TGF-β/YB-1/Atg7 axis promotes the proliferation of hepatic progenitor cells and liver fibrogenesis
TGF-β/YB-1/Atg7 axis promotes the proliferation of hepatic progenitor cells and liver fibrogenesis
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DOI：
10.1016/j.bbadis.2021.166290
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发表时间：
2021-10-19
影响因子：
6.2
通讯作者：
Lu, Lungen
中科院分区：
文献类型：
--
作者：
Guo, Yuecheng;Zhu, Jumo;Lu, Lungen
肝纤维化的特点是细胞外基质过度沉积和导管反应，表现为肝祖细胞（HPC）的扩张。我们之前报道过 HPC 中的 Y 盒结合蛋白 1 (YB-1) 与慢性肝损伤有关。在本研究中，我们构建了 YB-1(f/f) Foxl1-Cre 小鼠，并研究了 YB-1 在小鼠胆碱缺乏、补充乙硫氨酸 (CDE) 和 3,5-二乙氧基羰基-1,4-二氢可力丁 (DDC) 模型中 HPC 扩增中的作用。使用苏木精和伊红 (HE)、马森和天狼星红染色测量肝损伤和纤维化。使用 EdU 和免疫荧光 (IF) 检测 HPC 增殖。通过 mCherry-GFP-LC3B 染色和透射电子显微镜 (TEM) 测量自噬流。通过免疫荧光和蛋白质印迹法测量YB-1表达。通过 CUT 和 Tag 分析、染色质免疫沉淀和 RT-PCR 来探索 YB-1 对自噬相关蛋白 7 (Atg7) 转录的调节。我们的结果表明，在 CDE 和 DDC 模型中，肝损伤伴随着 YB-1 的高表达、HPC 的增殖和自噬的激活。在 CDE 和 DDC 模型中，YB-1(f/f) Cre(+/-) 小鼠比 YB-1(f/f) Cre(-/-) 小鼠表现出更少的肝损伤和纤维化。 YB-1 在体外和体内促进 HPC 的增殖和自噬。转化生长因子-β (TGF-β) 诱导 YB-1 核转位并促进 HPC 的增殖和自噬。 YB-1 核易位促进 Atg7 的转录，这对于 TGF-β/YB-1 介导的 HPC 体外和体内扩增至关重要。综上所述，TGF-β诱导的HPCs中YB-1核转位促进HPCs的增殖和自噬，Atg7参与YB-1介导的HPC扩张和肝纤维化。
Hepatic fibrosis is characterized by excessive extracellular matrix deposition and ductular reactions, manifested as the expansion of hepatic progenitor cells (HPCs). We previously reported that the Y-box binding protein 1 (YB-1) in HPCs is involved in chronic liver injury. In this study, we constructed YB-1(f/f) Foxl1-Cre mice and investigated the role of YB-1 in HPC expansion in murine choline-deficient, ethionine-supplemented (CDE), and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) models. Liver injury and fibrosis were measured using hematoxylin and eosin (HE), Masson, and Sirius Red staining. HPC proliferation was detected using EdU and immunofluorescence (IF). Autophagic flow was measured by mCherry-GFP-LC3B staining and transmission electron microscopy (TEM). YB-1 expression was measured by immunofluorescence and western blotting. CUT & Tag analysis, chromatin immunoprecipitation, and RT-PCR were performed to explore the regulation of autophagy-related protein 7 (Atg7) transcription by YB-1. Our results indicated that liver injury was accompanied by high expression of YB-1, proliferative HPCs, and activated autophagy in the CDE and DDC models. YB-1(f/f) Cre(+/-) mice displayed less liver injury and fibrosis than YB-1(f/f) Cre(-/-) mice in the CDE and DDC models. YB-1 promoted proliferation and autophagy of HPCs in vitro and in vivo. Transforming growth factor-beta (TGF-beta) induced YB-1 nuclear translocation and facilitated the proliferation and autophagy of HPCs. YB-1 nuclear translocation promoted the transcription of Atg7, which is essential for TGF-beta/YB-1 mediated HPCs expansion in vitro and in vivo. In summary, YB-1 nuclear translocation induced by TGF-beta in HPCs promotes the proliferation and autophagy of HPCs and Atg7 participates in YB-1-mediated HPC-expansion and liver fibrosis.