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Pharmacologic Modulation of Bile Acid-FXR-FGF15/FGF19 Pathway for the Treatment of Nonalcoholic Steatohepatitis

  • Justin D. Schumacher
  • Grace L. GuoEmail author
Part of the Handbook of Experimental Pharmacology book series


Nonalcoholic steatohepatitis (NASH) is within the spectrum of nonalcoholic fatty liver disease (NAFLD) and can progress to fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). The prevalence of NASH is rising and has become a large burden to the medical system worldwide. Unfortunately, despite its high prevalence and severe health consequences, there is currently no therapeutic agent approved to treat NASH. Therefore, the development of efficacious therapies is of utmost urgency and importance. Many molecular targets are currently under investigation for their ability to halt NASH progression. One of the most promising and well-studied targets is the bile acid (BA)-activated nuclear receptor, farnesoid X receptor (FXR). In this chapter, the characteristics, etiology, and prevalence of NASH will be discussed. A brief introduction to FXR regulation of BA homeostasis will be described. However, for more details regarding FXR in BA homeostasis, please refer to previous chapters. In this chapter, the mechanisms by which tissue and cell type-specific FXR regulates NASH development will be discussed in detail. Several FXR agonists have reached later phase clinical trials for treatment of NASH. The progress of these compounds and summary of released data will be provided. Lastly, this chapter will address safety liabilities specific to the development of FXR agonists.


