Obeticholic acid prevents carbon tetrachloride-induced liver fibrosis through interaction between farnesoid X receptor and Smad3

Abstract

Liver fibrosis results from sustained liver injury and is characterized by inflammation, hepatic stellate cell (HSC) activation, extracellular matrix (ECM) accumulation and liver structure destruction. The Farnesoid-X receptor (FXR) antagonizes toxic liver injury and fibrosis, yet the mechanism in liver fibrosis remains unclear. We investigated the effects of FXR agonist obeticholic acid (OCA) on liver fibrosis in mice. Mice were injected with carbon tetrachloride (CCl₄) for 3 weeks or 6 weeks to induce liver fibrosis. OCA (5 mg/kg) or PBS is administered daily during CCl₄-treatment. At sacrifice, biochemical parameters and fibrosis were assessed. Pretreatment with OCA alleviated hepatic injury in 6 weeks group but not in 3 weeks group of CCl₄ liver cirrhosis. At same time, pretreatment with OCA exhibit a dramatic protection of liver fibrosis in both 3 weeks group and 6 weeks group. Further experiments found that OCA pretreatment inhibited α-SMA expression and the activation of hepatic pSmad3 in 3 weeks group and 6 weeks group of CCl₄-induced liver cirrhosis. Moreover, OCA activated FXR nuclear translocation and increased the interaction between liver FXR and pSmad3. This led to the discovery of a novel role for FXR in regulating fibrosis through interaction with pSmad3. Our data suggest that CCl₄-induced liver fibrosis is protected by OCA through interaction between farnesoid X receptor and Smad3.

Keywords: Carbon tetrachloride; Liver fibrosis; Obeticholic acid.