| First Author | Hao L | Year | 2020 |
| Journal | JCI Insight | Volume | 5 |
| Issue | 17 | PubMed ID | 32701506 |
| Mgi Jnum | J:301821 | Mgi Id | MGI:6505001 |
| Doi | 10.1172/jci.insight.137566 | Citation | Hao L, et al. (2020) ERRgamma suppression by Sirt6 alleviates cholestatic liver injury and fibrosis. JCI Insight 5(17) |
| abstractText | Orphan nuclear receptor estrogen-related receptor gamma (ERRgamma) stimulates bile acid production; however, the role and the regulatory mechanism of ERRgamma in cholestatic liver disease are largely unknown. This study identifies that Sirt6 is a deacetylase of ERRgamma and suggests a potentially novel mechanism by which Sirt6 activation alleviates cholestatic liver damage and fibrosis through regulating ERRgamma. We observed that hepatic expression of Sirt6 is repressed, whereas hepatic expression of ERRgamma 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 ERRgamma, thereby destabilizing ERRgamma and inhibiting its transcriptional activity. Elimination of hepatic ERRgamma using Ad-shERRgamma abolished the deleterious effects of Sirt6 deficiency, whereas ERRgamma 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 ERRgamma and acetylated ERRgamma levels were increased, confirming negative regulation of ERRgamma by Sirt6. Thus, Sirt6 activation represents a potentially novel therapeutic strategy for treating cholestatic liver injury. |
