内分泌学
内科学
胰岛素
锡尔图因
SIRT6型
下调和上调
生物
雌激素
信号转导
胰岛素受体
胰岛素耐受试验
蛋白激酶B
肝细胞
葡萄糖稳态
激素
胰岛素抵抗
细胞生物学
NAD+激酶
胰岛素敏感性
医学
体外
酶
生物化学
基因
作者
Cheng-Yi Tang,Peiyu Liu,Yu Zhou,Bijie Jiang,Yu Song,Liang Sheng
摘要
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.
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