Hepatic nitric oxide synthase 1 adaptor protein regulates glucose homeostasis and hepatic insulin sensitivity in obese mice depending on its PDZ binding domain
Hepatic nitric oxide synthase 1 adaptor protein regulates glucose homeostasis and hepatic insulin sensitivity in obese mice depending on its PDZ binding domain
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DOI：
10.1016/j.ebiom.2019.08.033
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发表时间：
2019-09-01
期刊：
影响因子：
11.1
通讯作者：
Jia, Weiping
中科院分区：
文献类型：
--
作者：
Mu, Kaida;Sun, Yun;Jia, Weiping
背景：NOS1AP是一种连接蛋白，其SNP rs12742393与2型糖尿病(T2D)相关。然而，NOS1AP是否在调节胰岛素敏感性方面发挥作用仍不确定。肝脏胰岛素抵抗参与了T2D的发生。本研究旨在探讨NOS1AP是否参与肝脏胰岛素敏感性的调节及其机制。方法：建立肝脏特异性NOS1AP条件基因敲除(CKO)和NOS1AP高表达小鼠，并给予高脂饮食。对86名受试者NOS1AP基因的SNPs进行了基因分型。结果：NOS1AP蛋白在人和小鼠肝脏中均有表达。CKO小鼠表现出丙酮酸、葡萄糖和胰岛素耐量受损，肝脏脂质沉积增加。相反，NOS1AP在肥胖小鼠肝脏中的过表达改善了丙酮酸和/或葡萄糖，以及胰岛素耐量，并减弱了肝脏脂肪堆积。此外，CKO小鼠的肝细胞表现出较高的葡萄糖产量以及Pc和Pock1的mRNA表达。NOS1AP的过表达增强了胰岛素刺激的肥胖小鼠肝脏IR/Akt的激活。NOS1AP的胰岛素增敏作用可通过NOS1AP C端区在ob/ob小鼠体内的过表达来模拟。此外，NOS1AP在肝脏中的过表达显著抑制p38MAPK的磷酸化，并通过p-eIF2a-ATF4-CHOP途径维持ER的动态平衡。携带NOS1AP基因rsl2742393的受试者发生肝脏脂肪变性的风险更高。解释：我们的数据表明NOS1AP在调节肥胖小鼠肝脏胰岛素敏感性和p38MAPK失活方面具有新的作用，这使NOS1AP成为预防和治疗T2D的潜在治疗靶点。(C)2019年提交人。爱思唯尔出版公司(Elsevier B.V.)
Background: NOS1AP is an adaptor protein and its SNP rs12742393 was associated with type 2 diabetes (T2D). However, it remains uncertain whether NOS1AP plays a role in regulation of insulin sensitivity. Hepatic insulin resistance contributed to the development of T2D. Here, our investigation was focused on whether NOS1AP is involved in the regulation of hepatic insulin sensitivity and its underlying mechanisms.Methods: Liver specific NOS1AP condition knockout (CKO) and NOS1AP overexpression mice were generated and given a high fat diet. SNPs of NOS1AP gene were genotyped in 86 human subjects.Findings: NOS1AP protein is expressed in human and mouse liver. CKO mice exhibited impaired pyruvate, glucose and insulin tolerance, and increased lipid deposits in the liver. Conversely, NOS1AP overexpression in livers of obese mice improved pyruvate and/or glucose, and insulin tolerance, and attenuated liver lipid accumulation. Moreover, hepatocytes from CKO mice exhibited an elevated glucose production and mRNA expressions of Pc and Pck1. Overexpression of NOS1AP potentiated insulin-stimulated activation of IR/Akt in livers from obese mice. The insulin sensitizing effect of NOS1AP could be mimicked by overexpression of C-terminal domain of NOS1AP in ob/ob mice. Furthermore, NOS1AP overexpression in liver significantly inhibited p38 MAPK phosphorylation, and maintained ER homeostasis through p-eIF2a-ATF4-CHOP pathway. Subjects with rsl2742393 of NOS1AP have higher risk to develop hepatic steatosis.Interpretation: Our data demonstrate a novel role of NOS1AP in regulating hepatic insulin sensitivity and p38 MAPK inactivation in obese mice, which makes NOS1AP a potential therapeutic target for the prevention and treatment of T2D. (C) 2019 The Authors. Published by Elsevier B.V.