pp 1-39 | Cite as

Nonsteroidal FXR Ligands: Current Status and Clinical Applications

  • Christian Gege
  • Eva Hambruch
  • Nina Hambruch
  • Olaf Kinzel
  • Claus KremoserEmail author
Part of the Handbook of Experimental Pharmacology book series


FXR agonists have demonstrated very promising clinical results in the treatment of liver disorders such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and nonalcoholic steatohepatitis (NASH). NASH, in particular, is one of the last uncharted white territories in the pharma landscape, and there is a huge medical need and a large potential pharmaceutical market for a NASH pharmacotherapy. Clinical efficacy superior to most other treatment options was shown by FXR agonists such as obeticholic acid (OCA) as they improved various metabolic features including liver steatosis as well as liver inflammation and fibrosis. But OCA’s clinical success comes with some major liabilities such as pruritus, high-density lipoprotein cholesterol (HDLc) lowering, low-density lipoprotein cholesterol (LDLc) increase, and a potential for drug-induced liver toxicity. Some of these effects can be attributed to on-target effects exerted by FXR, but with others it is not clear whether it is FXR- or OCA-related. Therefore a quest for novel, proprietary FXR agonists is ongoing with the aim to increase FXR potency and selectivity over other proteins and to overcome at least some of the OCA-associated clinical side effects through an improved pharmacology. In this chapter we will discuss the historical and ongoing efforts in the identification and development of nonsteroidal, which largely means non-bile acid-type, FXR agonists for clinical use.


Cilofexor Farnesoid X receptor GS-9674 NASH Tropifexor 


  1. Alemi F, Kwon E, Poole DP, Lieu T, Lyo V, Cattaruzza F et al (2013) The TGR5 receptor mediates bile acid-induced itch and analgesia. J Clin Invest 123(4):1513–1530Google Scholar
  2. Ames BN, Kammen HO, Yamasaki E (1975) Hair dyes are mutagenic: identification of a variety of mutagenic ingredients. Proc Natl Acad Sci U S A 72(6):2423–2427Google Scholar
  3. Amslinger S (2010) The tunable functionality of alpha,beta-unsaturated carbonyl compounds enables their differential application in biological systems. ChemMedChem 5(3):351–356Google Scholar
  4. 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
  5. Attinkara R, Mwinyi J, Truninger K, Regula J, Gaj P, Rogler G et al (2012) Association of genetic variation in the NR1H4 gene, encoding the nuclear bile acid receptor FXR, with inflammatory bowel disease. BMC Res Notes 5:461Google Scholar
  6. Bailey AM, Zhan L, Maru D, Shureiqi I, Pickering CR, Kiriakova G et al (2014) FXR silencing in human colon cancer by DNA methylation and KRAS signaling. Am J Physiol Gastrointest Liver Physiol 306(1):G48–G58Google Scholar
  7. Bedossa P (2017) Pathology of non-alcoholic fatty liver disease. Liver Int 37(Suppl 1):85–89Google Scholar
  8. Bernstein H, Bernstein C, Payne CM, Dvorakova K, Garewal H (2005) Bile acids as carcinogens in human gastrointestinal cancers. Mutat Res 589(1):47–65Google Scholar
  9. Bosch J, Iwakiri Y (2018) The portal hypertension syndrome: etiology, classification, relevance, and animal models. Hepatol Int 12(Suppl 1):1–10Google Scholar
  10. Boyer JL, Trauner M, Mennone A, Soroka CJ, Cai S-Y, Moustafa T et al (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
  11. Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engström O et al (1997) Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389(6652):753–758Google Scholar
  12. Bulynko YA, O’Malley BW (2011) Nuclear receptor coactivators: structural and functional biochemistry. Biochemistry (Mosc) 50(3):313–328Google Scholar
  13. Burris TP, Solt LA, Wang Y, Crumbley C, Banerjee S, Griffett K et al (2013) Nuclear receptors and their selective pharmacologic modulators. Pharmacol Rev 65(2):710–778Google Scholar
