Histone deacetylase 8 inhibition alleviates cholestatic liver injury and fibrosis

Abstract

Cholestasis is a pathological condition involving blockage of bile flow that results in hepatotoxicity, inflammation, and fibrosis. Although recent studies have shown that histone deacetylases (HDACs) are involved in the progression of fibrosis in various organs, the role of HDAC8 on liver fibrosis has until now remained unexplored. This study presents a newly-synthesized, selective HDAC8 inhibitor SPA3014 composed of a vinyl disulfidesulfoxide core, and evaluates its therapeutic efficacy against cholestatic liver injury and fibrosis in bile ductligated (BDL) mice. We first observed the increase in HDAC8 protein levels in mice with BDL and patients with cholestatic liver disease. Mice with BDL that were pretreated with SPA3014 had lower liver damage and fibrosis, based on gross examination, histopathologic findings, and biochemical analyses, than did vehicletreated mice. Studies with LX-2 human hepatic stellate cells showed that SPA3014 exerted protective effects by inhibiting TGF-beta-mediated activation of MAPK-Smad2/3 and JAK2-STAT3 pathways and by upregulating PPAR gamma expression. Overall, these results strongly suggest that HDAC8 inhibition constitutes a new therapeutic strategy for treatment of cholestatic liver injury.