TGF-beta Type I Receptor Kinase Inhibitor EW-7197 Suppresses Cholestatic Liver Fibrosis by Inhibiting HIF1 alpha-Induced Epithelial Mesenchymal Transition
- Authors
- Kim, Min-Jin; Park, Sang-A; Kim, Chun Hwa; Park, So-Yeon; Kim, Jung-Shin; Kim, Dae-Kee; Nam, Jeong-Seok; Sheen, Yhun Yhong
- Issue Date
- 2016
- Publisher
- KARGER
- Keywords
- Cholestatic liver injury; Hepatic stellate cell; TGF-beta; HIF1 alpha; Epithelial mesenchymal transition; EW-7197
- Citation
- CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, v.38, no.2, pp.571 - 588
- Journal Title
- CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
- Volume
- 38
- Number
- 2
- Start Page
- 571
- End Page
- 588
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/9701
- DOI
- 10.1159/000438651
- ISSN
- 1015-8987
- 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
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