https://doi.org/10.1016/j.bbadis.2017.07.023CrossRefPubMed

31.

Lazaridis KN, Strazzabosco M, LaRusso NF (2004) The cholangiopathies: disorders of biliary epithelia. Gastroenterology 127:1565–1577. https://doi.org/10.1053/j.gastro.2004.08.006CrossRefPubMed

32.

Yang M, Ramachandran A, Yan H-M et al (2014) Osteopontin is an initial mediator of inflammation and liver injury during obstructive cholestasis after bile duct ligation in mice. Toxicol Lett 224:186–195. https://doi.org/10.1016/j.toxlet.2013.10.030CrossRefPubMed

33.

Savard CE, Blinman TA, Choi H-S et al (2002) Expression of cytokine and chemokine mRNA and secretion of tumor necrosis factor-α by gallbladder epithelial cells: response to bacterial lipopolysaccharides. BMC Gastroenterol 2:23. https://doi.org/10.1186/1471-230X-2-23CrossRefPubMedPubMedCentral

34.

Lamireau T, Zoltowska M, Levy E et al (2003) Effects of bile acids on biliary epithelial cells: proliferation, cytotoxicity, and cytokine secretion. Life Sci 72:1401–1411. https://doi.org/10.1016/S0024-3205(02)02408-6CrossRefPubMed

35.

Wang Y, Aoki H, Yang J et al (2017) The role of sphingosine 1-phosphate receptor 2 in bile-acid-induced cholangiocyte proliferation and cholestasis-induced liver injury in mice. Hepatology 65:2005–2018. https://doi.org/10.1002/hep.29076CrossRefPubMed

36.

Xiao Y, Liu R, Li X et al (2019) Long noncoding RNA H19 contributes to cholangiocyte proliferation and cholestatic liver fibrosis in biliary atresia. Hepatology 70:1658–1673. https://doi.org/10.1002/hep.30698CrossRefPubMed

37.

Li X, Liu R, Wang Y et al (2020) Cholangiocyte-derived exosomal lncRNA H19 promotes macrophage activation and hepatic inflammation under cholestatic conditions. Cells 9:190. https://doi.org/10.3390/cells9010190CrossRefPubMedCentral

38.

Benedetti A, Alvaro D, Bassotti C et al (1997) Cytotoxicity of bile salts against biliary epithelium: a study in isolated bile ductule fragments and isolated perfused rat liver. Hepatology 26:9–21. https://doi.org/10.1002/hep.510260102CrossRefPubMed

39.

Matoba N, Une M, Hoshita T (1990) Identification of unconjugated bile acids in human bile. J Lipid Res 27:1154–1162. https://doi.org/10.1016/S0022-2275(20)38751-4CrossRef

40.

Keane RM, Gadacz TR, Munster AM et al (1984) Impairment of human lymphocyte function by bile salts. Surgery 95:439–443PubMed

41.

Gianni L, Di Padova F, Zuin M, Podda M (1980) Bile acid-induced inhibition of the lymphoproliferative response to phytohemagglutinin and pokeweed mitogen: an in vitro study. Gastroenterology 78:231–235. https://doi.org/10.1016/0016-5085(80)90570-3CrossRefPubMed

42.

Yoshikawa M, Tsujii T, Matsumura K et al (1992) Immunomodulatory effects of ursodeoxycholic acid on immune responses. Hepatology 16:358–364. https://doi.org/10.1002/hep.1840160213CrossRefPubMed

43.

Lacaille F, Paradis K (1993) The immunosuppressive effect of ursodeoxycholic acid: a comparative in vitro study on human peripheral blood mononuclear cells. Hepatology 18:165–172PubMed

44.

Yamada K, Lim BO, Sugano M (1993) Suppression of immunoglobulin production of rat lymphocytes by bile acids. Vitr Cell Dev Biol - Anim 29:840–841. https://doi.org/10.1007/BF02631360CrossRef

45.

Greve JW, Gouma DJ, Buurman WA (1989) Bile acids inhibit endotoxin-induced release of tumor necrosis factor by monocytes: Anin Vitro study. Hepatology 10:454–458. https://doi.org/10.1002/hep.1840100409CrossRefPubMed

46.

Calmus Y, Guechot J, Podevin P et al (1992) Differential effects of chenodeoxycholic and ursodeoxycholic acids on interleukin 1, interleukin 6 and tumor necrosis factor–α production by monocytes. Hepatology 16:719–723. https://doi.org/10.1002/hep.1840160317CrossRefPubMed

47.

Bergamini A, Dini L, Baiocchi L et al (1997) Bile acids with differing hydrophilic-hydrophobic properties do not influence cytokine production by human monocytes and murine Kupffer cells. Hepatology 25:927–933. https://doi.org/10.1002/hep.510250423CrossRefPubMed

48.

Sung JJY, Go MYY (1999) Reversible Kupffer cell suppression in biliary obstruction is caused by hydrophobic bile acids. J Hepatol 30:413–418. https://doi.org/10.1016/S0168-8278(99)80099-3CrossRefPubMed

49.

Van Bossuyt H, Desmaretz C, Gaeta GB, Wisse E (1990) The role of bile acids in the development of endotoxemia during obstructive jaundice in the rat. J Hepatol 10:274–279. https://doi.org/10.1016/0168-8278(90)90132-BCrossRefPubMed

50.

Hao H, Cao L, Jiang C et al (2017) Farnesoid X receptor regulation of the NLRP3 inflammasome underlies cholestasis-associated sepsis. Cell Metab 25:856-867.e5. https://doi.org/10.1016/j.cmet.2017.03.007CrossRefPubMedPubMedCentral

51.

Wang H, Chen J, Hollister K et al (1999) Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 3:543–553. https://doi.org/10.1016/S1097-2765(00)80348-2CrossRefPubMed

52.

Parks DJ, Blanchard SG, Bledsoe RK et al (1999) Bile acids: natural ligands for an orphan nuclear receptor. Science (80) 284:1365–1368. https://doi.org/10.1126/science.284.5418.1365CrossRef

53.