Bile Acids FGF15 FGF19 FXR NASH 



Alpha smooth muscle actin




Agouti-related peptide


Alkaline phosphatase


Alanine aminotransferase


Activator protein 1


Apolipoprotein A-IV


Apolipoprotein C-III


Apolipoprotein E


Apical sodium-dependent bile acid transporter


Bile acid


Blood-brain barrier


Bi-specific activating antibody of FGFR1 and β-Klotho


Bile salt hydrolase




Cholic acid


Caffeic acid phenethyl ester


Carbon tetrachloride


Chenodeoxycholic acid


Collagen type 1, α1


cAMP response element-binding protein


C-reactive protein


Connective tissue growth factor


Cytochrome P450 27A1


Cytochrome P450 7A1


Cytochrome P450 8B1


Deoxycholic acid


Dimethylarginine dimethylaminohydrolase 2


Epoxyeicosatrienoic acids


Endothelial nitric oxide synthase


Extracellular signal-regulated kinases




Fibroblast growth factor 15


Fibroblast growth factor 19


Fibroblast growth factor 21


Fibroblast growth factor receptor 1


Fibroblast growth factor receptor 4


Farnesoid X receptor


Farnesoid X receptor response element


Glucose 6-phosphatase




Glucagon-like peptide-1


Glycine-conjugated muricholic acid


Hepatocellular carcinoma


Hepatitis C virus


High-density lipoprotein


High-fat diet


Homeostatic model assessment of β-cell function and insulin resistance


Nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitor, alpha


Intracerebral-ventricular injection


Inhibitor of nuclear factor kappa-B kinase subunit beta


c-Jun N-terminal kinase


Lithocholic acid


Low-density lipoprotein


Low-density lipoprotein receptor




Muricholic acid


Methacholine-deficient diet


Macrophage chemoattractant protein 1


Matrix metalloprotease 2


Nonalcoholic fatty liver disease


NAFLD activity score


Nonalcoholic steatohepatitis


Nuclear factor kappa-light-chain-enhancer of activated B cells


Natural killer T cell


Neuropeptide Y


Obeticholic acid


Primary biliary cirrhosis


Pyruvate dehydrogenase complex


Pyruvate dehydrogenase kinase 4


Phosphoenolpyruvate carboxykinase


Peroxisome proliferator-activated receptor gamma coactivator 1-alpha


N-terminal propeptide of type III collagen


Patatin-like phospholipase domain-containing protein 3


Peroxisome proliferator-activated receptor alpha


Peroxisome proliferator-activated receptor gamma


N-terminal type III collagen propeptide


Retinoid X receptor


Serum amyloid A3


Steatosis, activity, and fibrosis scoring system


Serum amyloid P


Small heterodimer partner


Scavenger receptor class B type 1


Sterol regulatory element-binding protein 1c


Taurine-conjugated beta-muricholic acid


Taurocholic acid


Transforming growth factor beta


Transforming growth factor beta receptor 2


Takeda G-protein receptor 5


Tissue inhibitor of metalloproteases 1


Tumor necrosis factor alpha


Uncoupling protein 1


Ursodeoxycholic acid


Very low-density lipoprotein


  1. Alvarez-Sola G et al (2017) Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: development of an FGF19-based chimeric molecule to promote fatty liver regeneration. Gut 66:1818–1828Google Scholar
  2. Armstrong L et al (2017) Effects of acute-phase proteins in mediating hepatic FXR’s protection of mice from NASH development. In: AASLD 2017 liver meeting abstract 643Google Scholar
  3. Badman MK et al (2007) Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 5:426–437Google Scholar
  4. Bedossa P (2014) Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease. Hepatology 60:565–575Google Scholar
  5. Benedict M, Zhang X (2017) Non-alcoholic fatty liver disease: an expanded review. World J Hepatol 9:715–732Google Scholar
  6. Benoit B et al (2017) Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice. Nat Med 23:990–996Google Scholar
  7. Brunt EM, Janney CG, di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR (1999) Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 94:2467–2474Google Scholar
  8. Bullitt E (1990) Expression of c-fos-like protein as a marker for neuronal activity following noxious stimulation in the rat. J Comp Neurol 296:517–530Google Scholar
  9. Caldwell SH et al (2009) NASH and cryptogenic cirrhosis: a histological analysis. Ann Hepatol 8:346–352Google Scholar
  10. Carino A et al (2018) Disruption of TFGbeta-SMAD3 pathway by the nuclear receptor SHP mediates the antifibrotic activities of BAR704, a novel highly selective FXR ligand. Pharmacol Res 131:17–31Google Scholar
