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TGF-β type i receptor kinase inhibitor EW-7197 suppresses cholestatic liver fibrosis by inhibiting HIF1α-induced epithelial mesenchymal transition

Title
TGF-β type i receptor kinase inhibitor EW-7197 suppresses cholestatic liver fibrosis by inhibiting HIF1α-induced epithelial mesenchymal transition
Authors
Kim M.-J.Park S.-A.Kim C.H.Park S.-Y.Kim J.-S.Kim D.-K.Nam J.-S.Sheen Y.Y.
Ewha Authors
신윤용김대기
SCOPUS Author ID
신윤용scopus; 김대기scopus
Issue Date
2016
Journal Title
Cellular Physiology and Biochemistry
ISSN
1015-8987JCR Link
Citation
vol. 38, no. 2, pp. 571 - 588
Keywords
Cholestatic liver injuryEpithelial mesenchymal transitionEW-71/7Hepatic stellate cellHIFlαTGF-β
Publisher
S. Karger AG
Indexed
SCI; SCIE; SCOPUS scopus
Abstract
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).
DOI
10.1159/0000438651
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약학대학 > 약학과 > Journal papers
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