Sayin SI, Wahlström A, Felin J et al (2013) Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR ANTAGONIST. Cell Metab 17:225–235. https://doi.org/10.1016/j.cmet.2013.01.003CrossRefPubMed

54.

Panzitt K, Wagner M (2021) FXR in liver physiology: multiple faces to regulate liver metabolism. Biochim Biophys Acta - Mol Basis Dis 1867:166133. https://doi.org/10.1016/j.bbadis.2021.166133CrossRefPubMed

55.

Calkin AC, Tontonoz P (2012) Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat Rev Mol Cell Biol 13:213–224. https://doi.org/10.1038/nrm3312CrossRefPubMedPubMedCentral

56.

Uhlén M, Fagerberg L, Hallström BM et al (2015) Tissue-based map of the human proteome. Science 347(6220):1260419. https://doi.org/10.1126/SCIENCE.1260419

57.

The Human Protein Atlas (2021) Cell type atlas - NR1H4. https://www.proteinatlas.org/ENSG00000012504-NR1H4/celltype. Accessed 16 Nov 2021

58.

Houten SM, Volle DH, Cummins CL et al (2007) In vivo imaging of farnesoid X receptor activity reveals the ileum as the primary bile acid signaling tissue. Mol Endocrinol 21:1312–1323. https://doi.org/10.1210/me.2007-0113CrossRefPubMed

59.

Beigneux AP, Moser AH, Shigenaga JK et al (2000) The acute phase response is associated with retinoid X receptor repression in rodent liver. J Biol Chem 275:16390–16399. https://doi.org/10.1074/jbc.M000953200CrossRefPubMed

60.

Kim MS, Shigenaga J, Moser A et al (2003) Repression of farnesoid X receptor during the acute phase response. J Biol Chem 278:8988–8995. https://doi.org/10.1074/jbc.M212633200CrossRefPubMed

61.

Gadaleta RM, Oldenburg B, Willemsen ECL et al (2011) Activation of bile salt nuclear receptor FXR is repressed by pro-inflammatory cytokines activating NF-κB signaling in the intestine. Biochim Biophys Acta - Mol Basis Dis 1812:851–858. https://doi.org/10.1016/j.bbadis.2011.04.005CrossRef

62.

Renga B, Migliorati M, Mencarelli A, Fiorucci S (2009) Reciprocal regulation of the bile acid-activated receptor FXR and the interferon-γ-STAT-1 pathway in macrophages. Biochim Biophys Acta - Mol Basis Dis 1792:564–573. https://doi.org/10.1016/j.bbadis.2009.04.004CrossRef

63.

Wang Y-D, Chen W-D, Wang M et al (2008) Farnesoid X receptor antagonizes nuclear factor κB in hepatic inflammatory response. Hepatology 48:1632–1643. https://doi.org/10.1002/hep.22519CrossRefPubMed

64.

Pascual G, Glass CK (2006) Nuclear receptors versus inflammation: mechanisms of transrepression. Trends Endocrinol Metab 17:321–327. https://doi.org/10.1016/j.tem.2006.08.005CrossRefPubMed

65.

Liu T, Zhang L, Joo D, Sun S-C (2017) NF-κB signaling in inflammation. Signal Transduct Target Ther 2:17023. https://doi.org/10.1038/sigtrans.2017.23CrossRefPubMedPubMedCentral

66.

Gadaleta RM, van Erpecum KJ, Oldenburg B et al (2011) Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 60:463–472. https://doi.org/10.1136/gut.2010.212159CrossRefPubMed

67.

Li YTY, Swales KE, Thomas GJ et al (2007) Farnesoid X receptor ligands inhibit vascular smooth muscle cell inflammation and migration. Arterioscler Thromb Vasc Biol 27:2606–2611. https://doi.org/10.1161/ATVBAHA.107.152694CrossRefPubMed

68.

Chen Y-H, Hu X-G, Zhou Y et al (2016) Obeticholic acid protects against lipopolysaccharide-induced fetal death and intrauterine growth restriction through its anti-inflammatory activity. J Immunol 197:4762–4770. https://doi.org/10.4049/jimmunol.1601331CrossRefPubMed

69.

Zhang D-G, Zhang C, Wang J-X et al (2017) Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation. Toxicol Appl Pharmacol 314:39–47. https://doi.org/10.1016/j.taap.2016.11.006CrossRefPubMed

70.

Gai Z, Visentin M, Gui T et al (2018) Effects of farnesoid X receptor activation on arachidonic acid metabolism, NF-kB signaling, and hepatic inflammation. Mol Pharmacol 94:802–811. https://doi.org/10.1124/mol.117.111047CrossRefPubMed

71.

Fiorucci S, Antonelli E, Rizzo G et al (2004) The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 127:1497–1512. https://doi.org/10.1053/j.gastro.2004.08.001CrossRefPubMed

72.

Yang Z, Koehler AN, Wang L (2016) A novel small molecule activator of nuclear receptor SHP inhibits HCC cell migration via suppressing Ccl2. Mol Cancer Ther 15:2294–2301. https://doi.org/10.1158/1535-7163.MCT-16-0153CrossRefPubMedPubMedCentral

73.

Zhang Y, Liu C, Barbier O et al (2016) Bcl2 is a critical regulator of bile acid homeostasis by dictating Shp and lncRNA H19 function. Sci Rep 6:20559. https://doi.org/10.1038/srep20559CrossRefPubMedPubMedCentral

74.

Kim D, Xiao Z, Kwon S et al (2015) A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity. EMBO J. 34:184–199. https://doi.org/10.15252/embj.201489527CrossRefPubMed

75.

Bijsmans ITGW, Guercini C, Ramos Pittol JM et al (2015) The glucocorticoid mometasone furoate is a novel FXR ligand that decreases inflammatory but not metabolic gene expression. Sci Rep 5:14086. https://doi.org/10.1038/srep14086CrossRefPubMedPubMedCentral

76.