  14. Byrne CD, Targher G (2015) NAFLD: a multisystem disease. J Hepatol 62(1 Suppl):S47–S64Google Scholar
  15. Cariello M, Peres C, Zerlotin R, Porru E, Sabbà C, Roda A et al (2017) Long-term administration of nuclear bile acid receptor FXR agonist prevents spontaneous hepatocarcinogenesis in Abcb4−/− mice. Sci Rep 7(1):11203Google Scholar
  16. Cariou B, van Harmelen K, Duran-Sandoval D, van Dijk TH, Grefhorst A, Abdelkarim M et al (2006) The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem 281(16):11039–11049Google Scholar
  17. Chávez-Talavera O, Tailleux A, Lefebvre P, Staels B (2017) Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Gastroenterology 152(7):1679–1694.e3Google Scholar
  18. Chignard N, Poupon R (2009) Targeting farnesoid x receptor in hepatic and biliary inflammatory diseases. Gastroenterology 137(2):734–735; discussion 736Google Scholar
  19. Cipriani S, Mencarelli A, Palladino G, Fiorucci S (2010) FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res 51(4):771–784Google Scholar
  20. Copaci I, Micu L, Iliescu L, Voiculescu M (2005) New therapeutical indications of ursodeoxycholic acid. Rom J Gastroenterol 14(3):259–266Google Scholar
  21. Corpechot C, Abenavoli L, Rabahi N, Chrétien Y, Andréani T, Johanet C et al (2008) Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology 48(3):871–877Google Scholar
  22. de Boer JF, Schonewille M, Boesjes M, Wolters H, Bloks VW, Bos T et al (2017) Intestinal farnesoid X receptor controls transintestinal cholesterol excretion in mice. Gastroenterology 152(5):1126–1138.e6Google Scholar
  23. de Gottardi A, Touri F, Maurer CA, Perez A, Maurhofer O, Ventre G et al (2004) The bile acid nuclear receptor FXR and the bile acid binding protein IBABP are differently expressed in colon cancer. Dig Dis Sci 49(6):982–989Google Scholar
  24. Debruyne PR, Bruyneel EA, Li X, Zimber A, Gespach C, Mareel MM (2001) The role of bile acids in carcinogenesis. Mutat Res 480–481:359–369Google Scholar
  25. Deuschle U, Schüler J, Schulz A, Schlüter T, Kinzel O, Abel U et al (2012) FXR controls the tumor suppressor NDRG2 and FXR agonists reduce liver tumor growth and metastasis in an orthotopic mouse xenograft model. PLoS One 7(10):e43044Google Scholar
  26. Ding L, Yang L, Wang Z, Huang W (2015) Bile acid nuclear receptor FXR and digestive system diseases. Acta Pharm Sin B 5(2):135–144Google Scholar
  27. Downes M, Verdecia MA, Roecker AJ, Hughes R, Hogenesch JB, Kast-Woelbern HR et al (2003) A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR. Mol Cell 11(4):1079–1092Google Scholar
  28. Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z et al (2017) Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology 65(5):1557–1565Google Scholar
  29. Dwivedi SKD, Singh N, Kumari R, Mishra JS, Tripathi S, Banerjee P et al (2011) Bile acid receptor agonist GW4064 regulates PPARγ coactivator-1α expression through estrogen receptor-related receptor α. Mol Endocrinol 25(6):922–932Google Scholar
  30. Evans MJ, Mahaney PE, Borges-Marcucci L, Lai K, Wang S, Krueger JA et al (2009) A synthetic farnesoid X receptor (FXR) agonist promotes cholesterol lowering in models of dyslipidemia. Am J Physiol Gastrointest Liver Physiol 296(3):G543–G552Google Scholar
  31. Fang S, Suh JM, Reilly SM, Yu E, Osborn O, Lackey D et al (2015) Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 21(2):159–165Google Scholar
  32. Fickert P, Fuchsbichler A, Moustafa T, Wagner M, Zollner G, Halilbasic E et al (2009) Farnesoid X receptor critically determines the fibrotic response in mice but is expressed to a low extent in human hepatic stellate cells and periductal myofibroblasts. Am J Pathol 175(6):2392–2405Google Scholar
