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ERR? suppression by Sirt6 alleviates cholestatic liver injury and fibrosis.


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

SUBMITTER: Hao L 

PROVIDER: S-EPMC7526444 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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ERRγ suppression by Sirt6 alleviates cholestatic liver injury and fibrosis.

Hao Lihua L   Bang In Hyuk IH   Wang Jie J   Mao Yuancheng Y   Yang Jae Do JD   Na Soon-Young SY   Seo Jeong Kon JK   Choi Hueng-Sik HS   Bae Eun Ju EJ   Park Byung-Hyun BH  

JCI insight 20200903 17


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 upreg  ...[more]

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