Yang C-S, Kim J-J, Kim TS et al (2015) Small heterodimer partner interacts with NLRP3 and negatively regulates activation of the NLRP3 inflammasome. Nat Commun 6:6115. https://doi.org/10.1038/ncomms7115CrossRefPubMed

77.

Iracheta-Vellve A, Calenda CD, Petrasek J et al (2018) FXR and TGR5 agonists ameliorate liver injury, steatosis, and inflammation after binge or prolonged alcohol feeding in mice. Hepatol Commun 2:1379–1391. https://doi.org/10.1002/hep4.1256CrossRefPubMedPubMedCentral

78.

Yao J, Zhou C-S, Ma X et al (2014) FXR agonist GW4064 alleviates endotoxin-induced hepatic inflammation by repressing macrophage activation. World J Gastroenterol 20:14430–14441. https://doi.org/10.3748/wjg.v20.i39.14430CrossRefPubMedPubMedCentral

79.

Liu H, Lee T, Liao J (2018) GW4064 attenuates lipopolysaccharide-induced hepatic inflammation and apoptosis through inhibition of the Toll-like receptor 4-mediated p38 mitogen-activated protein kinase signaling pathway in mice. Int J Mol Med 41:1455–1462. https://doi.org/10.3892/ijmm.2018.3366CrossRefPubMedPubMedCentral

80.

Xu Z, Huang G, Gong W et al (2012) FXR ligands protect against hepatocellular inflammation via SOCS3 induction. Cell Signal 24:1658–1664. https://doi.org/10.1016/j.cellsig.2012.04.015CrossRefPubMed

81.

He G, Karin M (2011) NF-κB and STAT3 – key players in liver inflammation and cancer. Cell Res 21:159–168. https://doi.org/10.1038/cr.2010.183CrossRefPubMed

82.

Li G, Zhu Y, Tawfik O et al (2013) Mechanisms of STAT3 activation in the liver of FXR knockout mice. Am J Physiol Liver Physiol 305:G829–G837. https://doi.org/10.1152/ajpgi.00155.2013CrossRef

83.

Yang F, Huang X, Yi T et al (2007) Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res 67:863–867. https://doi.org/10.1158/0008-5472.CAN-06-1078CrossRefPubMed

84.

Kim I, Morimura K, Shah Y et al (2007) Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis 28:940–946. https://doi.org/10.1093/carcin/bgl249CrossRefPubMed

85.

Takahashi S, Tanaka N, Fukami T et al (2018) Role of farnesoid X receptor and bile acids in hepatic tumor development. Hepatol Commun 2:1567–1582. https://doi.org/10.1002/hep4.1263CrossRefPubMedPubMedCentral

86.

Martinez-Becerra P, Vaquero J, Romero MR et al (2012) No Correlation between the expression of FXR and genes involved in multidrug resistance phenotype of primary liver tumors. Mol Pharm 9:1693–1704. https://doi.org/10.1021/mp300028aCrossRefPubMed

87.

Su H, Ma C, Liu J et al (2012) Downregulation of nuclear receptor FXR is associated with multiple malignant clinicopathological characteristics in human hepatocellular carcinoma. Am J Physiol Liver Physiol 303:G1245–G1253. https://doi.org/10.1152/ajpgi.00439.2011CrossRef

88.

Girisa S, Henamayee S, Parama D et al (2021) Targeting farnesoid X receptor (FXR) for developing novel therapeutics against cancer. Mol Biomed 2:21. https://doi.org/10.1186/s43556-021-00035-2CrossRefPubMedPubMedCentral

89.

Huang X, Zhao W, Huang W (2015) FXR and liver carcinogenesis. Acta Pharmacol Sin 36:37–43. https://doi.org/10.1038/aps.2014.117CrossRefPubMed

90.

Fiorucci S, Biagioli M, Zampella A, Distrutti E (2018) Bile acids activated receptors regulate innate immunity. Front Immunol 9:1–17. https://doi.org/10.3389/fimmu.2018.01853CrossRef

91.

Zhang H, Liu Y, Bian Z et al (2014) The critical role of myeloid-derived suppressor cells and FXR activation in immune-mediated liver injury. J Autoimmun 53:55–66. https://doi.org/10.1016/j.jaut.2014.02.010CrossRefPubMed

92.

Cui YJ, Aleksunes LM, Tanaka Y et al (2009) Compensatory induction of liver efflux transporters in response to ANIT-induced liver injury is impaired in FXR-null mice. Toxicol Sci 110:47–60. https://doi.org/10.1093/toxsci/kfp094CrossRefPubMedPubMedCentral

93.

Liu Y, Binz J, Numerick MJ et al (2003) Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. J Clin Invest 112:1678–1687. https://doi.org/10.1172/JCI18945CrossRefPubMedPubMedCentral

94.

van Golen RF, Olthof PB, Lionarons DA et al (2018) FXR agonist obeticholic acid induces liver growth but exacerbates biliary injury in rats with obstructive cholestasis. Sci Rep 8:16529. https://doi.org/10.1038/s41598-018-33070-1CrossRefPubMedPubMedCentral

95.

Stedman C, Liddle C, Coulter S et al (2006) Benefit of farnesoid X receptor inhibition in obstructive cholestasis. Proc Natl Acad Sci 103:11323–11328. https://doi.org/10.1073/pnas.0604772103CrossRefPubMedPubMedCentral

96.

Nevens F, Andreone P, Mazzella G et al (2016) A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 375:631–643. https://doi.org/10.1056/NEJMoa1509840CrossRefPubMed

97.

Trauner M, Nevens F, Shiffman ML et al (2019) Long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis: 3-year results of an international open-label extension study. Lancet Gastroenterol Hepatol 4:445–453. https://doi.org/10.1016/S2468-1253(19)30094-9CrossRefPubMed

98.

