Songwen Zhang1, Juan Wang, Qiangyuan Liu, Douglas C Harnish. 1. Department of Cardiovascular and Metabolic Diseases Research, Wyeth Research, Collegeville, PA 19426, USA. songwen.zhang@boehringer-ingelheim.com
Abstract
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.
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.
Authors: Jessica K Dyson; Gideon M Hirschfield; David H Adams; Ulrich Beuers; Derek A Mann; Keith D Lindor; David E J Jones Journal: Nat Rev Gastroenterol Hepatol Date: 2015-02-03 Impact factor: 46.802