TGF-β/YB-1/Atg7 axis promotes the proliferation of hepatic progenitor cells and liver fibrogenesis.

Abstract

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-1f/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-1f/f Cre+/- mice displayed less liver injury and fibrosis than YB-1f/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-β (TGF-β) 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-β/YB-1 mediated HPCs expansion in vitro and in vivo. In summary, YB-1 nuclear translocation induced by TGF-β in HPCs promotes the proliferation and autophagy of HPCs and Atg7 participates in YB-1-mediated HPC-expansion and liver fibrosis.

• Authors: Yuecheng Guo, Jumo Zhu, Xianjun Xu, Bo Shen, Zhenyang Shen, Binghang Li, Fei Li, Tianyi Gu, Xiaobo Cai, Hui Dong, Lungen Lu
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1868 Issue 1 Pg. 166290 (01 01 2022) ISSN: 1879-260X [Electronic] Netherlands
• PMID: 34662704 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• 3,5-diethoxycarbonyl-1,4-dihydrocollidine
• Pyridines
• Transcription Factors
• Transforming Growth Factor beta
• YB-1 protein, mouse
• Autophagy-Related Protein 7
• Ethionine

Topics

• Animals
• Autophagy (drug effects)
• Autophagy-Related Protein 7 (genetics)
• Cell Proliferation (drug effects)
• Chemical and Drug Induced Liver Injury (genetics, pathology)
• Choline Deficiency (chemically induced, genetics, pathology)
• Disease Models, Animal
• Ethionine (toxicity)
• Extracellular Matrix (drug effects, pathology)
• Gene Expression Regulation (drug effects)
• Liver (drug effects, metabolism, pathology)
• Liver Cirrhosis (chemically induced, genetics, pathology)
• Mice, Knockout
• Microscopy, Electron, Transmission
• Pyridines (toxicity)
• Stem Cells (drug effects, pathology)
• Transcription Factors (genetics)
• Transforming Growth Factor beta (genetics)