  11. Cariou B et al (2005) Transient impairment of the adaptive response to fasting in FXR-deficient mice. FEBS Lett 579:4076–4080Google Scholar
  12. Chalasani N et al (2018) The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 67:328–357Google Scholar
  13. Chen MZ et al (2017) FGF21 mimetic antibody stimulates UCP1-independent brown fat thermogenesis via FGFR1/betaKlotho complex in non-adipocytes. Mol Metab 6:1454–1467Google Scholar
  14. Chiang JY (2009) Bile acids: regulation of synthesis. J Lipid Res 50:1955–1966Google Scholar
  15. Chiang JY (2017) Recent advances in understanding bile acid homeostasis. F1000Res 6:2029Google Scholar
  16. Cray C, Zaias J, Altman NH (2009) Acute phase response in animals: a review. Comp Med 59:517–526Google Scholar
  17. Cyphert HA et al (2012) Activation of the farnesoid X receptor induces hepatic expression and secretion of fibroblast growth factor 21. J Biol Chem 287:25123–25138Google Scholar
  18. Dai M et al (2015) Epoxyeicosatrienoic acids regulate macrophage polarization and prevent LPS-induced cardiac dysfunction. J Cell Physiol 230:2108–2119Google Scholar
  19. Day CP, James OF (1998) Steatohepatitis: a tale of two “hits”? Gastroenterology 114:842–845Google Scholar
  20. de Boer JF et al (2017) Intestinal farnesoid X receptor controls transintestinal cholesterol excretion in mice. Gastroenterology 152:1126–1138.e6Google Scholar
  21. Deshmane SL, Kremlev S, Amini S, Sawaya BE (2009) Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interf Cytokine Res 29:313–326Google Scholar
  22. Dongiovanni P, Anstee QM, Valenti L (2013) Genetic predisposition in NAFLD and NASH: impact on severity of liver disease and response to treatment. Curr Pharm Des 19:5219–5238Google Scholar
  23. Drafahl KA, McAndrew CW, Meyer AN, Haas M, Donoghue DJ (2010) The receptor tyrosine kinase FGFR4 negatively regulates NF-kappaB signaling. PLoS One 5:e14412Google Scholar
  24. Enanta Pharmaceuticals (2018) A study to assess the safety, tolerability, pharmacokinetics and efficacy of EDP-305 in subjects with non-alcoholic steatohepatitis. Identifier: NCT03421431
  25. Evans MJ et al (2009) A synthetic farnesoid X receptor (FXR) agonist promotes cholesterol lowering in models of dyslipidemia. Am J Physiol Gastrointest Liver Physiol 296:G543–G552Google Scholar
  26. Fang S et al (2015) Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 21:159–165Google Scholar
  27. Faouzi M et al (2007) Differential accessibility of circulating leptin to individual hypothalamic sites. Endocrinology 148:5414–5423Google Scholar
  28. FDA approval letter – Ocaliva (2016) NDA 207999Google Scholar
  29. FDA (2018) Drug safety communication – Ocaliva (obeticholic acid): drug safety communication – boxed warning added to highlight correct dosingGoogle Scholar
  30. Fickert P 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 175:2392–2405Google Scholar
  31. Fiorucci S et al (2004) The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 127:1497–1512Google Scholar
  32. Fiorucci S et al (2005a) 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 314:584–595Google Scholar
  33. Fiorucci S et al (2005b) 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 315:58–68Google Scholar
  34. Fisher FM et al (2014) Fibroblast growth factor 21 limits lipotoxicity by promoting hepatic fatty acid activation in mice on methionine and choline-deficient diets. Gastroenterology 147:1073–83.e6Google Scholar
  35. Fon Tacer K et al (2010) Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol 24:2050–2064Google Scholar
  36. Fu L et al (2004) Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology 145:2594–2603Google Scholar
  37. Fu T et al (2016) FXR primes the liver for intestinal FGF15 signaling by transient induction of beta-Klotho. Mol Endocrinol 30:92–103Google Scholar
  38. Gai Z et al (2018) The effects of farnesoid X receptor activation on arachidonic acid metabolism, NF-kB signaling and hepatic inflammation. Mol Pharmacol 94:802–811Google Scholar
  39. Gilead Sciences (2018a) Evaluating the safety, tolerability, and efficacy of GS-9674 in participants with nonalcoholic steatohepatitis (NASH). Identifier: NCT02854605
