pp 1-26 | Cite as

Targeting FXR in Cholestasis

  • Verena KeitelEmail author
  • Carola Dröge
  • Dieter Häussinger
Part of the Handbook of Experimental Pharmacology book series


The farnesoid X receptor (FXR, NR1H4) is a bile acid (BA)-activated transcription factor, which is essential for BA homeostasis. FXR and its hepatic and intestinal target genes, small heterodimer partner (SHP, NR0B2) and fibroblast growth factor 15/19 (Fgf15 in mice, FGF19 in humans), transcriptionally regulate BA synthesis, detoxification, secretion, and absorption in the enterohepatic circulation. Furthermore, FXR modulates a large variety of physiological processes, such as lipid and glucose homeostasis as well as the inflammatory response. Targeted deletion of FXR renders mice highly susceptible to cholic acid feeding resulting in cholestatic liver injury, weight loss, and increased mortality. Combined deletion of FXR and SHP spontaneously triggers early-onset intrahepatic cholestasis in mice resembling human progressive familial intrahepatic cholestasis (PFIC). Reduced expression levels and activity of FXR have been reported in human cholestatic conditions, such as PFIC type 1 and intrahepatic cholestasis of pregnancy. Recently, two pairs of siblings with homozygous FXR truncation or deletion variants were identified. All four children suffered from severe, early-onset PFIC and liver failure leading to death or need for liver transplantation before the age of 2. These findings underscore the central role of FXR as regulator of systemic and hepatic BA levels. Therefore, targeting FXR has been exploited in different animal models of both intrahepatic and obstructive cholestasis, and the first FXR agonist obeticholic acid (OCA) has been approved for the treatment of primary biliary cholangitis (PBC). Further FXR agonists as well as a FGF19 analogue are currently tested in clinical trials for different cholestatic liver diseases. This chapter will summarize the current knowledge on the role of FXR in cholestasis both in rodent models and in human diseases.


Bile acid homeostasis Cholestasis Farnesoid X receptor (FXR) FGF19 Fibroblast growth factor Obeticholic acid Primary biliary cholangitis (PBC) Primary sclerosing cholangitis (PSC) 



Our own studies are supported by DFG through SFB974 “Communication and systems relevance in liver damage and regeneration.”


  1. Abu-Hayyeh S, Williamson C (2015) Progesterone metabolites as farnesoid X receptor inhibitors. Dig Dis 33(3):300–306Google Scholar
  2. Abu-Hayyeh S, Papacleovoulou G, Lovgren-Sandblom A, Tahir M, Oduwole O, Jamaludin NA, Ravat S, Nikolova V, Chambers J, Selden C, Rees M, Marschall HU, Parker MG, Williamson C (2013) Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit farnesoid X receptor resulting in a cholestatic phenotype. Hepatology 57(2):716–726Google Scholar
  3. Abu-Hayyeh S, Ovadia C, Lieu T, Jensen DD, Chambers J, Dixon PH, Lovgren-Sandblom A, Bolier R, Tolenaars D, Kremer AE, Syngelaki A, Noori M, Williams D, Marin JJ, Monte MJ, Nicolaides KH, Beuers U, Oude-Elferink R, Seed PT, Chappell L, Marschall HU, Bunnett NW, Williamson C (2016) Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum. Hepatology 63(4):1287–1298Google Scholar
  4. Alvarez-Sola G, Uriarte I, Latasa MU, Urtasun R, Barcena-Varela M, Elizalde M, Jimenez M, Rodriguez-Ortigosa CM, Corrales FJ, Fernandez-Barrena MG, Berasain C, Avila MA (2017) Fibroblast growth factor 15/19 in hepatocarcinogenesis. Dig Dis 35(3):158–165Google Scholar
  5. Anakk S, Watanabe M, Ochsner SA, McKenna NJ, Finegold MJ, Moore DD (2011) Combined deletion of Fxr and Shp in mice induces Cyp17a1 and results in juvenile onset cholestasis. J Clin Invest 121(1):86–95Google Scholar
  6. Ananthanarayanan M, Balasubramanian N, Makishima M, Mangelsdorf DJ, Suchy FJ (2001) Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J Biol Chem 276(31):28857–28865Google Scholar
  7. Bacq Y (2011) Liver diseases unique to pregnancy: a 2010 update. Clin Res Hepatol Gastroenterol 35(3):182–193Google Scholar
  8. Bacq Y, Sentilhes L, Reyes HB, Glantz A, Kondrackiene J, Binder T, Nicastri PL, Locatelli A, Floreani A, Hernandez I, Di Martino V (2012) Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis. Gastroenterology 143(6):1492–1501Google Scholar