  33. Filozof C, Chow S-C, Dimick-Santos L, Chen Y-F, Williams RN, Goldstein BJ et al (2017) Clinical endpoints and adaptive clinical trials in precirrhotic nonalcoholic steatohepatitis: facilitating development approaches for an emerging epidemic. Hepatol Commun 1(7):577–585Google Scholar
  34. Fiorucci S, Antonelli E, Rizzo G, Renga B, Mencarelli A, Riccardi L et al (2004) The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 127(5):1497–1512Google Scholar
  35. Fiorucci S, Clerici C, Antonelli E, Orlandi S, Goodwin B, Sadeghpour BM et al (2005a) 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
  36. Fiorucci S, Rizzo G, Antonelli E, Renga B, Mencarelli A, Riccardi L et al (2005b) A farnesoid x receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis. J Pharmacol Exp Ther 314(2):584–595Google Scholar
  37. Fiorucci S, Rizzo G, Antonelli E, Renga B, Mencarelli A, Riccardi L et al (2005c) Cross-talk between farnesoid-X-receptor (FXR) and peroxisome proliferator-activated receptor gamma contributes to the antifibrotic activity of FXR ligands in rodent models of liver cirrhosis. J Pharmacol Exp Ther 315(1):58–68Google Scholar
  38. Fiorucci S, Distrutti E, Ricci P, Giuliano V, Donini A, Baldelli F (2014) Targeting FXR in cholestasis: hype or hope. Expert Opin Ther Targets 18(12):1449–1459Google Scholar
  39. Flatt B, Martin R, Wang T-L, Mahaney P, Murphy B, Gu X-H et al (2009) Discovery of XL335 (WAY-362450), a highly potent, selective, and orally active agonist of the farnesoid X receptor (FXR). J Med Chem 52(4):904–907Google Scholar
  40. French DM, Lin BC, Wang M, Adams C, Shek T, Hötzel K et al (2012) Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models. PLoS One 7(5):e36713Google Scholar
  41. Gadaleta RM, van Mil SWC, Oldenburg B, Siersema PD, Klomp LWJ, van Erpecum KJ (2010) Bile acids and their nuclear receptor FXR: relevance for hepatobiliary and gastrointestinal disease. Biochim Biophys Acta 1801(7):683–692Google Scholar
  42. Gadaleta RM, van Erpecum KJ, Oldenburg B, Willemsen ECL, Renooij W, Murzilli S et al (2011) Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 60(4):463–472Google Scholar
  43. Gardès C, Chaput E, Staempfli A, Blum D, Richter H, Benson GM (2013) Differential regulation of bile acid and cholesterol metabolism by the farnesoid X receptor in Ldlr −/− mice versus hamsters. J Lipid Res 54(5):1283–1299Google Scholar
  44. Gege C, Kinzel O, Steeneck C, Schulz A, Kremoser C (2014) Knocking on FXR’s door: the ‘hammerhead’-structure series of FXR agonists – amphiphilic isoxazoles with potent in vitro and in vivo activities. Curr Top Med Chem 14(19):2143–2158Google Scholar
  45. Genin MJ, Bueno AB, Agejas Francisco J, Manninen PR, Bocchinfuso WP, Montrose-Rafizadeh C et al (2015) Discovery of 6-(4-{[5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic acid: a novel FXR agonist for the treatment of dyslipidemia. J Med Chem 58(24):9768–9772Google Scholar
  46. Glickman JF, Wu X, Mercuri R, Illy C, Bowen BR, He Y et al (2002) A comparison of ALPHAScreen, TR-FRET, and TRF as assay methods for FXR nuclear receptors. J Biomol Screen 7(1):3–10Google Scholar
  47. Goldstein J, Levy C (2018) Novel and emerging therapies for cholestatic liver diseases. Liver Int 38(9):1520–1535Google Scholar
  48. Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB et al (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
  49. Gronemeyer H, Gustafsson J-A, Laudet V (2004) Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 3(11):950–964Google Scholar
  50. Hagström H, Nasr P, Ekstedt M, Hammar U, Stål P, Hultcrantz R et al (2017) Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol 67(6):1265–1273Google Scholar
  51. Hambruch E, Miyazaki-Anzai S, Hahn U, Matysik S, Boettcher A, Perović-Ottstadt S et al (2012) Synthetic farnesoid X receptor agonists induce high-density lipoprotein-mediated transhepatic cholesterol efflux in mice and monkeys and prevent atherosclerosis in cholesteryl ester transfer protein transgenic low-density lipoprotein receptor (−/−) mice. J Pharmacol Exp Ther 343(3):556–567Google Scholar
