ERRγ suppression by Sirt6 alleviates cholestatic liver injury and fibrosis
Orphan nuclear receptor estrogen-related receptor γ (ERRγ) stimulates bile acid production; however, the role and the regulatory mechanism of ERRγ in cholestatic liver disease are largely unknown. This study identifies that Sirt6 is a deacetylase of ERRγ and suggests a potentially novel mechanism by...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2020-12-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.137566 |
| _version_ | 1818574742200778752 |
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| author | Lihua Hao In Hyuk Bang Jie Wang Yuancheng Mao Jae Do Yang Soon-Young Na Jeong Kon Seo Hueng-Sik Choi Eun Ju Bae Byung-Hyun Park |
| author_facet | Lihua Hao In Hyuk Bang Jie Wang Yuancheng Mao Jae Do Yang Soon-Young Na Jeong Kon Seo Hueng-Sik Choi Eun Ju Bae Byung-Hyun Park |
| author_sort | Lihua Hao |
| collection | DOAJ |
| description | Orphan nuclear receptor estrogen-related receptor γ (ERRγ) stimulates bile acid production; however, the role and the regulatory mechanism of ERRγ in cholestatic liver disease are largely unknown. This study identifies that Sirt6 is a deacetylase of ERRγ and suggests a potentially novel mechanism by which Sirt6 activation alleviates cholestatic liver damage and fibrosis through regulating ERRγ. We observed that hepatic expression of Sirt6 is repressed, whereas hepatic expression of ERRγ is upregulated in murine cholestasis models. Hepatocyte-specific Sirt6-KO mice were more severely injured after a bile duct ligation (BDL) than WT mice, and adenoviral reexpression of Sirt6 reversed liver damage and fibrosis as demonstrated by biochemical and histological analyses. Mechanistically, Sirt6 deacetylated ERRγ, thereby destabilizing ERRγ and inhibiting its transcriptional activity. Elimination of hepatic ERRγ using Ad-shERRγ abolished the deleterious effects of Sirt6 deficiency, whereas ERRγ overexpression aggravated cholestatic liver injury. Administration of a Sirt6 deacetylase activator prevented BDL-induced liver damage and fibrosis. In patients with cholestasis, Sirt6 expression was decreased, whereas total ERRγ and acetylated ERRγ levels were increased, confirming negative regulation of ERRγ by Sirt6. Thus, Sirt6 activation represents a potentially novel therapeutic strategy for treating cholestatic liver injury. |
| first_indexed | 2024-12-15T00:30:35Z |
| format | Article |
| id | doaj.art-8d84a4fccccd4fcbbee0c3c5d144912b |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-15T00:30:35Z |
| publishDate | 2020-12-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-8d84a4fccccd4fcbbee0c3c5d144912b2022-12-21T22:42:01ZengAmerican Society for Clinical investigationJCI Insight2379-37082020-12-01517ERRγ suppression by Sirt6 alleviates cholestatic liver injury and fibrosisLihua HaoIn Hyuk BangJie WangYuancheng MaoJae Do YangSoon-Young NaJeong Kon SeoHueng-Sik ChoiEun Ju BaeByung-Hyun ParkOrphan nuclear receptor estrogen-related receptor γ (ERRγ) stimulates bile acid production; however, the role and the regulatory mechanism of ERRγ in cholestatic liver disease are largely unknown. This study identifies that Sirt6 is a deacetylase of ERRγ and suggests a potentially novel mechanism by which Sirt6 activation alleviates cholestatic liver damage and fibrosis through regulating ERRγ. We observed that hepatic expression of Sirt6 is repressed, whereas hepatic expression of ERRγ is upregulated in murine cholestasis models. Hepatocyte-specific Sirt6-KO mice were more severely injured after a bile duct ligation (BDL) than WT mice, and adenoviral reexpression of Sirt6 reversed liver damage and fibrosis as demonstrated by biochemical and histological analyses. Mechanistically, Sirt6 deacetylated ERRγ, thereby destabilizing ERRγ and inhibiting its transcriptional activity. Elimination of hepatic ERRγ using Ad-shERRγ abolished the deleterious effects of Sirt6 deficiency, whereas ERRγ overexpression aggravated cholestatic liver injury. Administration of a Sirt6 deacetylase activator prevented BDL-induced liver damage and fibrosis. In patients with cholestasis, Sirt6 expression was decreased, whereas total ERRγ and acetylated ERRγ levels were increased, confirming negative regulation of ERRγ by Sirt6. Thus, Sirt6 activation represents a potentially novel therapeutic strategy for treating cholestatic liver injury.https://doi.org/10.1172/jci.insight.137566HepatologyMetabolism |
| spellingShingle | Lihua Hao In Hyuk Bang Jie Wang Yuancheng Mao Jae Do Yang Soon-Young Na Jeong Kon Seo Hueng-Sik Choi Eun Ju Bae Byung-Hyun Park ERRγ suppression by Sirt6 alleviates cholestatic liver injury and fibrosis JCI Insight Hepatology Metabolism |
| title | ERRγ suppression by Sirt6 alleviates cholestatic liver injury and fibrosis |
| title_full | ERRγ suppression by Sirt6 alleviates cholestatic liver injury and fibrosis |
| title_fullStr | ERRγ suppression by Sirt6 alleviates cholestatic liver injury and fibrosis |
| title_full_unstemmed | ERRγ suppression by Sirt6 alleviates cholestatic liver injury and fibrosis |
| title_short | ERRγ suppression by Sirt6 alleviates cholestatic liver injury and fibrosis |
| title_sort | errγ suppression by sirt6 alleviates cholestatic liver injury and fibrosis |
| topic | Hepatology Metabolism |
| url | https://doi.org/10.1172/jci.insight.137566 |
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