  9. Baghdasaryan A, Claudel T, Gumhold J, Silbert D, Adorini L, Roda A, Vecchiotti S, Gonzalez FJ, Schoonjans K, Strazzabosco M, Fickert P, Trauner M (2011) Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2−/− (Abcb4−/−) mouse cholangiopathy model by promoting biliary HCO output. Hepatology 54(4):1303–1312Google Scholar
  10. Bahar R, Wong KA, Liu CH, Bowlus CL (2018) Update on new drugs and those in development for the treatment of primary biliary cholangitis. Gastroenterol Hepatol (N Y) 14(3):154–163Google Scholar
  11. Beuers U, Trauner M, Jansen P, Poupon R (2015) New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond. J Hepatol 62(1 Suppl):S25–S37Google Scholar
  12. Boonstra K, Beuers U, Ponsioen CY (2012a) Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol 56(5):1181–1188Google Scholar
  13. Boonstra K, van Erpecum KJ, van Nieuwkerk KM, Drenth JP, Poen AC, Witteman BJ, Tuynman HA, Beuers U, Ponsioen CY (2012b) Primary sclerosing cholangitis is associated with a distinct phenotype of inflammatory bowel disease. Inflamm Bowel Dis 18(12):2270–2276Google Scholar
  14. Boyer JL, Trauner M, Mennone A, Soroka CJ, Cai SY, Moustafa T, Zollner G, Lee JY, Ballatori N (2006) Upregulation of a basolateral FXR-dependent bile acid efflux transporter OSTalpha-OSTbeta in cholestasis in humans and rodents. Am J Physiol Gastrointest Liver Physiol 290(6):G1124–G1130Google Scholar
  15. Cai SY, Gautam S, Nguyen T, Soroka CJ, Rahner C, Boyer JL (2009) ATP8B1 deficiency disrupts the bile canalicular membrane bilayer structure in hepatocytes, but FXR expression and activity are maintained. Gastroenterology 136(3):1060–1069Google Scholar
  16. Carey EJ, Ali AH, Lindor KD (2015) Primary biliary cirrhosis. Lancet 386(10003):1565–1575Google Scholar
  17. Cariello M, Peres C, Zerlotin R, Porru E, Sabba C, Roda A, Moschetta A (2017) Long-term administration of nuclear bile acid receptor FXR agonist prevents spontaneous hepatocarcinogenesis in Abcb4(−/−) mice. Sci Rep 7(1):11203Google Scholar
  18. Chen F, Ananthanarayanan M, Emre S, Neimark E, Bull LN, Knisely AS, Strautnieks SS, Thompson RJ, Magid MS, Gordon R, Balasubramanian N, Suchy FJ, Shneider BL (2004) Progressive familial intrahepatic cholestasis, type 1, is associated with decreased farnesoid X receptor activity. Gastroenterology 126(3):756–764Google Scholar
  19. Cho JY, Matsubara T, Kang DW, Ahn SH, Krausz KW, Idle JR, Luecke H, Gonzalez FJ (2010) Urinary metabolomics in Fxr-null mice reveals activated adaptive metabolic pathways upon bile acid challenge. J Lipid Res 51(5):1063–1074Google Scholar
  20. Corpechot C, Abenavoli L, Rabahi N, Chretien Y, Andreani T, Johanet C, Chazouilleres O, Poupon R (2008) Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology 48(3):871–877Google Scholar
  21. Corpechot C, Chazouilleres O, Poupon R (2011) Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome. J Hepatol 55(6):1361–1367Google Scholar
  22. Cui YJ, Aleksunes LM, Tanaka Y, Goedken MJ, Klaassen CD (2009) Compensatory induction of liver efflux transporters in response to ANIT-induced liver injury is impaired in FXR-null mice. Toxicol Sci 110(1):47–60Google Scholar
  23. Dawson PA, Haywood J, Craddock AL, Wilson M, Tietjen M, Kluckman K, Maeda N, Parks JS (2003) Targeted deletion of the ileal bile acid transporter eliminates enterohepatic cycling of bile acids in mice. J Biol Chem 278(36):33920–33927Google Scholar
  24. de Vree JM, Jacquemin E, Sturm E, Cresteil D, Bosma PJ, Aten J, Deleuze JF, Desrochers M, Burdelski M, Bernard O, Oude Elferink RP, Hadchouel M (1998) Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci U S A 95(1):282–287Google Scholar
  25. Denk GU, Soroka CJ, Takeyama Y, Chen WS, Schuetz JD, Boyer JL (2004) Multidrug resistance-associated protein 4 is up-regulated in liver but down-regulated in kidney in obstructive cholestasis in the rat. J Hepatol 40(4):585–591Google Scholar
  26. Denson LA, Sturm E, Echevarria W, Zimmerman TL, Makishima M, Mangelsdorf DJ, Karpen SJ (2001) The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp. Gastroenterology 121(1):140–147Google Scholar
  27. Dietrich CG, Ottenhoff R, de Waart DR, Oude Elferink RP (2001) Role of MRP2 and GSH in intrahepatic cycling of toxins. Toxicology 167(1):73–81Google Scholar