  52. Hannah WN, Torres DM, Harrison SA (2016) Nonalcoholic steatohepatitis and endpoints in clinical trials. Gastroenterol Hepatol 12(12):756–763Google Scholar
  53. Hartman HB, Gardell SJ, Petucci CJ, Wang S, Krueger JA, Evans MJ (2009) Activation of farnesoid X receptor prevents atherosclerotic lesion formation in LDLR−/− and apoE−/− mice. J Lipid Res 50(6):1090–1100Google Scholar
  54. Ho HK, Pok S, Streit S, Ruhe JE, Hart S, Lim KS et al (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
  55. Holt JA, Luo G, Billin AN, Bisi J, McNeill YY, Kozarsky KF et al (2003) Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev 17(13):1581–1591Google Scholar
  56. Houten SM, Volle DH, Cummins CL, Mangelsdorf DJ, Auwerx J (2007) In vivo imaging of farnesoid X receptor activity reveals the ileum as the primary bile acid signaling tissue. Mol Endocrinol 21(6):1312–1323Google Scholar
  57. Hu M, Phan F, Bourron O, Ferré P, Foufelle F (2017) Steatosis and NASH in type 2 diabetes. Biochimie 143:37–41Google Scholar
  58. Huttner K, Desai S, DeCristofaro M, Laffitte B, Lin T, Chen J et al (2017) First-in-human study of LMB763, a novel, orally-available farnesoid X receptor agonist that demonstrates modulation of the pharmacodynamic markers FGF19 and C4 in healthy subjects. J Hepatol 66(1):S425Google Scholar
  59. Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG et al (2005) Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2(4):217–225Google Scholar
  60. Jiang Y, Iakova P, Jin J, Sullivan E, Sharin V, Hong I-H et al (2013) Farnesoid X receptor inhibits gankyrin in mouse livers and prevents development of liver cancer. Hepatology 57(3):1098–1106Google Scholar
  61. Jiang C, Xie C, Lv Y, Li J, Krausz KW, Shi J et al (2015) Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat Commun 6:10166Google Scholar
  62. Joly S, Porcherot M, Radreau P, Vonderscher J, André P, Meldrum E et al (2017) The selective FXR agonist EYP001 is well tolerated in healthy subjects and has additive anti-HBV effect with nucleoside analogues in HepaRG cells. J Hepatol 66(1):S690Google Scholar
  63. Kast HR, Goodwin B, Tarr PT, Jones SA, Anisfeld AM, Stoltz CM 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(4):2908–2915Google Scholar
  64. Keely SJ, Walters JRF (2016) The farnesoid X receptor: good for BAD. Cell Mol Gastroenterol Hepatol 2(6):725–732Google Scholar
  65. Kim I, Ahn S-H, Inagaki T, Choi M, Ito S, Guo GL et al (2007) Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J Lipid Res 48(12):2664–2672Google Scholar
  66. Kinzel O, Steeneck C, Schlüter T, Schulz A, Gege C, Hahn U et al (2016) Novel substituted isoxazole FXR agonists with cyclopropyl, hydroxycyclobutyl and hydroxyazetidinyl linkers: understanding and improving key determinants of pharmacological properties. Bioorg Med Chem Lett 26(15):3746–3753Google Scholar
  67. Konerman MA, Jones JC, Harrison SA (2018) Pharmacotherapy for NASH: current and emerging. J Hepatol 68(2):362–375Google Scholar
  68. Kong B, Wang L, Chiang JYL, Zhang Y, Klaassen CD, Guo GL (2012) Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice. Hepatology 56(3):1034–1043Google Scholar
  69. Kowdley KV, Luketic V, Chapman R, Hirschfield GM, Poupon R, Schramm C et al (2018) A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology 67(5):1890–1902Google Scholar
  70. Kremer AE, Martens JJWW, Kulik W, Ruëff F, Kuiper EMM, van Buuren HR et al (2010) Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology 139(3):1008–1018.e1Google Scholar
  71. Kremoser C, Albers M, Burris TP, Deuschle U, Koegl M (2007) Panning for SNuRMs: using cofactor profiling for the rational discovery of selective nuclear receptor modulators. Drug Discov Today 12(19–20):860–869Google Scholar
