Orphan nuclear receptor estrogen-related receptor (ERR)γ 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 novel mechanism by which Sirt6 activation alleviates cholestatic liver damage and fibrosis through regulating ERRγ. We observed that hepatic expression of Sirt6 is repressed while that of ERRγ is upregulated in murine cholestasis models. Hepatocyte-specific Sirt6 knockout mice were more severely injured following a bile duct ligation (BDL) compared to wild-type mice and adenoviral re-expression of Sirt6 reversed liver damage and fibrosis as demonstrated by biochemical and histological analyses. Mechanistically, Sirt6 deacetylated ERRγ, thereby destabilized ERRγ and inhibited its transcriptional activity. Elimination of hepatic ERRγ using Ad-shERRγ abolished the deleterious effects of Sirt6 deficiency, while 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 while total- and acetylated-ERRγ levels were increased, confirming negative regulation of ERRγ by Sirt6. Thus, Sirt6 activation represents a new therapeutic strategy for treating cholestatic liver injury.
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