  28. Dixon PH, van Mil SW, Chambers J, Strautnieks S, Thompson RJ, Lammert F, Kubitz R, Keitel V, Glantz A, Mattsson LA, Marschall HU, Molokhia M, Moore GE, Linton KJ, Williamson C (2009) Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy. Gut 58(4):537–544Google Scholar
  29. Dixon PH, Wadsworth CA, Chambers J, Donnelly J, Cooley S, Buckley R, Mannino R, Jarvis S, Syngelaki A, Geenes V, Paul P, Sothinathan M, Kubitz R, Lammert F, Tribe RM, Ch’ng CL, Marschall HU, Glantz A, Khan SA, Nicolaides K, Whittaker J, Geary M, Williamson C (2014) A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy. Am J Gastroenterol 109(1):76–84Google Scholar
  30. Dixon PH, Sambrotta M, Chambers J, Taylor-Harris P, Syngelaki A, Nicolaides K, Knisely AS, Thompson RJ, Williamson C (2017) An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy. Sci Rep 7(1):11823Google Scholar
  31. Eaton JE, Talwalkar JA, Lazaridis KN, Gores GJ, Lindor KD (2013) Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management. Gastroenterology 145(3):521–536Google Scholar
  32. European Association for the Study of the Liver (2009) EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 51(2):237–267Google Scholar
  33. European Association for the Study of the Liver. Electronic address:; European Association for the Study of the Liver (2017) EASL Clinical Practice Guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol 67(1):145–172Google Scholar
  34. Fickert P, Zollner G, Fuchsbichler A, Stumptner C, Weiglein AH, Lammert F, Marschall HU, Tsybrovskyy O, Zatloukal K, Denk H, Trauner M (2002) Ursodeoxycholic acid aggravates bile infarcts in bile duct-ligated and Mdr2 knockout mice via disruption of cholangioles. Gastroenterology 123(4):1238–1251Google Scholar
  35. Fickert P, Fuchsbichler A, Wagner M, Zollner G, Kaser A, Tilg H, Krause R, Lammert F, Langner C, Zatloukal K, Marschall HU, Denk H, Trauner M (2004) Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 127(1):261–274Google Scholar
  36. Fiorucci S, Clerici C, Antonelli E, Orlandi S, Goodwin B, Sadeghpour BM, Sabatino G, Russo G, Castellani D, Willson TM, Pruzanski M, Pellicciari R, Morelli A (2005) Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis. J Pharmacol Exp Ther 313(2):604–612Google Scholar
  37. Forman BM, Goode E, Chen J, Oro AE, Bradley DJ, Perlmann T, Noonan DJ, Burka LT, McMorris T, Lamph WW (1995) Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 81(5):687–693Google Scholar
  38. Geenes V, Chappell LC, Seed PT, Steer PJ, Knight M, Williamson C (2014) Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: a prospective population-based case-control study. Hepatology 59(4):1482–1491Google Scholar
  39. Gerloff T, Stieger B, Hagenbuch B, Madon J, Landmann L, Roth J, Hofmann AF, Meier PJ (1998) The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J Biol Chem 273(16):10046–10050Google Scholar
  40. Glantz A, Marschall HU, Mattsson LA (2004) Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates. Hepatology 40(2):467–474Google Scholar
  41. Gomez-Ospina N, Potter CJ, Xiao R, Manickam K, Kim MS, Kim KH, Shneider BL, Picarsic JL, Jacobson TA, Zhang J, He W, Liu P, Knisely AS, Finegold MJ, Muzny DM, Boerwinkle E, Lupski JR, Plon SE, Gibbs RA, Eng CM, Yang Y, Washington GC, Porteus MH, Berquist WE, Kambham N, Singh RJ, Xia F, Enns GM, Moore DD (2016) Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nat Commun 7:10713Google Scholar
  42. Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB, Galardi C, Wilson JG, Lewis MC, Roth ME, Maloney PR, Willson TM, Kliewer SA (2000) A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 6(3):517–526Google Scholar
  43. Gudbjartsson DF, Helgason H, Gudjonsson SA, Zink F, Oddson A, Gylfason A, Besenbacher S, Magnusson G, Halldorsson BV, Hjartarson E, Sigurdsson GT, Stacey SN, Frigge ML, Holm H, Saemundsdottir J, Helgadottir HT, Johannsdottir H, Sigfusson G, Thorgeirsson G, Sverrisson JT, Gretarsdottir S, Walters GB, Rafnar T, Thjodleifsson B, Bjornsson ES, Olafsson S, Thorarinsdottir H, Steingrimsdottir T, Gudmundsdottir TS, Theodors A, Jonasson JG, Sigurdsson A, Bjornsdottir G, Jonsson JJ, Thorarensen O, Ludvigsson P, Gudbjartsson H, Eyjolfsson GI, Sigurdardottir O, Olafsson I, Arnar DO, Magnusson OT, Kong A, Masson G, Thorsteinsdottir U, Helgason A, Sulem P, Stefansson K (2015) Large-scale whole-genome sequencing of the Icelandic population. Nat Genet 47(5):435–444Google Scholar
