TGF-β type i receptor kinase inhibitor EW-7197 suppresses cholestatic liver fibrosis by inhibiting HIF1α-induced epithelial mesenchymal transition
- 주제(키워드) Cholestatic liver injury , Epithelial mesenchymal transition , EW-71/7 , Hepatic stellate cell , HIFlα , TGF-β
- 등재 SCIE, SCOPUS
- 발행기관 S. Karger AG
- 발행년도 2016
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000132367
- 본문언어 영어
- Published As http://dx.doi.org/10.1159/0000438651
- 저작권 이화여자대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Background/Aims: Hypoxia is an environmental factor that aggravates liver fibrosis. HIFla activates hepatic stellate cells (HSCs) and increases transforming growth factor-ß (TGF-β) 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-β type I receptor kinase, EW-7197, on HIF1α-derived TGF-β signaling in cholestatic liver fibrosis. Methods: We used a bile duct ligation (BDL)-operated rat model to characterize the role of HIF1α-derived TGF-β signaling in liver fibrosis. Cellular assays were performed in LX-2 cells (human immortalized HSCs). The anti-fibrotic effects of EW-7197 in livertissues and HSCs were investigated via biochemical assays, immunohistochemistry (IHC), immunofiuorescence (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 HIF1α-induced activation of HSCs and EMT in vivo. In addition, EW-7197 inhibited HIF1α-derived HSC activation and expression of EMT markers in LX-2 cells in vitro. Conclusion: This study suggests that EW-7197 exhibits potential as a treatment for liver fibrosis because it inhibits HIF1α-induced TGF-β signaling. © 2016 The Author(s).
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