Bowlus CL, Pockros PJ, Kremer AE et al (2020) Long-term obeticholic acid therapy improves histological endpoints in patients with primary biliary cholangitis. Clin Gastroenterol Hepatol 18:1170-1178.e6. https://doi.org/10.1016/j.cgh.2019.09.050CrossRefPubMed

99.

Harms MH, Hirschfield GM, Floreani A et al (2021) Obeticholic acid is associated with improvements in AST-to-platelet ratio index and GLOBE score in patients with primary biliary cholangitis. JHEP Reports 3:100191. https://doi.org/10.1016/j.jhepr.2020.100191CrossRefPubMed

100.

Hirschfield GM, Mason A, Luketic V et al (2015) Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 148:751-761.e8. https://doi.org/10.1053/j.gastro.2014.12.005CrossRefPubMed

101.

Roberts SB, Ismail M, Kanagalingam G et al (2020) Real-world effectiveness of obeticholic acid in patients with primary biliary cholangitis. Hepatol Commun 4:1332–1345. https://doi.org/10.1002/hep4.1518CrossRefPubMedPubMedCentral

102.

D’Amato D, De Vincentis A, Malinverno F et al (2021) Real-world experience with obeticholic acid in patients with primary biliary cholangitis. JHEP Reports 3:100248. https://doi.org/10.1016/j.jhepr.2021.100248CrossRefPubMedPubMedCentral

103.

Lindor KD, Bowlus CL, Boyer J et al (2018) Primary biliary cholangitis: 2018 practice guidance from the American Association for the Study of Liver Diseases. Hepatology 69:hep.30145. https://doi.org/10.1002/hep.30145CrossRef

104.

Kjærgaard K, Frisch K, Sørensen M et al (2021) Obeticholic acid improves hepatic bile acid excretion in patients with primary biliary cholangitis. J Hepatol 74:58–65. https://doi.org/10.1016/j.jhep.2020.07.028CrossRefPubMed

105.

U.S FDA (2021) 05–26–2021 FDA Drug Safety Communication. https://www.fda.gov/drugs/drug-safety-and-availability/due-risk-serious-liver-injury-fda-restricts-use-ocaliva-obeticholic-acid-primary-biliary-cholangitis

106.

Kowdley KV, Vuppalanchi R, Levy C et al (2020) A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis. J Hepatol 73:94–101. https://doi.org/10.1016/j.jhep.2020.02.033CrossRefPubMedPubMedCentral

107.

Intercept (2022) Our clinical development program. https://www.interceptpharma.com/our-research/pipeline/. Accessed 19 Mar 2022

108.

Schramm C, Hirschfield G, Mason AL et al (2018) Early assessment of safety and efficacy of tropifexor, a potent non bile-acid FXR agonist, in patients with primary biliary cholangitis: an interim analysis of an ongoing phase 2 study. J Hepatol 68:S103. https://doi.org/10.1016/S0168-8278(18)30426-4CrossRef

109.

Trauner M, Gulamhusein A, Hameed B et al (2019) The nonsteroidal farnesoid X receptor agonist cilofexor (GS-9674) improves markers of cholestasis and liver injury in patients with primary sclerosing cholangitis. Hepatology 70:788–801. https://doi.org/10.1002/hep.30509CrossRefPubMed

110.

Kowdley K, Minuk G, Pagadala M et al (2019) The nonsteroidal farnesoid X receptor (FXR) agonist cilofexor improves liver biochemistry in patients with primary biliary cholangitis (PBC): a phase 2, randomized, placebo-controlled trial. Hepatology 70(Suppl.1):1A. https://doi.org/10.1002/hep.30940

111.

Pockros PJ, Fuchs M, Freilich B et al (2019) CONTROL: a randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients. Liver Int 39:2082–2093. https://doi.org/10.1111/liv.14209CrossRefPubMed

112.

Gadaleta RM, Moschetta A (2021) Dark and bright side of targeting fibroblast growth factor receptor 4 in the liver. J Hepatol 75:1440–1451. https://doi.org/10.1016/j.jhep.2021.07.029CrossRefPubMed

113.

Inagaki T, Choi M, Moschetta A et al (2005) Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2:217–225. https://doi.org/10.1016/j.cmet.2005.09.001CrossRefPubMed

114.

Nicholes K, Guillet S, Tomlinson E et al (2002) A mouse model of hepatocellular carcinoma. Am J Pathol 160:2295–2307. https://doi.org/10.1016/S0002-9440(10)61177-7CrossRefPubMedPubMedCentral

115.

Zhou M, Yang H, Learned RM et al (2017) Non-cell-autonomous activation of IL-6/STAT3 signaling mediates FGF19-driven hepatocarcinogenesis. Nat Commun 8:15433. https://doi.org/10.1038/ncomms15433CrossRefPubMedPubMedCentral

116.

Luo J, Ko B, Elliott M et al (2014) A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci Transl Med 6:1–12. https://doi.org/10.1126/scitranslmed.3009098CrossRef

117.

Sanyal AJ, Ling L, Beuers U et al (2021) Potent suppression of hydrophobic bile acids by aldafermin, an FGF19 analogue, across metabolic and cholestatic liver diseases. JHEP Reports 3:100255. https://doi.org/10.1016/j.jhepr.2021.100255CrossRefPubMedPubMedCentral

118.

Luo J, Ko B, Elliott M et al (2014) A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci Transl Med 6:247ra100-247ra100. https://doi.org/10.1126/scitranslmed.3009098CrossRefPubMed

119.

Zhou M, Learned RM, Rossi SJ et al (2016) Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2 -deficient mice. Hepatology 63:914–929. https://doi.org/10.1002/hep.28257CrossRefPubMed

120.

Gadaleta RM, Scialpi N, Peres C et al (2018) Suppression of hepatic bile acid synthesis by a non-tumorigenic FGF19 analogue protects mice from fibrosis and hepatocarcinogenesis. Sci Rep 8:17210. https://doi.org/10.1038/s41598-018-35496-zCrossRefPubMedPubMedCentral

121.

