Obeticholic acid aggravates liver fibrosis by activating hepatic farnesoid X receptor-induced apoptosis in cholestatic mice

Abstract

Obeticholic acid (OCA) was approved for the treatment of primary biliary cholangitis (PBC) patients. However, it can cause severe drug-induced liver injury (DILI), which may put PBC patients at risk of acute-on-chronic liver failure (ACLF) and even death. Farnesoid X receptor (FXR) is considered as the target of OCA for cholestasis, but there is still a lack of research on whether hepatic and ileal FXR have different effects after OCA treatment. The aim of this study was to investigate the mechanism of OCA aggravating liver fibrosis in cholestasis. The results showed that 40 mg/kg OCA elevated serum AST, ALT, ALP and γ-GT levels in bile duct ligation (BDL) mice. Besides, severe fibrosis and necrosis were observed in the OCA-treated BDL mice, which was related to hepatic apoptosis pathway activation. Both hepatic and ileal FXR signaling could be significantly activated by OCA. However, ileum-specific knockout of Fxr aggravated OCA-induced liver injury in BDL mice. On the contrary, hepatic-specific knockout of Fxr structurally and functionally ameliorated liver pathological processes in the OCA-treated BDL mice, which was due to the blockade of hepatic FXR-induced apoptosis. In conclusion, the mechanism of OCA aggravating liver fibrosis in cholestasis was based on the activation of hepatic FXR-induced apoptosis. It was also indicated ileal FXR might be a safer pharmacological target for bile acids regulation.