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SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis
Farnesoid X receptor (FXR) is a promising target for nonalcoholic steatohepatitis (NASH) and fibrosis. Although various FXR agonists have shown anti-fibrotic effects in diverse preclinical animal models, the response rate and efficacies in clinical trials were not optimum. Here we report that prophy...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957516/ https://www.ncbi.nlm.nih.gov/pubmed/31932588 http://dx.doi.org/10.1038/s41467-019-14138-6 |
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author | Zhou, Jiyu Cui, Shuang He, Qingxian Guo, Yitong Pan, Xiaojie Zhang, Pengfei Huang, Ningning Ge, Chaoliang Wang, Guangji Gonzalez, Frank J. Wang, Hong Hao, Haiping |
author_facet | Zhou, Jiyu Cui, Shuang He, Qingxian Guo, Yitong Pan, Xiaojie Zhang, Pengfei Huang, Ningning Ge, Chaoliang Wang, Guangji Gonzalez, Frank J. Wang, Hong Hao, Haiping |
author_sort | Zhou, Jiyu |
collection | PubMed |
description | Farnesoid X receptor (FXR) is a promising target for nonalcoholic steatohepatitis (NASH) and fibrosis. Although various FXR agonists have shown anti-fibrotic effects in diverse preclinical animal models, the response rate and efficacies in clinical trials were not optimum. Here we report that prophylactic but not therapeutic administration of obeticholic acid (OCA) prevents hepatic stellate cell (HSC) activation and fibrogenesis. Activated HSCs show limited response to OCA and other FXR agonists due to enhanced FXR SUMOylation. SUMOylation inhibitors rescue FXR signaling and thereby increasing the efficacy of OCA against HSC activation and fibrosis. FXR upregulates Perilipin-1, a direct target gene of FXR, to stabilize lipid droplets and thereby prevent HSC activation. Therapeutic coadministration of OCA and SUMOylation inhibitors drastically impedes liver fibrosis induced by CCl(4), bile duct ligation, and more importantly NASH. In conclusion, we propose a promising therapeutic approach by combining SUMOylation inhibitors and FXR agonists for liver fibrosis. |
format | Online Article Text |
id | pubmed-6957516 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-69575162020-01-15 SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis Zhou, Jiyu Cui, Shuang He, Qingxian Guo, Yitong Pan, Xiaojie Zhang, Pengfei Huang, Ningning Ge, Chaoliang Wang, Guangji Gonzalez, Frank J. Wang, Hong Hao, Haiping Nat Commun Article Farnesoid X receptor (FXR) is a promising target for nonalcoholic steatohepatitis (NASH) and fibrosis. Although various FXR agonists have shown anti-fibrotic effects in diverse preclinical animal models, the response rate and efficacies in clinical trials were not optimum. Here we report that prophylactic but not therapeutic administration of obeticholic acid (OCA) prevents hepatic stellate cell (HSC) activation and fibrogenesis. Activated HSCs show limited response to OCA and other FXR agonists due to enhanced FXR SUMOylation. SUMOylation inhibitors rescue FXR signaling and thereby increasing the efficacy of OCA against HSC activation and fibrosis. FXR upregulates Perilipin-1, a direct target gene of FXR, to stabilize lipid droplets and thereby prevent HSC activation. Therapeutic coadministration of OCA and SUMOylation inhibitors drastically impedes liver fibrosis induced by CCl(4), bile duct ligation, and more importantly NASH. In conclusion, we propose a promising therapeutic approach by combining SUMOylation inhibitors and FXR agonists for liver fibrosis. Nature Publishing Group UK 2020-01-13 /pmc/articles/PMC6957516/ /pubmed/31932588 http://dx.doi.org/10.1038/s41467-019-14138-6 Text en © The Author(s) 2020 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/. |
spellingShingle | Article Zhou, Jiyu Cui, Shuang He, Qingxian Guo, Yitong Pan, Xiaojie Zhang, Pengfei Huang, Ningning Ge, Chaoliang Wang, Guangji Gonzalez, Frank J. Wang, Hong Hao, Haiping SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis |
title | SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis |
title_full | SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis |
title_fullStr | SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis |
title_full_unstemmed | SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis |
title_short | SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis |
title_sort | sumoylation inhibitors synergize with fxr agonists in combating liver fibrosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957516/ https://www.ncbi.nlm.nih.gov/pubmed/31932588 http://dx.doi.org/10.1038/s41467-019-14138-6 |
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