Modica S, Petruzzelli M, Bellafante E et al (2012) Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis. Gastroenterology 142:355-365.e4. https://doi.org/10.1053/j.gastro.2011.10.028CrossRefPubMed

122.

Mayo MJ, Wigg AJ, Leggett BA et al (2018) <scp>NGM</scp> 282 for treatment of patients with primary biliary cholangitis: a multicenter, randomized, double-blind, placebo-controlled trial. Hepatol Commun 2:1037–1050. https://doi.org/10.1002/hep4.1209CrossRefPubMedPubMedCentral

123.

Hirschfield GM, Chazouillères O, Drenth JP et al (2019) Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: a multicenter, randomized, double-blind, placebo-controlled phase II trial. J Hepatol 70:483–493. https://doi.org/10.1016/j.jhep.2018.10.035CrossRefPubMed

124.

Bio N (2022) NGM Bio 2022 Strategic Priorities. https://ir.ngmbio.com/news-releases/news-release-details/ngm-bio-outlines-2022-strategic-priorities-across-its-portfolio. Accessed 19 Mar 2022

125.

The Human Protein Atlas (2021) Tissue expression of GPBAR1. https://www.proteinatlas.org/ENSG00000179921-GPBAR1/tissue. Accessed 16 Nov 2021

126.

Masyuk AI, Huang BQ, Radtke BN et al (2013) Ciliary subcellular localization of TGR5 determines the cholangiocyte functional response to bile acid signaling. Am J Physiol Liver Physiol 304:G1013–G1024. https://doi.org/10.1152/ajpgi.00383.2012CrossRef

127.

Keitel V, Cupisti K, Ullmer C et al (2009) The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology 50:861–870. https://doi.org/10.1002/hep.23032CrossRefPubMed

128.

Keitel V, Donner M, Winandy S et al (2008) Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun 372:78–84. https://doi.org/10.1016/j.bbrc.2008.04.171CrossRefPubMed

129.

Keitel V, Reinehr R, Gatsios P et al (2007) The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology 45:695–704. https://doi.org/10.1002/hep.21458CrossRefPubMed

130.

Sawitza I, Kordes C, Götze S et al (2015) Bile acids induce hepatic differentiation of mesenchymal stem cells. Sci Rep 5:13320. https://doi.org/10.1038/srep13320CrossRefPubMedPubMedCentral

131.

Biagioli M, Carino A, Fiorucci C et al (2019) GPBAR1 functions as gatekeeper for liver NKT cells and provides counterregulatory signals in mouse models of immune-mediated hepatitis. Cell Mol Gastroenterol Hepatol 8:447–473. https://doi.org/10.1016/j.jcmgh.2019.06.003CrossRefPubMedPubMedCentral

132.

Holter MM, Chirikjian MK, Briere DA et al (2020) Compound 18 improves glucose tolerance in a hepatocyte TGR5-dependent manner in mice. Nutrients 12:2124. https://doi.org/10.3390/nu12072124CrossRefPubMedCentral

133.

The Human Protein Atlas (2021) Cell type atlas - GPBAR1. https://www.proteinatlas.org/ENSG00000179921-GPBAR1/celltype. Accessed 16 Nov 2021

134.

Kawamata Y, Fujii R, Hosoya M et al (2003) A G protein-coupled receptor responsive to bile acids. J Biol Chem 278:9435–9440. https://doi.org/10.1074/jbc.M209706200CrossRefPubMed

135.

Maruyama T, Miyamoto Y, Nakamura T et al (2002) Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun 298:714–719. https://doi.org/10.1016/S0006-291X(02)02550-0CrossRefPubMed

136.

Guo C, Chen W-D, Wang Y-D (2016) TGR5, not only a metabolic regulator. Front Physiol 7:1–9. https://doi.org/10.3389/fphys.2016.00646CrossRef

137.

van Nierop FS, Scheltema MJ, Eggink HM et al (2017) Clinical relevance of the bile acid receptor TGR5 in metabolism. Lancet Diabetes Endocrinol 5:224–233. https://doi.org/10.1016/S2213-8587(16)30155-3CrossRefPubMed

138.

de Buy M, Wenniger LJ, Hohenester S, Maroni L et al (2015) The cholangiocyte glycocalyx stabilizes the ‘biliary HCO3- umbrella’’: an integrated line of defense against toxic bile acids’. Dig Dis 33:397–407. https://doi.org/10.1159/000371864CrossRef

139.

Reich M, Deutschmann K, Sommerfeld A et al (2016) TGR5 is essential for bile acid-dependent cholangiocyte proliferation in vivo and in vitro. Gut 65:487–501. https://doi.org/10.1136/gutjnl-2015-309458CrossRefPubMed

140.

Erice O, Labiano I, Arbelaiz A et al (2018) Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression. Biochim Biophys Acta - Mol Basis Dis 1864:1335–1344. https://doi.org/10.1016/j.bbadis.2017.08.016CrossRefPubMed

141.

Deutschmann K, Reich M, Klindt C et al (2018) Bile acid receptors in the biliary tree: TGR5 in physiology and disease. Biochim Biophys Acta - Mol Basis Dis 1864:1319–1325. https://doi.org/10.1016/j.bbadis.2017.08.021CrossRefPubMed

142.

Li T, Holmstrom SR, Kir S et al (2011) The G protein-coupled bile acid receptor, TGR5, stimulates gallbladder filling. Mol Endocrinol 25:1066–1071. https://doi.org/10.1210/me.2010-0460CrossRefPubMedPubMedCentral

143.

Merlen G, Kahale N, Ursic-Bedoya J et al (2020) TGR5-dependent hepatoprotection through the regulation of biliary epithelium barrier function. Gut 69:146–157. https://doi.org/10.1136/gutjnl-2018-316975CrossRefPubMed

144.

Hov JR, Keitel V, Laerdahl JK et al (2010) Mutational characterization of the bile acid receptor TGR5 in primary sclerosing cholangitis. PLoS ONE 5:e12403. https://doi.org/10.1371/journal.pone.0012403CrossRefPubMedPubMedCentral

145.

