detail content area
JCI insight, 2020.5(17), e137566-0, DOI: https://doi.org/10.1172/jci.insight.137566
ERRγ suppression by Sirt6 alleviates cholestatic liver injury and fibrosis
Hao L, Bang I;Wang J;Mao Y;Yang J;Na SY;Seo JK;Choi HS;Bae E;Park BH
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 tranional 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.
- DOI: https://doi.org/10.1172/jci.insight.137566
- ISBN or ISSN: 2379-3708
- 본 연구는 질병관리본부 연구개발과제연구비를 지원받아 수행되었습니다.
- This research was supported by a fund by Research of Korea Centers for Disease Control and Prevention.