Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis

J Hepatol. 2009 Aug;51(2):380-8. doi: 10.1016/j.jhep.2009.03.025. Epub 2009 May 18.


Background/aims: The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily, which plays an essential role in the regulation of enterohepatic circulation and lipid homeostasis. Here we investigated whether WAY-362450, a synthetic potent FXR agonist, could protect against non-alcoholic steatohepatitis (NASH) in mice fed a methionine and choline-deficient (MCD) diet.

Methods: Male C57BL/6 mice on the MCD diet were treated with or without WAY-362450 (30 mg/kg) for 4 weeks.

Results: The elevations of serum ALT and AST activities induced by the MCD diet were decreased with WAY-362450 treatment. In terms of liver histology, while WAY-362450 treatment showed no impact on hepatic triglyceride accumulation, it significantly reduced inflammatory cell infiltration and hepatic fibrosis. The reduction in inflammatory cell infiltration correlated with deceased serum levels of keratinocyte derived chemokine (mKC) and MCP 1 and decreased hepatic gene expression of MCP-1 and VCAM-1. The reduction of hepatic fibrosis by WAY-362450 treatment corresponded to a reduction in hepatic gene expression of fibrosis markers. The positive effects of WAY-362450 were FXR-dependent since no protection was observed in MCD diet-fed FXR deficient mice.

Conclusions: These findings demonstrate that FXR agonists may be useful for the treatment of non-alcoholic steatohepatitis.

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Aspartate Aminotransferases / blood
  • Azepines / pharmacology*
  • Chemokine CCL2 / blood
  • Chemokines / blood
  • Choline Deficiency / complications
  • Fatty Liver / drug therapy*
  • Fatty Liver / etiology
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Hepatitis / etiology
  • Hepatitis / prevention & control*
  • Indoles / pharmacology*
  • Lipids / blood
  • Liver Cirrhosis, Experimental / etiology
  • Liver Cirrhosis, Experimental / prevention & control*
  • Male
  • Methionine / deficiency
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Cytoplasmic and Nuclear / deficiency
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Triglycerides / metabolism


  • Azepines
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Chemokines
  • Indoles
  • Lipids
  • Receptors, Cytoplasmic and Nuclear
  • Triglycerides
  • WAY-362450
  • farnesoid X-activated receptor
  • keratinocyte-derived chemokines
  • Methionine
  • Aspartate Aminotransferases
  • Alanine Transaminase