SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis
Abstract 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 th...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2020-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-019-14138-6 |
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| author | Jiyu Zhou Shuang Cui Qingxian He Yitong Guo Xiaojie Pan Pengfei Zhang Ningning Huang Chaoliang Ge Guangji Wang Frank J. Gonzalez Hong Wang Haiping Hao |
| author_facet | Jiyu Zhou Shuang Cui Qingxian He Yitong Guo Xiaojie Pan Pengfei Zhang Ningning Huang Chaoliang Ge Guangji Wang Frank J. Gonzalez Hong Wang Haiping Hao |
| author_sort | Jiyu Zhou |
| collection | DOAJ |
| description | Abstract 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 CCl4, 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 | Article |
| id | doaj-art-cb0ac40b9ecd4e1ebc0d9be07e906d1a |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2020-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-cb0ac40b9ecd4e1ebc0d9be07e906d1a2025-08-20T03:08:43ZengNature PortfolioNature Communications2041-17232020-01-0111111610.1038/s41467-019-14138-6SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosisJiyu Zhou0Shuang Cui1Qingxian He2Yitong Guo3Xiaojie Pan4Pengfei Zhang5Ningning Huang6Chaoliang Ge7Guangji Wang8Frank J. Gonzalez9Hong Wang10Haiping Hao11State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical UniversityLaboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of HealthState Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical UniversityAbstract 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 CCl4, 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.https://doi.org/10.1038/s41467-019-14138-6 |
| spellingShingle | Jiyu Zhou Shuang Cui Qingxian He Yitong Guo Xiaojie Pan Pengfei Zhang Ningning Huang Chaoliang Ge Guangji Wang Frank J. Gonzalez Hong Wang Haiping Hao SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis Nature Communications |
| 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 |
| url | https://doi.org/10.1038/s41467-019-14138-6 |
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