  44. Guo GL, Lambert G, Negishi M, Ward JM, Brewer HB Jr, Kliewer SA, Gonzalez FJ, Sinal CJ (2003) Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicity. J Biol Chem 278(46):45062–45071Google Scholar
  45. Hagenbuch B, Meier PJ (1994) Molecular cloning, chromosomal localization, and functional characterization of a human liver Na+/bile acid cotransporter. J Clin Invest 93(3):1326–1331Google Scholar
  46. Häussinger D, Kubitz R, Reinehr R, Bode JG, Schliess F (2004) Molecular aspects of medicine: from experimental to clinical hepatology. Mol Aspects Med 25(3):221–360Google Scholar
  47. Hirschfield GM, Karlsen TH, Lindor KD, Adams DH (2013) Primary sclerosing cholangitis. Lancet 382(9904):1587–1599Google Scholar
  48. Hirschfield GM, Mason A, Luketic V, Lindor K, Gordon SC, Mayo M, Kowdley KV, Vincent C, Bodhenheimer HC Jr, Pares A, Trauner M, Marschall HU, Adorini L, Sciacca C, Beecher-Jones T, Castelloe E, Bohm O, Shapiro D (2015) Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 148(4):751–761 e8Google Scholar
  49. Hirschfield GM, Dyson JK, Alexander GJM, Chapman MH, Collier J, Hubscher S, Patanwala I, Pereira SP, Thain C, Thorburn D, Tiniakos D, Walmsley M, Webster G, Jones DEJ (2018a) The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines. Gut 67(9):1568–1594Google Scholar
  50. Hirschfield GM, Chazouilleres O, Drenth JP, Thorburn D, Harrison SA, Landis CS, Mayo MJ, Muir AJ, Trotter JF, Leeming DJ, Karsdal MA, Jaros MJ, Ling L, Kim KH, Rossi SJ, Somaratne RM, DePaoli AM, Beuers U (2018b) Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: a multicenter, randomized, double-blind, placebo-controlled phase II trial. J Hepatol 70(3):483–493Google Scholar
  51. Ho HK, Pok S, Streit S, Ruhe JE, Hart S, Lim KS, Loo HL, Aung MO, Lim SG, Ullrich A (2009) Fibroblast growth factor receptor 4 regulates proliferation, anti-apoptosis and alpha-fetoprotein secretion during hepatocellular carcinoma progression and represents a potential target for therapeutic intervention. J Hepatol 50(1):118–127Google Scholar
  52. Holt JA, Luo G, Billin AN, Bisi J, McNeill YY, Kozarsky KF, Donahee M, Wang d Y, Mansfield TA, Kliewer SA, Goodwin B, Jones SA (2003) Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev 17(13):1581–1591Google Scholar
  53. Huang L, Zhao A, Lew JL, Zhang T, Hrywna Y, Thompson JR, de PN, Royo I, Blevins RA, Pelaez F, Wright SD, Cui J (2003) Farnesoid X receptor activates transcription of the phospholipid pump MDR3. J Biol Chem 278(51):51085–51090Google Scholar
  54. Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, Luo G, Jones SA, Goodwin B, Richardson JA, Gerard RD, Repa JJ, Mangelsdorf DJ, Kliewer SA (2005) Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2(4):217–225Google Scholar
  55. Inagaki T, Moschetta A, Lee YK, Peng L, Zhao G, Downes M, Yu RT, Shelton JM, Richardson JA, Repa JJ, Mangelsdorf DJ, Kliewer SA (2006) Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci U S A 103(10):3920–3925Google Scholar
  56. Jacquemin E, Cresteil D, Manouvrier S, Boute O, Hadchouel M (1999) Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy. Lancet 353(9148):210–211Google Scholar
  57. Joshi D, James A, Quaglia A, Westbrook RH, Heneghan MA (2010) Liver disease in pregnancy. Lancet 375(9714):594–605Google Scholar
  58. Jung D, Kullak-Ublick GA (2003) Hepatocyte nuclear factor 1alpha: a key mediator of the effect of bile acids on gene expression. Hepatology 37(3):622–631Google Scholar
  59. Jung D, Podvinec M, Meyer UA, Mangelsdorf DJ, Fried M, Meier PJ, Kullak-Ublick GA (2002) Human organic anion transporting polypeptide 8 promoter is transactivated by the farnesoid X receptor/bile acid receptor. Gastroenterology 122(7):1954–1966Google Scholar
  60. Jung D, Hagenbuch B, Fried M, Meier PJ, Kullak-Ublick GA (2004) Role of liver-enriched transcription factors and nuclear receptors in regulating the human, mouse, and rat NTCP gene. Am J Physiol Gastrointest Liver Physiol 286(5):G752–G761Google Scholar
  61. Kalaany NY, Mangelsdorf DJ (2006) LXRS and FXR: the yin and yang of cholesterol and fat metabolism. Annu Rev Physiol 68:159–191Google Scholar
