A novel therapy for hepatic cholestasis treatment—the combination of rosiglitazone and fenofibrate

Abstract

Hepatic cholestasis can develop into liver fibrosis and eventually liver failure. Currently, ursodeoxycholic acid (UDCA) or UDCA combined with fenofibrate is used for cholestasis treatment. Rosiglitazone inhibited α-naphthyl isothiocyanate (ANIT)-induced cholestasis in mice. In this study, we compared the effect of rosiglitazone, UDCA, fenofibrate, combined rosiglitazone and fenofibrate or UDCA and fenofibrate on ANIT-induced cholestasis. C57BL/6J mice were induced cholestasis by ANIT while treated with rosiglitazone, UDCA, fenofibrate, combination of rosiglitazone and fenofibrate, or combination of UDCA and fenofibrate. Liver and serum samples were collected to determine liver necrosis and serum biochemical parameters. Rosiglitazone alone or combined with fenofibrate demonstrated better effects than UDCA alone or UDCA combined with fenofibrate in reduction of cholestasis-induced serum biochemical parameters and liver necrosis. Surprisingly, UDCA combined with fenofibrate, but not rosiglitazone combined with fenofibrate, potently increased accumulation of free fatty acids (FFAs) in the liver. Mechanistically, the protection of combination of rosiglitazone and fenofibrate against cholestasis was attributed to activated adiponectin pathway to enhance FXR and mitochondrial functions and reduce apoptosis in the liver. The accumulation of FFAs in the liver by combination of UDCA and fenofibrate was caused by activation of fatty acid biosynthesis and uptake, and triglyceride hydrolysis. Taken together, our study not only demonstrates the adverse effect of combination therapy of UDCA and fenofibrate, but also suggests the combination of rosiglitazone and fenofibrate can be another option for cholestasis treatment.