  72. Kremoser C, Hambruch E, Deuschle U, Kinzel O, Burnet M, Yoneyama H (2011) Novel FXR agonists with potent lipid lowering, insulin sensitising, anti-inflammatory and anti-fibrotisation effects in mouse models of metabolic syndrome and NASH. J Hepatol 54:S44Google Scholar
  73. Lambert G, Amar MJA, Guo G, Brewer HB, Gonzalez FJ, Sinal CJ (2003) The farnesoid X-receptor is an essential regulator of cholesterol homeostasis. J Biol Chem 278(4):2563–2570Google Scholar
  74. Lang L, Teng Y (2019) Fibroblast growth factor receptor 4 targeting in cancer: new insights into mechanisms and therapeutic strategies. Cells 8(1):31Google Scholar
  75. Larusso NF, Bowlus CL, Levy C, Vuppalanchi R, Floreani A, Andreone P et al (2018) The AESOP trial: a randomized, double-blind, placebo-controlled, phase 2 study of obeticholic acid in patients with primary sclerosing cholangitis. Dig Liver Dis 50(2):e67Google Scholar
  76. Lawitz E, Herring R, Younes ZH, Gane E, Ruane PJ, Aguilar R et al (2018) Proof of concept study of an apoptosis-signal regulating kinase (ASK-1) inhibitor (selonsertib) in combination with an acetyl-Coa carboxylase inhibitor (GS-0976) or a farnesoid X receptor (FXR) agonist (GS-9674) in NASH. Gastroenterology 154(6):S-1166–S-1167Google Scholar
  77. Lax S, Schauer G, Prein K, Kapitan M, Silbert D, Berghold A et al (2012) Expression of the nuclear bile acid receptor/farnesoid X receptor is reduced in human colon carcinoma compared to nonneoplastic mucosa independent from site and may be associated with adverse prognosis. Int J Cancer 130(10):2232–2239Google Scholar
  78. Lee FY, Lee H, Hubbert ML, Edwards PA, Zhang Y (2006) FXR, a multipurpose nuclear receptor. Trends Biochem Sci 31(10):572–580Google Scholar
  79. Lee CG, Kim YW, Kim EH, Meng Z, Huang W, Hwang SJ et al (2012) Farnesoid X receptor protects hepatocytes from injury by repressing miR-199a-3p, which increases levels of LKB1. Gastroenterology 142(5):1206–1217.e7Google Scholar
  80. Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B (2009) Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 89(1):147–191Google Scholar
  81. Li J, Kuruba R, Wilson A, Gao X, Zhang Y, Li S (2010) Inhibition of endothelin-1-mediated contraction of hepatic stellate cells by FXR ligand. PLoS One 5(11):e13955Google Scholar
  82. Li J, Zhang Y, Kuruba R, Gao X, Gandhi CR, Xie W et al (2011) Roles of microRNA-29a in the antifibrotic effect of farnesoid X receptor in hepatic stellate cells. Mol Pharmacol 80(1):191–200Google Scholar
  83. Lieu T, Jayaweera G, Zhao P, Poole DP, Jensen D, Grace M et al (2014) The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice. Gastroenterology 147(6):1417–1428Google Scholar
  84. Liles JT, Karnik S, Hambruch E, Kremoser C, Birkel M, Watkins WJ et al (2016) Fxr agonism by Gs-9674 decreases steatosis and fibrosis in a murine model of nash. J Hepatol 64(2):S169Google Scholar
  85. Liu Y, Binz J, Numerick MJ, Dennis S, Luo G, Desai B et al (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
  86. Liu X, Xue R, Ji L, Zhang X, Wu J, Gu J et al (2014) Activation of farnesoid X receptor (FXR) protects against fructose-induced liver steatosis via inflammatory inhibition and ADRP reduction. Biochem Biophys Res Commun 450(1):117–123Google Scholar
  87. Liu X, Guo GL, Kong B, Hilburn DB, Hubchak SC, Park S et al (2018) Farnesoid X receptor signaling activates the hepatic X-box binding protein 1 pathway in vitro and in mice. Hepatology 68(1):304–316Google Scholar
  88. Lonardo A, Nascimbeni F, Mantovani A, Targher G (2018) Hypertension, diabetes, atherosclerosis and NASH: cause or consequence? J Hepatol 68(2):335–352Google Scholar
  89. Loomba R, Sanyal AJ (2013) The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 10(11):686–690Google Scholar
