TGF-beta Type I Receptor Kinase Inhibitor EW-7197 Suppresses Cholestatic Liver Fibrosis by Inhibiting HIF1 alpha-Induced Epithelial Mesenchymal Transition

Abstract

Background/Aims: Hypoxia is an environmental factor that aggravates liver fibrosis. HIF1 alpha activates hepatic stellate cells (HSCs) and increases transforming growth factor-beta (TGF-beta) signaling and the epithelial mesenchymal transition (EMT), accelerating the progression of fibrosis. We evaluated the anti-fibrotic therapeutic potential of a small-molecule inhibitor of TGF-beta type I receptor kinase, EW-7197, on HIF1 alpha-derived TGF-beta signaling in cholestatic liver fibrosis. Methods: We used a bile duct ligation (BDL)-operated rat model to characterize the role of HIF1 alpha-derived TGF-beta signaling in liver fibrosis. Cellular assays were performed in LX-2 cells (human immortalized HSCs). The anti-fibrotic effects of EW-7197 in liver tissues and HSCs were investigated via biochemical assays, immunohistochemistry (IHC), immunofluorescence (IF), chromatin immunoprecipitation (ChIP) assays, real-time PCR, and western blotting. Results: In our BDL rat model, orally administered EW-7197 inhibited fibrosis and attenuated HIF1 alpha-induced activation of HSCs and EMT in vivo. In addition, EW-7197 inhibited HIF1 alpha-derived HS[activation and expression of EMT markers in LX-2 cells in vitro. Conclusion: This study suggests that FW-7197 exhibits potential as a treatment for liver fibrosis because it inhibits HIF1 alpha-induced TGF-beta signaling. (C) 2016 The Author(s) Published by S. Karger AG, Basel