  62. Kamisako T, Leier I, Cui Y, Kînig J, Buchholz U, Hummel-Eisenbeiss J, Keppler D (1999) Transport of monoglucuronosyl and bisglucuronosyl bilirubin by recombinant human and rat multidrug resistance protein 2. Hepatology 30(2):485–490Google Scholar
  63. Kast HR, Goodwin B, Tarr PT, Jones SA, Anisfeld AM, Stoltz CM, Tontonoz P, Kliewer S, Willson TM, Edwards PA (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(4):2908–2915Google Scholar
  64. Kazgan N, Metukuri MR, Purushotham A, Lu J, Rao A, Lee S, Pratt-Hyatt M, Lickteig A, Csanaky IL, Zhao Y, Dawson PA, Li X (2014) Intestine-specific deletion of SIRT1 in mice impairs DCoH2-HNF-1alpha-FXR signaling and alters systemic bile acid homeostasis. Gastroenterology 146(4):1006–1016Google Scholar
  65. Keitel V, Burdelski M, Warskulat U, Kuhlkamp T, Keppler D, Häussinger D, Kubitz R (2005) Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis. Hepatology 41(5):1160–1172Google Scholar
  66. Keitel V, Vogt C, Häussinger D, Kubitz R (2006) Combined mutations of canalicular transporter proteins cause severe intrahepatic cholestasis of pregnancy. Gastroenterology 131(2):624–629Google Scholar
  67. Keitel V, Kubitz R, Häussinger D (2008) Endocrine and paracrine role of bile acids. World J Gastroenterol 14(37):5620–5629Google Scholar
  68. Keitel V, Dröge C, Stepanow S, Fehm T, Mayatepek E, Kohrer K, Häussinger D (2016) Intrahepatic cholestasis of pregnancy (ICP): case report and review of the literature. Z Gastroenterol 54(12):1327–1333Google Scholar
  69. Keppler D, Kamisako T, Leier I, Cui Y, Nies AT, Tsujii H, König J (2000) Localization, substrate specificity, and drug resistance conferred by conjugate export pumps of the MRP family. Adv Enzyme Regul 40:339–349Google Scholar
  70. Kerr TA, Saeki S, Schneider M, Schaefer K, Berdy S, Redder T, Shan B, Russell DW, Schwarz M (2002) Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis. Dev Cell 2(6):713–720Google Scholar
  71. Kim I, Ahn SH, Inagaki T, Choi M, Ito S, Guo GL, Kliewer SA, Gonzalez FJ (2007) Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J Lipid Res 48(12):2664–2672Google Scholar
  72. Kliewer SA, Mangelsdorf DJ (2015) Bile acids as hormones: the FXR-FGF15/19 pathway. Dig Dis 33(3):327–331Google Scholar
  73. Kowdley KV, Luketic V, Chapman R, Hirschfield GM, Poupon R, Schramm C, Vincent C, Rust C, Pares A, Mason A, Marschall HU, Shapiro D, Adorini L, Sciacca C, Beecher-Jones T, Bohm O, Pencek R, Jones D, Obeticholic Acid PBC Monotherapy Study Group (2018) A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology 67(5):1890–1902Google Scholar
  74. Kuiper EM, Hansen BE, de Vries RA, den Ouden-Muller JW, van Ditzhuijsen TJ, Haagsma EB, Houben MH, Witteman BJ, van Erpecum KJ, van Buuren HR, Dutch PBCSG (2009) Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology 136(4):1281–1287Google Scholar
  75. Kullak-Ublick GA (2003) ABC transporter regulation by bile acids: where PXR meets FXR. J Hepatol 39(4):628–630Google Scholar
  76. Kullak-Ublick GA, Stieger B, Hagenbuch B, Meier PJ (2000) Hepatic transport of bile salts. Semin Liver Dis 20(3):273–292Google Scholar
  77. Kullak-Ublick G, Stieger B, Meier PJ (2004) Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology 126(1):322–342Google Scholar
  78. Lammers WJ, Hirschfield GM, Corpechot C, Nevens F, Lindor KD, Janssen HL, Floreani A, Ponsioen CY, Mayo MJ, Invernizzi P, Battezzati PM, Pares A, Burroughs AK, Mason AL, Kowdley KV, Kumagi T, Harms MH, Trivedi PJ, Poupon R, Cheung A, Lleo A, Caballeria L, Hansen BE, van Buuren HR, Global PBCSG (2015) Development and validation of a scoring system to predict outcomes of patients with primary biliary cirrhosis receiving ursodeoxycholic acid therapy. Gastroenterology 149(7):1804–1812 e4Google Scholar
  79. Lammert F, Marschall HU, Glantz A, Matern S (2000) Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol 33(6):1012–1021Google Scholar
  80. Landrier JF, Eloranta JJ, Vavricka SR, Kullak-Ublick GA (2006) The nuclear receptor for bile acids, FXR, transactivates human organic solute transporter-alpha and -beta genes. Am J Physiol Gastrointest Liver Physiol 290(3):G476–G485Google Scholar
  81. Lazaridis KN, LaRusso NF (2016) Primary sclerosing cholangitis. N Engl J Med 375(12):1161–1170Google Scholar
