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

Min Jin Kim, Sang A. Park, Chun Hwa Kim, So Yeon Park, Jung Shin Kim, Dae Kee Kim, Jeong Seok Nam, Yhun Yhong Sheen

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

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 languageEnglish
Pages (from-to)571-588
Number of pages18
JournalCellular Physiology and Biochemistry
Volume38
Issue number2
DOIs
StatePublished - 2016

Keywords

  • Cholestatic liver injury
  • Epithelial mesenchymal transition
  • EW-71/7
  • Hepatic stellate cell
  • HIFlα
  • TGF-β

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