Inhibition of notch signaling pathway prevents cholestatic liver fibrosis by decreasing the differentiation of hepatic progenitor cells into cholangiocytes

Xiao Zhang, Guangli Du, Ying Xu, Xuewei Li, Weiwei Fan, Jiamei Chen, Cheng Liu, Gaofeng Chen, Chenghai Liu, Mark A Zern, Yongping Mu, Ping Liu

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Although hepatic progenitor cells (HPCs) are known to contribute to cholestatic liver fibrosis (CLF), how Notch signaling modulates the differentiation of HPCs to cholangiocytes in CLF is unknown. Thus, using a rat model of CLF that is induced by bile duct ligation, we inhibited Notch signaling with DAPT. In vivo, CK19, OV6, Sox9, and EpCAM expression was increased significantly. Notch signaling increased after bile duct ligation, and DAPT treatment reduced the expression of CK19, OV6, Sox9, and EpCAM and blocked cholangiocyte proliferation and CLF. In vitro, treatment of a WB-F344 cell line with sodium butyrate resulted in increased mRNA and protein expression of CK19, Sox9, and EpCAM, but Notch signaling was activated. Both of these processes were inhibited by DAPT. This study reveals that Notch signaling activation is required for HPC differentiation into cholangiocytes in CLF, and inhibition of the Notch signaling pathway may offer a therapeutic approach for treating CLF.

Original languageEnglish (US)
Pages (from-to)350-360
Number of pages11
JournalLaboratory Investigation
Volume96
Issue number3
DOIs
StatePublished - Mar 1 2016

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

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