  40. Gilead Sciences (2018b) Safety, tolerability, and efficacy of selonsertib, GS-0976, and GS-9674 in adults with nonalcoholic steatohepatitis (NASH). Identifier: NCT02781584Google Scholar
  41. Gilead Sciences (2018c) Safety and efficacy of selonsertib, GS-0976, GS-9674, and combinations in participants with bridging fibrosis or compensated cirrhosis due to nonalcoholic steatohepatitis (NASH) (ATLAS). Identifier: NCT03449446Google Scholar
  42. Gimeno L, Brulet P, Martinez S (2003) Study of Fgf15 gene expression in developing mouse brain. Gene Expr Patterns 3:473–481Google Scholar
  43. Goetz R et al (2007) Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol Cell Biol 27:3417–3428Google Scholar
  44. Goodwin B et al (2000) A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 6:517–526Google Scholar
  45. Grundy SM et al (2005) Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 112:2735–2752Google Scholar
  46. Guan D, Zhao L, Chen D, Yu B, Yu J (2016) Regulation of fibroblast growth factor 15/19 and 21 on metabolism: in the fed or fasted state. J Transl Med 14:63Google Scholar
  47. Hambruch E 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 343:556–567Google Scholar
  48. Harrison SA et al (2018a) NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 391:1174–1185Google Scholar
  49. Harrison S et al (2018b) NGM282 improves fibrosis and NASH-related histology in 12 weeks in patients with biopsy-confirmed NASH, which is preceded by significant decreases in hepatic steatosis, liver transaminases and fibrosis markers at 6 weeks. J Hepatol 68:S65–S66Google Scholar
  50. Hashimoto E, Taniai M, Tokushige K (2013) Characteristics and diagnosis of NAFLD/NASH. J Gastroenterol Hepatol 28(Suppl 4):64–70Google Scholar
  51. Hsuchou H, Pan W, Kastin AJ (2013) Fibroblast growth factor 19 entry into brain. Fluids Barriers CNS 10:32Google Scholar
  52. Inagaki T et al (2005) Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2:217–225Google Scholar
  53. Intercept Pharmaceuticals (2018a) Study evaluating the efficacy and safety of obeticholic acid in subjects with compensated cirrhosis due to nonalcoholic steatohepatitis (REVERSE). Identifier: NCT03439254Google Scholar
  54. Intercept Pharmaceuticals (2018b) Randomized global phase 3 study to evaluate the impact on NASH with fibrosis of obeticholic acid treatment (REGENERATE). Identifier: NCT02548351Google Scholar
  55. Jiang C et al (2015a) Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest 125:386–402Google Scholar
  56. Jiang C et al (2015b) Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat Commun 6:10166Google Scholar
  57. Jung D et al (2014) FXR-induced secretion of FGF15/19 inhibits CYP27 expression in cholangiocytes through p38 kinase pathway. Pflugers Arch 466:1011–1019Google Scholar
  58. Kawamata Y et al (2003) A G protein-coupled receptor responsive to bile acids. J Biol Chem 278:9435–9440Google Scholar
  59. Kim I et al (2007) Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J Lipid Res 48:2664–2672Google Scholar
  60. Kim DH et al (2015) A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity. EMBO J 34:184–199Google Scholar
  61. Kir S et al (2011) FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. Science 331:1621–1624Google Scholar
  62. Kleiner DE et al (2005) Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41:1313–1321Google Scholar
  63. Kolumam G et al (2015) Sustained brown fat stimulation and insulin sensitization by a humanized bispecific antibody agonist for fibroblast growth factor receptor 1/betaKlotho complex. EBioMedicine 2:730–743Google Scholar
  64. Kong B, Luyendyk JP, Tawfik O, Guo GL (2009) Farnesoid X receptor deficiency induces nonalcoholic steatohepatitis in low-density lipoprotein receptor-knockout mice fed a high-fat diet. J Pharmacol Exp Ther 328:116–122Google Scholar
  65. Kong B et al (2012) Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice. Hepatology 56:1034–1043Google Scholar
  66. Kurosu H et al (2007) Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem 282:26687–26695Google Scholar
  67. Lambert G et al (2003) The farnesoid X-receptor is an essential regulator of cholesterol homeostasis. J Biol Chem 278:2563–2570Google Scholar
  68. Lee JH et al (2016) An engineered FGF21 variant, LY2405319, can prevent non-alcoholic steatohepatitis by enhancing hepatic mitochondrial function. Am J Transl Res 8:4750–4763Google Scholar