  90. Lu TT, Makishima M, Repa JJ, Schoonjans K, Kerr TA, Auwerx J et al (2000) Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 6(3):507–515Google Scholar
  91. Lundquist JT, Harnish DC, Kim CY, Mehlmann JF, Unwalla RJ, Phipps KM et al (2010) Improvement of physiochemical properties of the tetrahydroazepinoindole series of farnesoid X receptor (FXR) agonists: beneficial modulation of lipids in primates. J Med Chem 53(4):1774–1787Google Scholar
  92. Ma K, Saha PK, Chan L, Moore DD (2006) Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest 116(4):1102–1109Google Scholar
  93. Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A et al (1999) Identification of a nuclear receptor for bile acids. Science 284(5418):1362–1365Google Scholar
  94. Maloney PR, Parks DJ, Haffner CD, Fivush AM, Chandra G, Plunket KD et al (2000) Identification of a chemical tool for the orphan nuclear receptor FXR. J Med Chem 43(16):2971–2974Google Scholar
  95. Maran RRM, Thomas A, Roth M, Sheng Z, Esterly N, Pinson D et al (2009) Farnesoid X receptor deficiency in mice leads to increased intestinal epithelial cell proliferation and tumor development. J Pharmacol Exp Ther 328(2):469–477Google Scholar
  96. Marschall H-U, Luketic V, Lovgren-Sandblom A, Benthin L, Kowdley K, Hirschfield G et al (2012) 964 the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) increases plasma FGF-19 concentrations and decreases bile acid synthesis in primary biliary cirrhosis (PBC). J Hepatol 56:S377Google Scholar
  97. Mazuy C, Helleboid A, Staels B, Lefebvre P (2015) Nuclear bile acid signaling through the farnesoid X receptor. Cell Mol Life Sci 72(9):1631–1650Google Scholar
  98. Miura S, Mitsuhashi N, Shimizu H, Kimura F, Yoshidome H, Otsuka M et al (2012) Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma. BMC Cancer 12:56Google Scholar
  99. Modica S, Murzilli S, Salvatore L, Schmidt DR, Moschetta A (2008) Nuclear bile acid receptor FXR protects against intestinal tumorigenesis. Cancer Res 68(23):9589–9594Google Scholar
  100. Modica S, Petruzzelli M, Bellafante E, Murzilli S, Salvatore L, Celli N et al (2012) Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis. Gastroenterology 142(2):355–365.e1–4Google Scholar
  101. Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall H-U, Kipnes M et al (2013) Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 145(3):574–582.e1Google Scholar
  102. Murphy T, Darby S, Mathers ME, Gnanapragasam VJ (2010) Evidence for distinct alterations in the FGF axis in prostate cancer progression to an aggressive clinical phenotype. J Pathol 220(4):452–460Google Scholar
  103. Myers RP, Djedjos C, Kirby B, Bilin A, Khan M, Gosink J et al (2018) Pharmacodynamic effects of the oral, non-steroidal farnesoid X receptor agonist GS-9674 in healthy volunteers. J Can Assoc Gastroenterol 1(Suppl 1):346Google Scholar
  104. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF et al (2015) Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385(9972):956–965Google Scholar
  105. Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P et al (2016) A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 375(7):631–643Google Scholar
  106. Nicholes K, Guillet S, Tomlinson E, Hillan K, Wright B, Frantz GD et al (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
  107. Oude Elferink RPJ, Kremer AE, Martens JJWW, Beuers UH (2011) The molecular mechanism of cholestatic pruritus. Dig Dis 29(1):66–71Google Scholar
  108. Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA et al (1999) Bile acids: natural ligands for an orphan nuclear receptor. Science 284(5418):1365–1368Google Scholar
  109. Patel K, Harrison S, Trotter J, Herring R, Rojter S, Rinella M et al (2018) The nonsteroidal FXR agonist GS-9674 leads to significant reductions in hepatic steatosis, serum bile acids, and liver biochemistry in a phase 2, randomized, placebo-controlled trial of patients with NASH. Hepatology.
