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USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells
Liver fibrosis is a complex fibrotic process that develops early in the course of cirrhosis and is caused by chronic liver damage. The activation of hepatic stellate cells is primarily responsible for the fibrosis process. Studies show that NRP1 influences HSC motility and migration. However, whethe...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9849111/ https://www.ncbi.nlm.nih.gov/pubmed/36653359 http://dx.doi.org/10.1038/s41419-022-05527-9 |
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author | Zhao, Jinqiu Bai, Jie Peng, Fengling Qiu, Chan Li, Yongguo Zhong, Li |
author_facet | Zhao, Jinqiu Bai, Jie Peng, Fengling Qiu, Chan Li, Yongguo Zhong, Li |
author_sort | Zhao, Jinqiu |
collection | PubMed |
description | Liver fibrosis is a complex fibrotic process that develops early in the course of cirrhosis and is caused by chronic liver damage. The activation of hepatic stellate cells is primarily responsible for the fibrosis process. Studies show that NRP1 influences HSC motility and migration. However, whether NRP1 regulates HSC activation remains unknown. C57BL/6 male mice (6–8 weeks old) were intraperitoneally injected with 10% CCl(4) in olive oil (5 μl/g body weight) every three days for four weeks to create an animal model of liver fibrosis. Control mice received olive oil (5 μl/g body weight). Different assays such as immunohistochemistry, immunostaining, Western blotting, qRT-PCR, immunoprecipitation, immunoprecipitation, and GST pull-down assays, and in vivo and in vitro ubiquitination assays were conducted. We found that NRP1 expression was significantly elevated both in mouse and human fibrotic livers, mainly in activated HSCs at the fibrotic foci. NRP1 promoted HSC activation via the cytokine TGF-β1, VEGFA, and PDGF-BB. Moreover, USP9X was found to be a critical deubiquitinating enzyme for the stability and high activity of NRP1 and NRP1 deubiquitination mediated by USP9X enhanced HSC activation and liver fibrosis. NRP1 deubiquitination mediated by USP9X enhances HSC activation, implying that targeting NRP1 or USP9X potentiates novel options in the treatment of liver fibrosis. |
format | Online Article Text |
id | pubmed-9849111 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-98491112023-01-19 USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells Zhao, Jinqiu Bai, Jie Peng, Fengling Qiu, Chan Li, Yongguo Zhong, Li Cell Death Dis Article Liver fibrosis is a complex fibrotic process that develops early in the course of cirrhosis and is caused by chronic liver damage. The activation of hepatic stellate cells is primarily responsible for the fibrosis process. Studies show that NRP1 influences HSC motility and migration. However, whether NRP1 regulates HSC activation remains unknown. C57BL/6 male mice (6–8 weeks old) were intraperitoneally injected with 10% CCl(4) in olive oil (5 μl/g body weight) every three days for four weeks to create an animal model of liver fibrosis. Control mice received olive oil (5 μl/g body weight). Different assays such as immunohistochemistry, immunostaining, Western blotting, qRT-PCR, immunoprecipitation, immunoprecipitation, and GST pull-down assays, and in vivo and in vitro ubiquitination assays were conducted. We found that NRP1 expression was significantly elevated both in mouse and human fibrotic livers, mainly in activated HSCs at the fibrotic foci. NRP1 promoted HSC activation via the cytokine TGF-β1, VEGFA, and PDGF-BB. Moreover, USP9X was found to be a critical deubiquitinating enzyme for the stability and high activity of NRP1 and NRP1 deubiquitination mediated by USP9X enhanced HSC activation and liver fibrosis. NRP1 deubiquitination mediated by USP9X enhances HSC activation, implying that targeting NRP1 or USP9X potentiates novel options in the treatment of liver fibrosis. Nature Publishing Group UK 2023-01-19 /pmc/articles/PMC9849111/ /pubmed/36653359 http://dx.doi.org/10.1038/s41419-022-05527-9 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Zhao, Jinqiu Bai, Jie Peng, Fengling Qiu, Chan Li, Yongguo Zhong, Li USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells |
title | USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells |
title_full | USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells |
title_fullStr | USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells |
title_full_unstemmed | USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells |
title_short | USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells |
title_sort | usp9x-mediated nrp1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9849111/ https://www.ncbi.nlm.nih.gov/pubmed/36653359 http://dx.doi.org/10.1038/s41419-022-05527-9 |
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