  69. Lew JL et al (2004) The farnesoid X receptor controls gene expression in a ligand- and promoter-selective fashion. J Biol Chem 279:8856–8861Google Scholar
  70. Li J et al (2010) Inhibition of endothelin-1-mediated contraction of hepatic stellate cells by FXR ligand. PLoS One 5:e13955Google Scholar
  71. Li J et al (2011) Roles of microRNA-29a in the antifibrotic effect of farnesoid X receptor in hepatic stellate cells. Mol Pharmacol 80:191–200Google Scholar
  72. Li F et al (2013) Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat Commun 4:2384Google Scholar
  73. Li L et al (2015) Activation of farnesoid X receptor downregulates monocyte chemoattractant protein-1 in murine macrophage. Biochem Biophys Res Commun 467:841–846Google Scholar
  74. Liu X et al (2016) Lack of fibroblast growth factor 21 accelerates metabolic liver injury characterized by steatohepatities in mice. Am J Cancer Res 6:1011–1025Google Scholar
  75. Liu S et al (2018) A gut-brain axis regulating glucose metabolism mediated by bile acids and competitive fibroblast growth factor actions at the hypothalamus. Mol Metab 8:37–50Google Scholar
  76. Lu TT et al (2000) Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 6:507–515Google Scholar
  77. Luo J et al (2014) A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci Transl Med 6:247ra100Google Scholar
  78. Ma K, Saha PK, Chan L, Moore DD (2006) Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest 116:1102–1109Google Scholar
  79. Ma Y, Huang Y, Yan L, Gao M, Liu D (2013) Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance. Pharm Res 30:1447–1457Google Scholar
  80. Makishima M et al (1999) Identification of a nuclear receptor for bile acids. Science 284:1362–1365Google Scholar
  81. Marcelin G et al (2014) Central action of FGF19 reduces hypothalamic AGRP/NPY neuron activity and improves glucose metabolism. Mol Metab 3:19–28Google Scholar
  82. Markan KR, Potthoff MJ (2016) Metabolic fibroblast growth factors (FGFs): mediators of energy homeostasis. Semin Cell Dev Biol 53:85–93Google Scholar
  83. Maruyama T et al (2002) Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun 298:714–719Google Scholar
  84. Mencarelli A et al (2009) The bile acid sensor farnesoid X receptor is a modulator of liver immunity in a rodent model of acute hepatitis. J Immunol 183:6657–6666Google Scholar
  85. Michelotti GA, Machado MV, Diehl AM (2013) NAFLD, NASH and liver cancer. Nat Rev. Gastroenterol Hepatol 10:656–665Google Scholar
  86. Mittal S et al (2016) Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 14:124–31.e1Google Scholar
  87. Mudaliar S 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 145:574–82.e1Google Scholar
  88. Mueller M et al (2015) Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity. J Hepatol 62:1398–1404Google Scholar
  89. Neuschwander-Tetri BA et al (2015) Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385:956–965Google Scholar
  90. NGM Biopharmaceuticals (2013) Phase 1 SAD and MAD study of NGM282 in healthy adult participants. Identifier: NCT01776528Google Scholar
  91. NGM Biopharmaceuticals (2017a) Phase 1 study of NGM313 in healthy adult participants. Identifier: NCT02708576Google Scholar
  92. NGM Biopharmaceuticals (2017b) Study of NGM313 in obese participants. Identifier: NCT03298464Google Scholar
  93. Nies VJ et al (2015) Fibroblast growth factor signaling in metabolic regulation. Front Endocrinol (Lausanne) 6:193Google Scholar
  94. Nishimura T, Utsunomiya Y, Hoshikawa M, Ohuchi H, Itoh N (1999) Structure and expression of a novel human FGF, FGF-19, expressed in the fetal brain. Biochim Biophys Acta 1444:148–151Google Scholar
  95. Novartis Pharmaceuticals (2018a) Study of safety and efficacy of tropifexor (LJN452) in patients with non-alcoholic steatohepatitis (NASH) (FLIGHT-FXR). Identifier: NCT02855164Google Scholar
  96. Novartis Pharmaceuticals (2018b) 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). Identifier: NCT03517540Google Scholar
  97. Novartis Pharmaceuticals (2018c) Safety, tolerability, pharmacokinetics and efficacy of LMB763 in patients with NASH. Identifier: NCT02913105Google Scholar
  98. Ocaliva (obeticholic acid) (2018) Intercept Pharmaceuticals, New YorkGoogle Scholar