  110. Pathak P, Xie C, Nichols RG, Ferrell JM, Boehme S, Krausz KW et al (2018) Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology 68(4):1574–1588Google Scholar
  111. Pellicciari R, Fiorucci S, Camaioni E, Clerici C, Costantino G, Maloney PR et al (2002) 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem 45(17):3569–3572Google Scholar
  112. Podolsky DK (2002) Inflammatory bowel disease. N Engl J Med 347(6):417–429Google Scholar
  113. Puri P, Daita K, Joyce A, Mirshahi F, Santhekadur PK, Cazanave S et al (2018) The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids. Hepatology 67(2):534–548.Google Scholar
  114. Radreau P, Porcherot M, Ramière C, Mouzannar K, Lotteau V, André P (2016) Reciprocal regulation of farnesoid X receptor α activity and hepatitis B virus replication in differentiated HepaRG cells and primary human hepatocytes. FASEB J 30(9):3146–3154Google Scholar
  115. Richter HGF, Benson GM, Bleicher KH, Blum D, Chaput E, Clemann N et al (2011a) Optimization of a novel class of benzimidazole-based farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties. Bioorg Med Chem Lett 21(4):1134–1140Google Scholar
  116. Richter HGF, Benson GM, Blum D, Chaput E, Feng S, Gardes C et al (2011b) Discovery of novel and orally active FXR agonists for the potential treatment of dyslipidemia & diabetes. Bioorg Med Chem Lett 21(1):191–194Google Scholar
  117. Ripoll C, Groszmann R, Garcia-Tsao G, Grace N, Burroughs A, Planas R et al (2007) Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology 133(2):481–488Google Scholar
  118. Rizzo G, Renga B, Mencarelli A, Pellicciari R, Fiorucci S (2005) Role of FXR in regulating bile acid homeostasis and relevance for human diseases. Curr Drug Targets Immune Endocr Metabol Disord 5(3):289–303Google Scholar
  119. Sanyal AJ, Lopez P, Lawitz E, Kim W, Huang J, Andreone P et al (2018) Tropifexor (TXR), an FXR agonist for the treatment of NASH – interim results from first two parts of phase 2b study FLIGHT-FXR.
  120. Schaap FG, Trauner M, Jansen PLM (2014) Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol 11(1):55–67Google Scholar
  121. Schmitt J, Kong B, Stieger B, Tschopp O, Schultze SM, Rau M et al (2015) Protective effects of farnesoid X receptor (FXR) on hepatic lipid accumulation are mediated by hepatic FXR and independent of intestinal FGF15 signal. Liver Int 35(4):1133–1144Google Scholar
  122. Schwabl P, Hambruch E, Seeland BA, Hayden H, Wagner M, Garnys L et al (2017) The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction. J Hepatol 66(4):724–733Google Scholar
  123. 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
  124. Soisson SM, Parthasarathy G, Adams AD, Sahoo S, Sitlani A, Sparrow C et al (2008) Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation. Proc Natl Acad Sci U S A 105(14):5337–5342Google Scholar
  125. Stayrook KR, Bramlett KS, Savkur RS, Ficorilli J, Cook T, Christe ME et al (2005) Regulation of carbohydrate metabolism by the farnesoid X receptor. Endocrinology 146(3):984–991Google Scholar
  126. Stringer (2019) Safety, tolerability, and efficacy of a combination treatment of tropifexor (LJN452) and cenicriviroc (CVC) in adult patients with nonalcoholic steatohepatitis (NASH) and liver fibrosis (TANDEM). Full text view - [Internet].
