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

Autor: Guo Y; 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., Xu X; 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., Dong H; 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., Shen B; 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., Zhu J; Department of Cardiology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China., Shen Z; 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., Zhou C; 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., Luo X; 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., Qu Y; Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China., Cai X; Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China., Zhang Q; Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China., Lu L; 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., Li F; Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China. Electronic address: fei.li1@shgh.cn.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2022 Nov 01; Vol. 1868 (11), pp. 166510. Date of Electronic Publication: 2022 Aug 01.
DOI: 10.1016/j.bbadis.2022.166510
Abstrakt: 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-1 flox/flox cre +/- (YB-1 f/f cre +/- ) mice and YB-1 f/f cre -/- 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.
Competing Interests: Declaration of competing interest The authors declare that no conflicts of interest exist.
(Copyright © 2022. Published by Elsevier B.V.)
Databáze: MEDLINE
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