  99. Organ Procurement and Transplantation Network (n.d.) National data - Waiting List Additions Listing Year by Diagnosis; January, 1995–May 31, 2018Google Scholar
  100. Parks DJ et al (1999) Bile acids: natural ligands for an orphan nuclear receptor. Science 284:1365–1368Google Scholar
  101. Pathak P et al (2017) Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism. J Biol Chem 292:11055–11069Google Scholar
  102. Pathak P et al (2018) Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology 68:1574–1588Google Scholar
  103. Pharmaceuticals W (2008) Study evaluating the safety of FXR-450 in healthy subjects. Identifier: NCT00499629Google Scholar
  104. Pineda Torra I et al (2003) Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor. Mol Endocrinol 17:259–272Google Scholar
  105. Plyte SE, Hughes K, Nikolakaki E, Pulverer BJ, Woodgett JR (1992) Glycogen synthase kinase-3: functions in oncogenesis and development. Biochim Biophys Acta 1114:147–162Google Scholar
  106. Porez G et al (2013) The hepatic orosomucoid/alpha1-acid glycoprotein gene cluster is regulated by the nuclear bile acid receptor FXR. Endocrinology 154:3690–3701Google Scholar
  107. Potthoff MJ (2017) FGF21 and metabolic disease in 2016: a new frontier in FGF21 biology. Nat Rev Endocrinol 13:74–76Google Scholar
  108. Potthoff MJ et al (2011) FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1alpha pathway. Cell Metab 13:729–738Google Scholar
  109. Renga B et al (2011) SHP-dependent and -independent induction of peroxisome proliferator-activated receptor-gamma by the bile acid sensor farnesoid X receptor counter-regulates the pro-inflammatory phenotype of liver myofibroblasts. Inflamm Res 60:577–587Google Scholar
  110. Renga B et al (2012) Glucocorticoid receptor mediates the gluconeogenic activity of the farnesoid X receptor in the fasting condition. FASEB J 26:3021–3031Google Scholar
  111. Renga B et al (2013) FXR mediates a chromatin looping in the GR promoter thus promoting the resolution of colitis in rodents. Pharmacol Res 77:1–10Google Scholar
  112. Rizzo G et al (2010) Functional characterization of the semisynthetic bile acid derivative INT-767, a dual farnesoid X receptor and TGR5 agonist. Mol Pharmacol 78:617–630Google Scholar
  113. Romeo S et al (2008) Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 40:1461–1465Google Scholar
  114. Ryan KK et al (2013) Fibroblast growth factor-19 action in the brain reduces food intake and body weight and improves glucose tolerance in male rats. Endocrinology 154:9–15Google Scholar
  115. Savkur RS, Bramlett KS, Michael LF, Burris TP (2005) Regulation of pyruvate dehydrogenase kinase expression by the farnesoid X receptor. Biochem Biophys Res Commun 329:391–396Google Scholar
  116. Sayin SI 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 17:225–235Google Scholar
  117. Schaap FG, van der Gaag NA, Gouma DJ, Jansen PL (2009) High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis. Hepatology 49:1228–1235Google Scholar
  118. Schmitt J 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 35:1133–1144Google Scholar
  119. Schumacher JD et al (2017) The effect of fibroblast growth factor 15 deficiency on the development of high fat diet induced non-alcoholic steatohepatitis. Toxicol Appl Pharmacol 330:1–8Google Scholar
  120. Selwyn FP, Csanaky IL, Zhang Y, Klaassen CD (2015) Importance of large intestine in regulating bile acids and glucagon-like peptide-1 in germ-free mice. Drug Metab Dispos 43:1544–1556Google Scholar
  121. Singh S et al (2015) Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol 13:643–54.e1–9.; quiz e39–40Google Scholar
  122. Song KH, Li T, Owsley E, Strom S, Chiang JY (2009) Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression. Hepatology 49:297–305Google Scholar
  123. Staiger H, Keuper M, Berti L, Hrabe de Angelis M, Haring HU (2017) Fibroblast growth factor 21-metabolic role in mice and men. Endocr Rev 38:468–488Google Scholar
  124. Sun W, Liu Q, Leng J, Zheng Y, Li J (2015) The role of Pyruvate Dehydrogenase Complex in cardiovascular diseases. Life Sci 121:97–103Google Scholar
  125. Takahashi S et al (2016) Cyp2c70 is responsible for the species difference in bile acid metabolism between mice and humans. J Lipid Res 57:2130–2137Google Scholar