  127. Swales KE, Korbonits M, Carpenter R, Walsh DT, Warner TD, Bishop-Bailey D (2006) The farnesoid X receptor is expressed in breast cancer and regulates apoptosis and aromatase expression. Cancer Res 66(20):10120–10126Google Scholar
  128. Teodoro JS, Rolo AP, Palmeira CM (2011) Hepatic FXR: key regulator of whole-body energy metabolism. Trends Endocrinol Metabol 22(11):458–466Google Scholar
  129. Torres DM, Williams CD, Harrison SA (2012) Features, diagnosis, and treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 10(8):837–858Google Scholar
  130. Trauner M, Gulamhusein A, Hameed B, Caldwell S, Shiffman ML, Landis C et al (2019) The nonsteroidal FXR agonist cilofexor (GS-9674) improves markers of cholestasis and liver injury in patients with PSC. Hepatology.
  131. Tsuchida T, Friedman SL (2017) Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol 14(7):397–411Google Scholar
  132. Tully DC, Rucker PV, Chianelli D, Williams J, Vidal A, Alper PB et al (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
  133. Uriarte I, Latasa MU, Carotti S, Fernandez-Barrena MG, Garcia-Irigoyen O, Elizalde M et al (2015) Ileal FGF15 contributes to fibrosis-associated hepatocellular carcinoma development. Int J Cancer 136(10):2469–2475Google Scholar
  134. Verbeke L, Farre R, Trebicka J, Komuta M, Roskams T, Klein S et al (2014) Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology 59(6):2286–2298Google Scholar
  135. Verbeke L, Nevens F, Laleman W (2017) Steroidal or non-steroidal FXR agonists – is that the question? J Hepatol 66(4):680–681Google Scholar
  136. Walters JRF, Johnston IM, Nolan JD, Vassie C, Pruzanski ME, Shapiro DA (2015) The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid. Aliment Pharmacol Ther 41(1):54–64Google Scholar
  137. Wang J, Stockton DW, Ittmann M (2004) The fibroblast growth factor receptor-4 Arg388 allele is associated with prostate cancer initiation and progression. Clin Cancer Res 10(18 Pt 1):6169–6178Google Scholar
  138. Wang Y-D, Chen W-D, Moore DD, Huang W (2008a) FXR: a metabolic regulator and cell protector. Cell Res 18(11):1087–1095Google Scholar
  139. Wang Y-D, Chen W-D, Wang M, Yu D, Forman BM, Huang W (2008b) Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 48(5):1632–1643Google Scholar
  140. Wang N, Zou Q, Xu J, Zhang J, Liu J (2018) Ligand binding and heterodimerization with retinoid X receptor α (RXRα) induce farnesoid X receptor (FXR) conformational changes affecting coactivator binding. J Biol Chem 293(47):18180–18191Google Scholar
  141. Watanabe M, Houten SM, Wang L, Moschetta A, Mangelsdorf DJ, Heyman RA et al (2004) Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest 113(10):1408–1418Google Scholar
  142. Xu Y-F, Yang X-Q, Lu X-F, Guo S, Liu Y, Iqbal M et al (2014) Fibroblast growth factor receptor 4 promotes progression and correlates to poor prognosis in cholangiocarcinoma. Biochem Biophys Res Commun 446(1):54–60Google Scholar
  143. Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z et al (2012) Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. elife 1:e00049Google Scholar
  144. Yang F, Huang X, Yi T, Yen Y, Moore DD, Huang W (2007) Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res 67(3):863–867Google Scholar
  145. Yki-Järvinen H (2014) Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol 2(11):901–910Google Scholar
  146. Zhang Y, Edwards PA (2008) FXR signaling in metabolic disease. FEBS Lett 582(1):10–18Google Scholar
  147. Zhang Y, Lee FY, Barrera G, Lee H, Vales C, Gonzalez FJ et al (2006) Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci U S A 103(4):1006–1011Google Scholar
  148. Zhang S, Wang J, Liu Q, Harnish DC (2009) Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J Hepatol 51(2):380–388Google Scholar
  149. Zhou M, Wang X, Phung V, Lindhout DA, Mondal K, Hsu J-Y et al (2014) Separating tumorigenicity from bile acid regulatory activity for endocrine hormone FGF19. Cancer Res 74(12):3306–3316Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Christian Gege
    • 1
  • Eva Hambruch
    • 1
  • Nina Hambruch
    • 1
  • Olaf Kinzel
    • 1
  • Claus Kremoser
    • 1
    Email author
  1. 1.Phenex Pharmaceuticals AG, Drug Discovery ResearchHeidelbergGermany

Personalised recommendations