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.
| Original language | English |
|---|---|
| Pages (from-to) | 571-588 |
| Number of pages | 18 |
| Journal | Cellular Physiology and Biochemistry |
| Volume | 38 |
| Issue number | 2 |
| DOIs | |
| State | Published - 2016 |
Bibliographical note
Publisher Copyright:© 2016 The Author(s).
Keywords
- Cholestatic liver injury
- EW-71/7
- Epithelial mesenchymal transition
- HIFlα
- Hepatic stellate cell
- TGF-β