  82. Lazaridis KN, Pham L, Tietz P, Marinelli RA, de Groen PC, Levine S, Dawson PA, LaRusso NF (1997) Rat cholangiocytes absorb bile acids at their apical domain via the ileal sodium-dependent bile acid transporter. J Clin Invest 100(11):2714–2721Google Scholar
  83. Lee YK, Moore DD (2002) Dual mechanisms for repression of the monomeric orphan receptor liver receptor homologous protein-1 by the orphan small heterodimer partner. J Biol Chem 277(4):2463–2467Google Scholar
  84. Lee YK, Dell H, Dowhan DH, Hadzopoulou-Cladaras M, Moore DD (2000) The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: two mechanisms for repression. Mol Cell Biol 20(1):187–195Google Scholar
  85. Leuschner M, Guldutuna S, You T, Hubner K, Bhatti S, Leuschner U (1996) Ursodeoxycholic acid and prednisolone versus ursodeoxycholic acid and placebo in the treatment of early stages of primary biliary cirrhosis. J Hepatol 25(1):49–57Google Scholar
  86. Liu Y, Binz J, Numerick MJ, Dennis S, Luo G, Desai B, MacKenzie KI, Mansfield TA, Kliewer SA, Goodwin B, Jones SA (2003) Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. J Clin Invest 112(11):1678–1687Google Scholar
  87. Lu TT, Makishima M, Repa JJ, Schoonjans K, Kerr TA, Auwerx J, Mangelsdorf DJ (2000) Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 6(3):507–515Google Scholar
  88. Luo J, Ko B, Elliott M, Zhou M, Lindhout DA, Phung V, To C, Learned RM, Tian H, DePaoli AM, Ling L (2014) A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci Transl Med 6(247):247ra100Google Scholar
  89. 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):1362–1365Google Scholar
  90. Marschall HU, Wagner M, Bodin K, Zollner G, Fickert P, Gumhold J, Silbert D, Fuchsbichler A, Sjovall J, Trauner M (2006) Fxr(−/−) mice adapt to biliary obstruction by enhanced phase I detoxification and renal elimination of bile acids. J Lipid Res 47(3):582–592Google Scholar
  91. Marschall HU, Wikstrom Shemer E, Ludvigsson JF, Stephansson O (2013) Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: a population-based cohort study. Hepatology 58(4):1385–1391Google Scholar
  92. Massafra V, Pellicciari R, Gioiello A, van Mil SWC (2018) Progress and challenges of selective Farnesoid X Receptor modulation. Pharmacol Ther 191:162–177Google Scholar
  93. Mayo MJ, Wigg AJ, Leggett BA, Arnold H, Thompson AJ, Weltman M, Carey EJ, Muir AJ, Ling L, Rossi SJ, DePaoli AM (2018) NGM282 for treatment of patients with primary biliary cholangitis: a multicenter, randomized, double-blind, placebo-controlled trial. Hepatol Commun 2(9):1037–1050Google Scholar
  94. Milona A, Owen BM, Cobbold JF, Willemsen EC, Cox IJ, Boudjelal M, Cairns W, Schoonjans K, Taylor-Robinson SD, Klomp LW, Parker MG, White R, van Mil SW, Williamson C (2010) Raised hepatic bile acid concentrations during pregnancy in mice are associated with reduced farnesoid X receptor function. Hepatology 52(4):1341–1349Google Scholar
  95. Modica S, Petruzzelli M, Bellafante E, Murzilli S, Salvatore L, Celli N, Di Tullio G, Palasciano G, Moustafa T, Halilbasic E, Trauner M, Moschetta A (2012) Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis. Gastroenterology 142(2):355–365 e1–4Google Scholar
  96. Müllenbach R, Linton KJ, Wiltshire S, Weerasekera N, Chambers J, Elias E, Higgins CF, Johnston DG, McCarthy MI, Williamson C (2003) ABCB4 gene sequence variation in women with intrahepatic cholestasis of pregnancy. J Med Genet 40(5):e70Google Scholar
  97. Müllenbach R, Bennett A, Tetlow N, Patel N, Hamilton G, Cheng F, Chambers J, Howard R, Taylor-Robinson SD, Williamson C (2005) ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy. Gut 54(6):829–834Google Scholar
  98. Neimark E, Chen F, Li X, Shneider BL (2004) Bile acid-induced negative feedback regulation of the human ileal bile acid transporter. Hepatology 40(1):149–156Google Scholar
  99. Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P, Drenth JP, Pockros PJ, Regula J, Beuers U, Trauner M, Jones DE, Floreani A, Hohenester S, Luketic V, Shiffman M, van Erpecum KJ, Vargas V, Vincent C, Hirschfield GM, Shah H, Hansen B, Lindor KD, Marschall HU, Kowdley KV, Hooshmand-Rad R, Marmon T, Sheeron S, Pencek R, MacConell L, Pruzanski M, Shapiro D, Group PS (2016) A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 375(7):631–643Google Scholar
