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Sirt6 deletion in hepatocytes increases insulin sensitivity of female mice by enhancing ERα expression.

Authors
  • Tang, Chuanfeng1
  • Liu, Peiyu1
  • Zhou, Yu1
  • Jiang, Bijie2
  • Song, Yu2
  • Sheng, Liang1, 2, 3
  • 1 Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu, China. , (China)
  • 2 Pharmacy College, Xinxiang Medical University, Xinxiang, Henan, China. , (China)
  • 3 Key Laboratory of Rare Metabolic Diseases, Nanjing Medical University, Nanjing, Jiangsu, China. , (China)
Type
Published Article
Journal
Journal of Cellular Physiology
Publisher
Wiley (John Wiley & Sons)
Publication Date
Aug 01, 2019
Volume
234
Issue
10
Pages
18615–18625
Identifiers
DOI: 10.1002/jcp.28500
PMID: 30912134
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Sirtuin 6 (Sirt6), a NAD+ -dependent protein deacetylase, is involved in hepatic glucose metabolism and insulin sensitivity, which impact metabolic homeostasis. In this paper, we discover that Sirt6 affects the insulin sensitivity of mice in a gender-dependent manner; few studies have been conducted on this issue. Based on reports revealing the influences of sex hormones on insulin signaling, this investigation explores the mechanism by which Sirt6 regulates the estrogen pathway and disrupts insulin signal transduction. Hepatocyte-specific Sirt6 knockout (Sirt6HKO) mice were generated to investigate the function of Sirt6 in hepatocytes. Mice were castrated or spayed to eliminate sex hormones. Insulin sensitivity was assessed via an insulin tolerance test (ITT) in vivo. The interaction of Sirt6 with the estrogen pathway and their impacts on insulin signal transduction were revealed by immunoblot and immunoprecipitation. Sirt6 deletion in hepatocytes significantly enhanced insulin sensitivity and signal transduction in female mice but not in male or spayed female mice as demonstrated by ITT and the phosphorylation level of Akt in the liver. We also identified upregulation of p300, ERα, and interaction of ERα with p85 in the liver of female Sirt6HKO mice. Additionally, Sirt6 was found to inhibit ERα protein stability in a p300-dependent manner without interacting directly with ERα. Our findings show that hepatic Sirt6 downregulates the ERα protein level in a p300-dependent manner and thus disturbs estrogen-induced improvement in insulin sensitivity in the liver, which may partially explain the gender difference in insulin sensitivity. © 2019 Wiley Periodicals, Inc.

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