Biagioli M, Carino A, Cipriani S et al (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 199:718–733. https://doi.org/10.4049/jimmunol.1700183CrossRefPubMed

146.

Högenauer K, Arista L, Schmiedeberg N et al (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 57:10343–10354. https://doi.org/10.1021/jm501052cCrossRefPubMed

147.

Haselow K, Bode JG, Wammers M et al (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 94:1253–1264. https://doi.org/10.1189/jlb.0812396CrossRefPubMed

148.

Hu J, Wang C, Huang X et al (2021) Gut microbiota-mediated secondary bile acids regulate dendritic cells to attenuate autoimmune uveitis through TGR5 signaling. Cell Rep 36:109726. https://doi.org/10.1016/j.celrep.2021.109726CrossRefPubMed

149.

Kida T, Tsubosaka Y, Hori M et al (2013) Bile acid receptor TGR5 agonism induces NO production and reduces monocyte adhesion in vascular endothelial cells. Arterioscler Thromb Vasc Biol 33:1663–1669. https://doi.org/10.1161/ATVBAHA.113.301565CrossRefPubMed

150.

Yoneno K, Hisamatsu T, Shimamura K et al (2013) TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn’s disease. Immunology 139:19–29. https://doi.org/10.1111/imm.12045CrossRefPubMedPubMedCentral

151.

Wang Y-D, Chen W-D, Yu D et al (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-κB) in mice. Hepatology 54:1421–1432. https://doi.org/10.1002/hep.24525CrossRefPubMed

152.

Pols TWH, Nomura M, Harach T et al (2011) TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab 14:747–757. https://doi.org/10.1016/j.cmet.2011.11.006CrossRefPubMedPubMedCentral

153.

Yang H, Luo F, Wei Y et al (2021) TGR5 protects against cholestatic liver disease via suppressing the NF-κB pathway and activating the Nrf2/HO-1 pathway. Ann Transl Med 9:1158–1158. https://doi.org/10.21037/atm-21-2631CrossRefPubMedPubMedCentral

154.

Rao J, Yang C, Yang S et al (2020) Deficiency of TGR5 exacerbates immune-mediated cholestatic hepatic injury by stabilizing the β-catenin destruction complex. Int Immunol 32:321–334. https://doi.org/10.1093/intimm/dxaa002CrossRefPubMedPubMedCentral

155.

Zhang L, Fu X, Gui T et al (2019) Effects of farnesiferol B on ischemia-reperfusion-induced renal damage, inflammation, and NF-κB signaling. Int J Mol Sci 20:6280. https://doi.org/10.3390/ijms20246280CrossRefPubMedCentral

156.

Perino A, Pols TWH, Nomura M et al (2014) TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation. J Clin Invest 124:5424–5436. https://doi.org/10.1172/JCI76289CrossRefPubMedPubMedCentral

157.

Guo C, Xie S, Chi Z et al (2016) Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. Immunity 45:802–816. https://doi.org/10.1016/j.immuni.2016.09.008CrossRefPubMed

158.

Chen Y, Le TH, Du Q et al (2019) Genistein protects against DSS-induced colitis by inhibiting NLRP3 inflammasome via TGR5-cAMP signaling. Int Immunopharmacol 71:144–154. https://doi.org/10.1016/j.intimp.2019.01.021CrossRefPubMed

159.

Hu X, Yan J, Huang L et al (2021) INT-777 attenuates NLRP3-ASC inflammasome-mediated neuroinflammation via TGR5/cAMP/PKA signaling pathway after subarachnoid hemorrhage in rats. Brain Behav Immun 91:587–600. https://doi.org/10.1016/j.bbi.2020.09.016CrossRefPubMed

160.

Leonhardt J, Haider RS, Sponholz C et al (2021) Circulating bile acids in liver failure activate TGR5 and induce monocyte dysfunction. Cell Mol Gastroenterol Hepatol 12:25–40. https://doi.org/10.1016/j.jcmgh.2021.01.011CrossRefPubMedPubMedCentral

161.

Péan N, Doignon I, Garcin I et al (2013) The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice. Hepatology 58:1451–1460. https://doi.org/10.1002/hep.26463CrossRefPubMed

162.

Baghdasaryan A, Claudel T, Gumhold J et al (2011) Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2 −/− ( Abcb4 −/− ) mouse cholangiopathy model by promoting biliary HCO 3− output. Hepatology 54:1303–1312. https://doi.org/10.1002/hep.24537CrossRefPubMed

163.

Reich M, Spomer L, Klindt C et al (2021) Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis. J Hepatol 75:634–646. https://doi.org/10.1016/j.jhep.2021.03.029CrossRefPubMed

164.

Masyuk TV, Masyuk AI, Lorenzo Pisarello M et al (2017) TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate/Gαs signaling. Hepatology 66:1197–1218. https://doi.org/10.1002/hep.29284CrossRefPubMed

165.

Masyuk TV, Masyuk AI, LaRusso NF (2015) TGR5 in the cholangiociliopathies. Dig Dis 33:420–425. https://doi.org/10.1159/000371696CrossRefPubMed

166.

Li A-D, Xie X-L, Qi W et al (2020) TGR5 promotes cholangiocarcinoma by interacting with mortalin. Exp Cell Res 389:111855. https://doi.org/10.1016/j.yexcr.2020.111855CrossRefPubMed

167.

Renga B, Cipriani S, Carino A et al (2015) 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:e0141082. https://doi.org/10.1371/journal.pone.0141082CrossRefPubMedPubMedCentral

168.

Renga B, Bucci M, Cipriani S et al (2015) Cystathionine γ-lyase, a H 2 S-generating enzyme, is a GPBAR1-regulated gene and contributes to vasodilation caused by secondary bile acids. Am J Physiol Circ Physiol 309:H114–H126. https://doi.org/10.1152/ajpheart.00087.2015CrossRef

169.

