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ERRγ suppression by Sirt6 alleviates cholestatic liver injury and fibrosis
Lihua Hao, … , Eun Ju Bae, Byung-Hyun Park
Lihua Hao, … , Eun Ju Bae, Byung-Hyun Park
Published July 23, 2020
Citation Information: JCI Insight. 2020;5(17):e137566. https://doi.org/10.1172/jci.insight.137566.
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Research Article Hepatology Metabolism

ERRγ suppression by Sirt6 alleviates cholestatic liver injury and fibrosis

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Abstract

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 transcriptional 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.

Authors

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

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Figure 5

Regulation of ERRγ protein stability by Sirt6.

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Regulation of ERRγ protein stability by Sirt6.
(A) After transfection of...
(A) After transfection of HEK293T cells with the indicated plasmids in the presence of MG132 (2 μM), protein lysates were immunoprecipitated with anti-ERRγ antibodies and immunoblotted with anti-ubiquitin antibodies. (B) Cells transfected with p300 and ERRγ with or without either Sirt6 or mutant Sirt6 were treated with cycloheximide (CHX, 10 μg/mL) for the indicated times, and ERRγ protein levels were compared (n = 3). (C) Cells were transfected with p300 with WT or mutant ERRγ, and ERRE-luciferase activity was assayed (n = 4). (D) Cells were transfected with WT or mutant ERRγ (K125R and K195R) and then treated with CHX (10 μg/mL) for the indicated time periods. Protein levels of ERRγ were compared (n = 3). Values are shown as mean ± SEM. Comparisons were made using 1-way ANOVA followed by Tukey’s multiple-comparisons test. *P < 0.05 and **P < 0.01 versus mock or WT.

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