Obeticholic acid improved triptolide/lipopolysaccharide-induced hepatotoxicity by inhibiting caspase-11-GSDMD pyroptosis pathway.

Abstract

This study was designed to investigate the potential role of farnesoid X receptor (FXR) in abnormal bile acid metabolism and pyroptosis during the pathogenesis of triptolide (TP)/lipopolysaccharide (LPS)-induced hepatotoxicity. Moreover, the protective effect of obeticholic acid (OCA) was explored under this condition. In vivo, female C57BL/6 mice were administrated with OCA (40 mg/kg bw, intragastrical injection) before (500 μg/kg bw, intragastrical injection)/LPS (0.1 mg/kg bw, intraperitoneal injection) administration. In vitro, AML12 cells were treated with TP (50 nM) and TNF-α (50 ng/ml) to induce hepatotoxicity; GW4064 (5 μM) and cholestyramine (CHO) (0.1 mg/ml and 0.05 mg/ml) were introduced to explain the role of FXR/total bile acid (TBA) in it. Serum TBA level was significantly elevated, which was induced by FXR suppression. And both GW4064 and CHO intervention presented remarkable protective effects against TP/TNF-α-induced NLRP3 upregulation and pyroptosis pathway activation. Pre-administration of FXR agonist OCA successfully attenuated TP/LPS-induced severe liver injury by reducing serum bile acids accumulation and inhibiting the activation of caspase-11-GSDMD (gasdermin D) pyroptosis pathway. We have drawn conclusions that TP aggravated liver hypersensitivity to LPS and inhibited FXR-SHP (small heterodimer partner) axis, which was served as endogenous signals to activate caspase-11-GSDMD-mediated pyroptosis contributing to liver injury. OCA alleviated TP/LPS-induced liver injury accompanied by inhibiting caspase-11-GSDMD-mediated pyroptosis pathway and decreased serum TBA level. The results indicated that FXR might be an attractive therapeutic target for TP/LPS-induced hepatotoxicity, providing an effective strategy for drug-induced liver injury.