ERR gamma suppression by Sirt6 alleviates cholestatic liver injury and fibrosis

Abstract

Orphan nuclear receptor estrogen-related receptor gamma (ERR gamma) stimulates bile acid production; however, the role and the regulatory mechanism of ERR gamma in cholestatic liver disease are largely unknown. This study identifies that Sirt6 is a deacetylase of ERR gamma and suggests a potentially novel mechanism by which Sirt6 activation alleviates cholestatic liver damage and fibrosis through regulating ERR gamma. We observed that hepatic expression of Sirt6 is repressed, whereas hepatic expression of ERR gamma 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 ERR gamma, thereby destabilizing ERR gamma and inhibiting its transcriptional activity. Elimination of hepatic ERR gamma using Ad-shERR gamma abolished the deleterious effects of Sirt6 deficiency, whereas ERR gamma 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 ERR gamma and acetylated ERR gamma levels were increased, confirming negative regulation of ERR gamma by Sirt6. Thus, Sirt6 activation represents a potentially novel therapeutic strategy for treating cholestatic liver injury.