  126. Tomlinson E et al (2002) Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology 143:1741–1747Google Scholar
  127. U.S. Census Bureau (2017) QuickFactsGoogle Scholar
  128. U.S. Food and Drug Administration (2017) Drug safety communication: FDA drug safety communication: FDA warns about serious liver injury with Ocaliva (obeticholic acid) for rare chronic liver diseaseGoogle Scholar
  129. Uriarte I et al (2015) Ileal FGF15 contributes to fibrosis-associated hepatocellular carcinoma development. Int J Cancer 136:2469–2475Google Scholar
  130. Vallance P, Leone A, Calver A, Collier J, Moncada S (1992) Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339:572–575Google Scholar
  131. Verbeke L et al (2014) Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology 59:2286–2298Google Scholar
  132. Verbeke L et al (2016) FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis. Sci Rep 6:33453Google Scholar
  133. Vilar-Gomez E, Chalasani N (2018) Non-invasive assessment of non-alcoholic fatty liver disease: clinical prediction rules and blood-based biomarkers. J Hepatol 68:305–315Google Scholar
  134. Wang KX, Denhardt DT (2008) Osteopontin: role in immune regulation and stress responses. Cytokine Growth Factor Rev 19:333–345Google Scholar
  135. Wang H, Chen J, Hollister K, Sowers LC, Forman BM (1999) Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 3:543–553Google Scholar
  136. Wang YD et al (2008) Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 48:1632–1643Google Scholar
  137. Watanabe M et al (2004) Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest 113:1408–1418Google Scholar
  138. Wu X et al (2010) FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation. J Biol Chem 285:5165–5170Google Scholar
  139. Wu W et al (2014) Bile acids override steatosis in farnesoid X receptor deficient mice in a model of non-alcoholic steatohepatitis. Biochem Biophys Res Commun 448:50–55Google Scholar
  140. Wunsch E et al (2015) Expression of hepatic fibroblast growth factor 19 is enhanced in primary biliary cirrhosis and correlates with severity of the disease. Sci Rep 5:13462Google Scholar
  141. Xie MH et al (1999) FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4. Cytokine 11:729–735Google Scholar
  142. Xie C et al (2017) An intestinal farnesoid X receptor-ceramide signaling axis modulates hepatic gluconeogenesis in mice. Diabetes 66:613–626Google Scholar
  143. Xu W, Lu C, Zhang F, Shao J, Zheng S (2016) Dihydroartemisinin restricts hepatic stellate cell contraction via an FXR-S1PR2-dependent mechanism. IUBMB Life 68:376–387Google Scholar
  144. Younossi ZM et al (2016) Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64:73–84Google Scholar
  145. Younossi Z et al (2018) Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 15:11–20Google Scholar
  146. Yu C, Wang F, Jin C, Huang X, McKeehan WL (2005) Independent repression of bile acid synthesis and activation of c-Jun N-terminal kinase (JNK) by activated hepatocyte fibroblast growth factor receptor 4 (FGFR4) and bile acids. J Biol Chem 280:17707–17714Google Scholar
  147. Zhang Y et al (2006) Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci U S A 103:1006–1011Google Scholar
  148. Zhang S, Wang J, Liu Q, Harnish DC (2009a) Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J Hepatol 51:380–388Google Scholar
  149. Zhang S, Liu Q, Wang J, Harnish DC (2009b) Suppression of interleukin-6-induced C-reactive protein expression by FXR agonists. Biochem Biophys Res Commun 379:476–479Google Scholar
  150. Zhang F et al (2015) Minireview: roles of fibroblast growth factors 19 and 21 in metabolic regulation and chronic diseases. Mol Endocrinol 29:1400–1413Google Scholar
  151. Zhou M et al (2014) Separating tumorigenicity from bile acid regulatory activity for endocrine hormone FGF19. Cancer Res 74:3306–3316Google Scholar
  152. Zhou M et al (2017a) Engineered FGF19 eliminates bile acid toxicity and lipotoxicity leading to resolution of steatohepatitis and fibrosis in mice. Hepatol Commun 1:1024–1042Google Scholar
  153. Zhou M et al (2017b) Mouse species-specific control of hepatocarcinogenesis and metabolism by FGF19/FGF15. J Hepatol 66:1182–1192Google Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Pharmacology and ToxicologyRutgers UniversityPiscatawayUSA

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