  100. Nicholes K, Guillet S, Tomlinson E, Hillan K, Wright B, Frantz GD, Pham TA, Dillard-Telm L, Tsai SP, Stephan JP, Stinson J, Stewart T, French DM (2002) A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathol 160(6):2295–2307Google Scholar
  101. Padrissa-Altes S, Bachofner M, Bogorad RL, Pohlmeier L, Rossolini T, Bohm F, Liebisch G, Hellerbrand C, Koteliansky V, Speicher T, Werner S (2015) Control of hepatocyte proliferation and survival by Fgf receptors is essential for liver regeneration in mice. Gut 64(9):1444–1453Google Scholar
  102. Pares A, Caballeria L, Rodes J (2006) Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid. Gastroenterology 130(3):715–720Google Scholar
  103. 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):1365–1368Google Scholar
  104. Pauli-Magnus C, Lang T, Meier Y, Zodan-Marin T, Jung D, Breymann C, Zimmermann R, Kenngott S, Beuers U, Reichel C, Kerb R, Penger A, Meier PJ, Kullak-Ublick GA (2004) Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy. Pharmacogenetics 14(2):91–102Google Scholar
  105. Poupon RE, Balkau B, Eschwege E, Poupon R (1991) A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group. N Engl J Med 324(22):1548–1554Google Scholar
  106. Poupon RE, Bonnand AM, Chretien Y, Poupon R (1999) Ten-year survival in ursodeoxycholic acid-treated patients with primary biliary cirrhosis. The UDCA-PBC Study Group. Hepatology 29(6):1668–1671Google Scholar
  107. Rioseco AJ, Ivankovic MB, Manzur A, Hamed F, Kato SR, Parer JT, Germain AM (1994) Intrahepatic cholestasis of pregnancy: a retrospective case-control study of perinatal outcome. Am J Obstet Gynecol 170(3):890–895Google Scholar
  108. Ropponen A, Sund R, Riikonen S, Ylikorkala O, Aittomaki K (2006) Intrahepatic cholestasis of pregnancy as an indicator of liver and biliary diseases: a population-based study. Hepatology 43(4):723–728Google Scholar
  109. Russell DW (2003) The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem 72:137–174Google Scholar
  110. Sawey ET, Chanrion M, Cai C, Wu G, Zhang J, Zender L, Zhao A, Busuttil RW, Yee H, Stein L, French DM, Finn RS, Lowe SW, Powers S (2011) Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by Oncogenomic screening. Cancer Cell 19(3):347–358Google Scholar
  111. Schuetz EG, Strom S, Yasuda K, Lecureur V, Assem M, Brimer C, Lamba J, Kim RB, Ramachandran V, Komoroski BJ, Venkataramanan R, Cai H, Sinal CJ, Gonzalez FJ, Schuetz JD (2001) Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450. J Biol Chem 276(42):39411–39418Google Scholar
  112. Seol W, Choi HS, Moore DD (1996) An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors. Science 272(5266):1336–1339Google Scholar
  113. Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ (2000) Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102(6):731–744Google Scholar
  114. Sinha J, Chen F, Miloh T, Burns RC, Yu Z, Shneider BL (2008) Beta-Klotho and FGF-15/19 inhibit the apical sodium-dependent bile acid transporter in enterocytes and cholangiocytes. Am J Physiol Gastrointest Liver Physiol 295(5):G996–G1003Google Scholar
  115. Smit JJ, Schinkel AH, Oude Elferink RP, Groen AK, Wagenaar E, van Deemter L, Mol CA, Ottenhoff R, van der Lugt NM, van Roon MA (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(3):451–462Google Scholar
  116. Song X, Vasilenko A, Chen Y, Valanejad L, Verma R, Yan B, Deng R (2014) Transcriptional dynamics of bile salt export pump during pregnancy: mechanisms and implications in intrahepatic cholestasis of pregnancy. Hepatology 60(6):1993–2007Google Scholar
  117. Stedman C, Liddle C, Coulter S, Sonoda J, Alvarez JG, Evans RM, Downes M (2006) Benefit of farnesoid X receptor inhibition in obstructive cholestasis. Proc Natl Acad Sci U S A 103(30):11323–11328Google Scholar
  118. Stroup D, Crestani M, Chiang JY (1997) Identification of a bile acid response element in the cholesterol 7 alpha-hydroxylase gene CYP7A. Am J Physiol 273(2 Pt 1):G508–G517Google Scholar
  119. Trauner M, Gulamhusein A, Hameed B, Caldwell S, Shiffman ML, Landis C, Eksteen B, Agarwal K, Muir A, Rushbrook S, Lu X, Xu J, Chuang JC, Billin AN, Chung C, Li G, Subramanian GM, Myers RP, Bowlus CL, Kowdley KV (2019) The nonsteroidal FXR agonist cilofexor (GS-9674) improves markers of cholestasis and liver injury in patients with PSC. Hepatology.