Klindt C, Reich M, Hellwig B et al (2019) The G protein-coupled bile acid receptor TGR5 (Gpbar1) modulates endothelin-1 signaling in liver. Cells 8:1467. https://doi.org/10.3390/cells8111467CrossRefPubMedCentral

170.

Fryer RM, Ng KJ, Mazurek SGN et al (2014) Correction to “G protein–coupled bile acid receptor 1 stimulation mediates arterial vasodilation through a KCa1.1 (BKCa)–dependent mechanism.” J Pharmacol Exp Ther 348:492–492. https://doi.org/10.1124/jpet.114.03er14cCrossRef

171.

Alemi F, Kwon E, Poole DP et al (2013) The TGR5 receptor mediates bile acid–induced itch and analgesia. J Clin Invest 123:1513–1530. https://doi.org/10.1172/JCI64551CrossRefPubMedPubMedCentral

172.

Hodge RJ, Lin J, Vasist Johnson LS et al (2013) Safety, pharmacokinetics, and pharmacodynamic effects of a selective TGR5 agonist, SB-756050, in type 2 diabetes. Clin Pharmacol Drug Dev 2:213–222. https://doi.org/10.1002/cpdd.34CrossRefPubMed

173.

The Human Protein Atlas (2021) Single cell type - NR1I2. https://www.proteinatlas.org/ENSG00000144852-NR1I2/single+cell+type. Accessed 4 Jan 2022

174.

Staudinger JL, Goodwin B, Jones SA et al (2001) The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci 98:3369–3374. https://doi.org/10.1073/pnas.051551698CrossRefPubMedPubMedCentral

175.

Oladimeji PO, Chen T (2018) PXR: more than just a master xenobiotic receptor. Mol Pharmacol 93:119–127. https://doi.org/10.1124/mol.117.110155CrossRefPubMedPubMedCentral

176.

Jonker JW, Liddle C, Downes M (2012) FXR and PXR: potential therapeutic targets in cholestasis. J Steroid Biochem Mol Biol 130:147–158. https://doi.org/10.1016/j.jsbmb.2011.06.012CrossRefPubMed

177.

Mackowiak B, Hodge J, Stern S, Wang H (2018) The roles of xenobiotic receptors: beyond chemical disposition. Drug Metab Dispos 46:1361–1371. https://doi.org/10.1124/dmd.118.081042CrossRefPubMedPubMedCentral

178.

Jung D, Mangelsdorf DJ, Meyer UA (2006) Pregnane X receptor is a target of farnesoid X receptor. J Biol Chem 281:19081–19091. https://doi.org/10.1074/jbc.M600116200CrossRefPubMed

179.

Kast HR, Goodwin B, Tarr PT et al (2002) 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 277:2908–2915. https://doi.org/10.1074/jbc.M109326200CrossRefPubMed

180.

Xie W, Radominska-Pandya A, Shi Y et al (2001) An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids. Proc Natl Acad Sci 98:3375–3380. https://doi.org/10.1073/pnas.051014398CrossRefPubMedPubMedCentral

181.

Wagner M, Halilbasic E, Marschall H-U et al (2005) CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice. Hepatology 42:420–430. https://doi.org/10.1002/hep.20784CrossRefPubMed

182.

Stedman CAM, Liddle C, Coulter SA et al (2005) Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury. Proc Natl Acad Sci 102:2063–2068. https://doi.org/10.1073/pnas.0409794102CrossRefPubMedPubMedCentral

183.

Teng S, Piquette-Miller M (2007) Hepatoprotective role of PXR activation and MRP3 in cholic acid-induced cholestasis. Br J Pharmacol 151:367–376. https://doi.org/10.1038/sj.bjp.0707235CrossRefPubMedPubMedCentral

184.

Gu X, Ke S, Liu D et al (2006) Role of NF-κB in regulation of PXR-mediated gene expression. J Biol Chem 281:17882–17889. https://doi.org/10.1074/jbc.M601302200CrossRefPubMed

185.

Zhou C, Tabb MM, Nelson EL et al (2006) Mutual repression between steroid and xenobiotic receptor and NF-κB signaling pathways links xenobiotic metabolism and inflammation. J Clin Invest 116:2280–2289. https://doi.org/10.1172/JCI26283CrossRefPubMedPubMedCentral

186.

Okamura M, Shizu R, Abe T et al (2020) PXR functionally interacts with NF-κB and AP-1 to downregulate the inflammation-induced expression of chemokine CXCL2 in mice. Cells 9:2296. https://doi.org/10.3390/cells9102296CrossRefPubMedCentral

187.

Qiu Z, Cervantes JL, Cicek BB et al (2016) Pregnane X receptor regulates pathogen-induced inflammation and host defense against an intracellular bacterial infection through Toll-like receptor 4. Sci Rep 6:31936. https://doi.org/10.1038/srep31936CrossRefPubMedPubMedCentral

188.

Venkatesh M, Mukherjee S, Wang H et al (2014) Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity 41:296–310. https://doi.org/10.1016/j.immuni.2014.06.014CrossRefPubMedPubMedCentral

189.

Rysä J, Buler M, Savolainen MJ et al (2013) Pregnane X receptor agonists impair postprandial glucose tolerance. Clin Pharmacol Ther 93:556–563. https://doi.org/10.1038/clpt.2013.48CrossRefPubMed

190.

Hassani-Nezhad-Gashti F, Salonurmi T, Hautajärvi H et al (2020) Pregnane X receptor activator rifampin increases blood pressure and stimulates plasma renin activity. Clin Pharmacol Ther 108:856–865. https://doi.org/10.1002/cpt.1871CrossRefPubMed

191.

Karpale M, Käräjämäki AJ, Kummu O et al (2021) Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2-mediated mechanism. Br J Pharmacol 178:2461–2481. https://doi.org/10.1111/bph.15433CrossRefPubMed

192.

