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  2. Loss of YB-1 alleviates liver fibrosis by suppressing epithelial-mesenchymal transition in hepatic progenitor cells

Loss of YB-1 alleviates liver fibrosis by suppressing epithelial-mesenchymal transition in hepatic progenitor cells

  • Biochim Biophys Acta Mol Basis Dis. 2022 Nov 1;1868(11):166510. doi: 10.1016/j.bbadis.2022.166510.
Yuecheng Guo 1 Xianjun Xu 1 Hui Dong 1 Bo Shen 1 Jumo Zhu 2 Zhenyang Shen 1 Cui Zhou 1 Xin Luo 1 Ying Qu 3 Xiaobo Cai 3 Qidi Zhang 3 Lungen Lu 4 Fei Li 5
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai JiaoTong University School of Medicine, Shanghai, China.
  • 2 Department of Cardiology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
  • 3 Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
  • 4 Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai JiaoTong University School of Medicine, Shanghai, China. Electronic address: lungen.lu@shgh.cn.
  • 5 Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China. Electronic address: fei.li1@shgh.cn.
Abstract

Previously, we reported that the nuclear translocation of Y-box binding protein 1 (YB-1) is induced by Transforming Growth Factor-β (TGF-β) and promotes hepatic progenitor cells (HPCs) expansion. Here, we explored the mechanisms underlying YB-1 translocation and the impact of YB-1 on the epithelial-mesenchymal transition (EMT) in HPCs. YB-1flox/floxcre+/- (YB-1f/fcre+/-) mice and YB-1f/fcre-/- mice were fed with a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or a choline-deficient, ethionine-supplemented (CDE) diet. Liver injury and fibrosis were assessed by performing hematoxylin and eosin (HE) and Masson staining. The expression of collagen and EMT-related markers (E-cadherin, N-Cadherin, and Snail) was detected by reverse transcription-polymerase chain reaction (RT-PCR), western blotting, and immunofluorescence analyses. Protein kinase B (Akt) expression in HPCs was silenced via RNA interference. Nuclear YB-1 expression in HPCs was detected via western blotting and immunofluorescence analyses. HPC proliferation was detected by immunofluorescence. Our results indicate that YB-1 transcriptionally regulated the biological behavior of HPCs. HPC-specific YB-1 knockout alleviated liver fibrosis in mice fed with DDC or CDE diet. YB-1 nuclear translocation promoted matrix metallopeptidase 9 transcription. YB-1 depletion in HPCs significantly dampened the EMT and inhibited Akt phosphorylation in vitro and in vivo. Akt knockdown compromised TGF-β-induced YB-1 nuclear translocation, thereby inhibiting the EMT and HPC proliferation. EMT and Akt were highly activated in HPCs in cirrhotic livers. Collectively, our findings indicate that the loss of YB-1 suppressed EMT in HPCs and alleviated liver fibrosis in mice, and that Akt was essential for TGF-β-induced YB-1 nuclear translocation and HPC proliferation.

Keywords

Epithelial–mesenchymal transformation; Hepatic progenitor cell; Liver fibrosis; Transforming growth factor β; Y-box binding protein 1.

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