  120. Tully DC, Rucker PV, Chianelli D, Williams J, Vidal A, Alper PB, Mutnick D, Bursulaya B, Schmeits J, Wu X, Bao D, Zoll J, Kim Y, Groessl T, McNamara P, Seidel HM, Molteni V, Liu B, Phimister A, Joseph SB, Laffitte B (2017) Discovery of tropifexor (LJN452), a highly potent non-bile acid FXR agonist for the treatment of cholestatic liver diseases and nonalcoholic steatohepatitis (NASH). J Med Chem 60(24):9960–9973Google Scholar
  121. Uriarte I, Fernandez-Barrena MG, Monte MJ, Latasa MU, Chang HC, Carotti S, Vespasiani-Gentilucci U, Morini S, Vicente E, Concepcion AR, Medina JF, Marin JJ, Berasain C, Prieto J, Avila MA (2013) Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice. Gut 62(6):899–910Google Scholar
  122. Uriarte I, Latasa MU, Carotti S, Fernandez-Barrena MG, Garcia-Irigoyen O, Elizalde M, Urtasun R, Vespasiani-Gentilucci U, Morini S, de Mingo A, Mari M, Corrales FJ, Prieto J, Berasain C, Avila MA (2015) Ileal FGF15 contributes to fibrosis-associated hepatocellular carcinoma development. Int J Cancer 136(10):2469–2475Google Scholar
  123. van Helvoort A, Smith AJ, Sprong H, Fritzsche I, Schinkel AH, Borst P, van Meer G (1996) MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell 87(3):507–517Google Scholar
  124. van Mil SW, Milona A, Dixon PH, Mullenbach R, Geenes VL, Chambers J, Shevchuk V, Moore GE, Lammert F, Glantz AG, Mattsson LA, Whittaker J, Parker MG, White R, Williamson C (2007) Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy. Gastroenterology 133(2):507–516Google Scholar
  125. Wagner M, Fickert P, Zollner G, Fuchsbichler A, Silbert D, Tsybrovskyy O, Zatloukal K, Guo GL, Schuetz JD, Gonzalez FJ, Marschall HU, Denk H, Trauner M (2003) Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice. Gastroenterology 125(3):825–838Google Scholar
  126. 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):543–553Google Scholar
  127. Wang R, Salem M, Yousef IM, Tuchweber B, Lam P, Childs SJ, Helgason CD, Ackerley C, Phillips MJ, Ling V (2001) Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis. Proc Natl Acad Sci U S A 98(4):2011–2016Google Scholar
  128. Wang L, Lee YK, Bundman D, Han Y, Thevananther S, Kim CS, Chua SS, Wei P, Heyman RA, Karin M, Moore DD (2002) Redundant pathways for negative feedback regulation of bile acid production. Dev Cell 2(6):721–731Google Scholar
  129. Wang L, Han Y, Kim CS, Lee YK, Moore DD (2003) Resistance of SHP-null mice to bile acid-induced liver damage. J Biol Chem 278(45):44475–44481Google Scholar
  130. Wasmuth HE, Glantz A, Keppeler H, Simon E, Bartz C, Rath W, Mattsson LA, Marschall HU, Lammert F (2007) Intrahepatic cholestasis of pregnancy: the severe form is associated with common variants of the hepatobiliary phospholipid transporter ABCB4 gene. Gut 56(2):265–270Google Scholar
  131. Wikstrom Shemer E, Marschall HU, Ludvigsson JF, Stephansson O (2013) Intrahepatic cholestasis of pregnancy and associated adverse pregnancy and fetal outcomes: a 12-year population-based cohort study. BJOG 120(6):717–723Google Scholar
  132. Wikstrom Shemer EA, Stephansson O, Thuresson M, Thorsell M, Ludvigsson JF, Marschall HU (2015) Intrahepatic cholestasis of pregnancy and cancer, immune-mediated and cardiovascular diseases: a population-based cohort study. J Hepatol 63(2):456–461Google Scholar
  133. Williamson C, Geenes V (2014) Intrahepatic cholestasis of pregnancy. Obstet Gynecol 124(1):120–133Google Scholar
  134. Williamson C, Hems LM, Goulis DG, Walker I, Chambers J, Donaldson O, Swiet M, Johnston DG (2004) Clinical outcome in a series of cases of obstetric cholestasis identified via a patient support group. BJOG 111(7):676–681Google Scholar
  135. Yang Y, Zhang M, Eggertsen G, Chiang JY (2002) On the mechanism of bile acid inhibition of rat sterol 12alpha-hydroxylase gene (CYP8B1) transcription: roles of alpha-fetoprotein transcription factor and hepatocyte nuclear factor 4alpha. Biochim Biophys Acta 1583(1):63–73Google Scholar
  136. Zhang M, Chiang JY (2001) Transcriptional regulation of the human sterol 12alpha-hydroxylase gene (CYP8B1): roles of heaptocyte nuclear factor 4alpha in mediating bile acid repression. J Biol Chem 276(45):41690–41699Google Scholar
  137. Zhou M, Wang X, Phung V, Lindhout DA, Mondal K, Hsu JY, Yang H, Humphrey M, Ding X, Arora T, Learned RM, DePaoli AM, Tian H, Ling L (2014) Separating tumorigenicity from bile acid regulatory activity for endocrine hormone FGF19. Cancer Res 74(12):3306–3316Google Scholar
  138. Zhou M, Learned RM, Rossi SJ, DePaoli AM, Tian H, Ling L (2016) Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-deficient mice. Hepatology 63(3):914–929Google Scholar
  139. Zollner G, Fickert P, Silbert D, Fuchsbichler A, Marschall HU, Zatloukal K, Denk H, Trauner M (2003) Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol 38(6):717–727Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Verena Keitel
    • 1
    Email author
  • Carola Dröge
    • 1
  • Dieter Häussinger
    • 1
  1. 1.Clinic for Gastroenterology, Hepatology and Infectious DiseasesUniversity Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-UniversityDüsseldorfGermany

Personalised recommendations