Bhagyaraj E, Ahuja N, Kumar S et al (2019) TGF-β induced chemoresistance in liver cancer is modulated by xenobiotic nuclear receptor PXR. Cell Cycle 18:3589–3602. https://doi.org/10.1080/15384101.2019.1693120CrossRefPubMedPubMedCentral

193.

Yang H, Porte RJ, Verkade HJ et al (2009) Partial external biliary diversion in children with progressive familial intrahepatic cholestasis and alagille disease. J Pediatr Gastroenterol Nutr 49:216–221. https://doi.org/10.1097/MPG.0b013e31819a4e3dCrossRefPubMed

194.

Baghdasaryan A, Fuchs CD, Österreicher CH et al (2016) Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis. J Hepatol 64:674–681. https://doi.org/10.1016/j.jhep.2015.10.024CrossRefPubMed

195.

Miethke AG, Zhang W, Simmons J et al (2016) Pharmacological inhibition of apical sodium-dependent bile acid transporter changes bile composition and blocks progression of sclerosing cholangitis in multidrug resistance 2 knockout mice. Hepatology 63:512–523. https://doi.org/10.1002/hep.27973CrossRefPubMed

196.

Hegade VS, Kendrick SFW, Dobbins RL et al (2017) Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study. Lancet 389:1114–1123. https://doi.org/10.1016/S0140-6736(17)30319-7CrossRefPubMed

197.

Shirley M (2022) Maralixibat: first approval. Drugs 82:71–76. https://doi.org/10.1007/s40265-021-01649-0CrossRefPubMed

198.

Karpen SJ, Kelly D, Mack C, Stein P (2020) Ileal bile acid transporter inhibition as an anticholestatic therapeutic target in biliary atresia and other cholestatic disorders. Hepatol Int 14:677–689. https://doi.org/10.1007/s12072-020-10070-wCrossRefPubMed

199.

Trauner M, Fuchs CD, Halilbasic E, Paumgartner G (2017) New therapeutic concepts in bile acid transport and signaling for management of cholestasis. Hepatology 65:1393–1404. https://doi.org/10.1002/hep.28991CrossRefPubMed

200.

Slijepcevic D, Roscam Abbing RLP, Fuchs CD et al (2018) Na+-taurocholate cotransporting polypeptide inhibition has hepatoprotective effects in cholestasis in mice. Hepatology 68:1057–1069. https://doi.org/10.1002/hep.29888CrossRefPubMed

201.

Roscam Abbing RLP, Slijepcevic D, Donkers JM et al (2020) Blocking sodium-taurocholate cotransporting polypeptide stimulates biliary cholesterol and phospholipid secretion in mice. Hepatology 71:247–258. https://doi.org/10.1002/hep.30792CrossRefPubMed

202.

Beuers U (2006) Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol 3:318–328. https://doi.org/10.1038/ncpgasthep0521CrossRefPubMed

203.

Yoon YB, Hagey LR, Hofmann AF et al (1986) Effect of side-chain shortening on the physiologic properties of bile acids: hepatic transport and effect on biliary secretion of 23-nor-ursodeoxycholate in rodents. Gastroenterology 90:837–852. https://doi.org/10.1016/0016-5085(86)90859-0CrossRefPubMed

204.

Cabrera D, Arab JP, Arrese M (2019) UDCA, NorUDCA, and TUDCA in liver diseases: a review of their mechanisms of action and clinical applications. In: Distrutti E (ed) Fiorucci S. Bile acids and their receptors, Springer, pp 237–264

205.

Fickert P, Hirschfield GM, Denk G et al (2017) norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis. J Hepatol 67:549–558. https://doi.org/10.1016/j.jhep.2017.05.009CrossRefPubMed

206.

Mazzetti M, Marconi G, Mancinelli M et al (2021) The management of cholestatic liver diseases: current therapies and emerging new possibilities. J Clin Med 10:1763. https://doi.org/10.3390/jcm10081763CrossRefPubMedPubMedCentral

207.

Zhu C, Boucheron N, Müller AC et al (2021) 24-Norursodeoxycholic acid reshapes immunometabolism in CD8+ T cells and alleviates hepatic inflammation. J Hepatol 75:1164–1176. https://doi.org/10.1016/j.jhep.2021.06.036CrossRefPubMedPubMedCentral

208.

Li T, Chiang JYL (2020) Bile acid-based therapies for non-alcoholic steatohepatitis and alcoholic liver disease. Hepatobiliary Surg Nutr 9:152–169. https://doi.org/10.21037/hbsn.2019.09.03CrossRefPubMedPubMedCentral

209.

Tannous BA, Teng J (2011) Secreted blood reporters: insights and applications. Biotechnol Adv 29:997–1003. https://doi.org/10.1016/j.biotechadv.2011.08.021CrossRefPubMedPubMedCentral

210.

Quigley EM, Gajula P (2020) Recent advances in modulating the microbiome. F1000Research 9:46. https://doi.org/10.12688/f1000research.20204.1CrossRef

211.

Wang R, Tang R, Li B et al (2021) Gut microbiome, liver immunology, and liver diseases. Cell Mol Immunol 18:4–17. https://doi.org/10.1038/s41423-020-00592-6CrossRefPubMed

Title: Bile acids and their receptors: modulators and therapeutic targets in liver inflammation
Authors: Anna Bertolini
Romina Fiorotto
Mario Strazzabosco
Publication date: 12-04-2022
Publisher: Springer Berlin Heidelberg
Keyword: Primary Biliary Cholangitis
Published in: Seminars in Immunopathology / Issue 4/2022
Print ISSN: 1863-2297
Electronic ISSN: 1863-2300
DOI: https://doi.org/10.1007/s00281-022-00935-7

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2022

Tolerance and autoimmunity in the liver

Correction to: Cellular senescence in the cholangiopathies: a driver of immunopathology and a novel therapeutic target

Challenges and opportunities in achieving effective regulatory T cell therapy in autoimmune liver disease

MAIT cells in liver inflammation and fibrosis

How genetic risk contributes to autoimmune liver disease

Harnessing the liver to induce antigen-specific immune tolerance

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage