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.
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DOI：
10.1016/j.bbadis.2022.166510
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发表时间：
2022-08
期刊：
影响因子：
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通讯作者：
Yuecheng Guo;Xianjun Xu;H. Dong;B. Shen;Jumo Zhu;Zhenyang Shen;Cui Zhou;Xin Luo;Y. Qu;X. Cai;Qidi Zhang;Lungen Lu;Fei Li
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文献类型：
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作者：
Yuecheng Guo;Xianjun Xu;H. Dong;B. Shen;Jumo Zhu;Zhenyang Shen;Cui Zhou;Xin Luo;Y. Qu;X. Cai;Qidi Zhang;Lungen Lu;Fei Li
在此之前，我们曾报道Y盒结合蛋白1(YB-1)的核易位是由转化生长因子-β(转化生长因子-β)诱导的，并促进肝祖细胞(HPC)的增殖。在这里，我们探讨了YB-1易位的机制以及YB-1对HPC上皮-间充质转化(EMT)的影响。YB-1FLOX/FLOXCRE+/−(YB-1f/FCRE+/−)和YB-1f/FCRE−/−小鼠分别饲喂3，5-二乙氧甲酰基-1，4-二氢氯仿碱(DDC)和胆碱缺乏、乙硫氨酸补充(CDE)饲料。苏木精-伊红(HE)染色和Masson染色评价肝损伤和肝纤维化程度。逆转录-聚合酶链式反应(RT-PCR)、Western blotting和免疫荧光分析检测胶原和EMT相关标记物(E-钙粘蛋白、N-钙粘蛋白和Snail)的表达。通过RNA干扰抑制蛋白激酶B(AKT)在HPC中的表达。免疫印迹和免疫荧光分析检测HPC中YB-1的核表达。免疫荧光法检测HPC增殖情况。我们的结果表明，YB-1转录调控HPC的生物学行为。HPC特异性YB-1基因敲除减轻了喂食DDC或CDE饮食的小鼠的肝纤维化。YB-1核易位促进基质金属肽酶9转录。在体外和体内，去YB-1基因显著抑制了EMT，抑制了AKT的磷酸化。AKT基因敲除可抑制转化生长因子-β诱导的YB-1核转位，从而抑制内皮间充质干细胞和系膜细胞的增殖。在肝硬变的HPC中，EMT和AKT高度激活。总之，我们的研究结果表明，YB-1的缺失抑制了小鼠肝星状细胞的EMT，减轻了小鼠的肝纤维化，并且AKT在转化生长因子-β诱导的YB-1核移位和HPC增殖中是必不可少的。
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.