Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

Abstract

The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl₄)-induced acute liver injury. Mice were intraperitoneally injected with CCl₄ (0.15ml/kg). In CCl₄+OCA group, mice were orally with OCA (5mg/kg) 48, 24 and 1h before CCl₄. As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl₄-induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl₄-induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl₄-induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl₄-induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl₄-induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl₄-induced acute liver injury. These results suggest that OCA protects against CCl₄-induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury.

Keywords: Acute liver injury; Carbon tetrachloride (CCl(4)); Farnesoid X receptor (FXR); Inflammation; Obeticholic acid.