Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, People's Republic of China; Shanghai Diabetes Institute, Shanghai Jiao Tong University, People's Republic of China; Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, People's Republic of China.
Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, People's Republic of China; Shanghai Diabetes Institute, Shanghai Jiao Tong University, People's Republic of China; Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, People's Republic of China.
EBioMedicine. 2019 Sep;47:352-364. doi: 10.1016/j.ebiom.2019.08.033. Epub 2019 Aug 28.
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.
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.
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.
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. FUND: This work was supported by the National Natural Science Foundation of China (81670707, 31340072) (to C. Wang), and National Basic Research Program of China (Nation 973 Program) (2011CB504001) (to W. Jia).
NOS1AP 是一种衔接蛋白，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。肝胰岛素抵抗导致 T2D 的发生。在这里，我们的研究重点是 NOS1AP 是否参与调节肝胰岛素敏感性及其潜在机制。
生成了肝脏特异性 NOS1AP 条件敲除（CKO）和 NOS1AP 过表达小鼠，并给予高脂肪饮食。对 86 名人类受试者的 NOS1AP 基因 SNP 进行了基因分型。
NOS1AP 蛋白在人和小鼠的肝脏中表达。CKO 小鼠表现出丙酮酸、葡萄糖和胰岛素耐量受损，以及肝脏脂质沉积增加。相反，肥胖小鼠肝脏中 NOS1AP 的过表达改善了丙酮酸和/或葡萄糖和胰岛素耐量，并减轻了肝脏脂质堆积。此外，CKO 小鼠的肝细胞表现出葡萄糖生成增加和 Pc 和 Pck1 的 mRNA 表达增加。NOS1AP 的过表达增强了肥胖小鼠肝脏中 IR/Akt 的胰岛素刺激激活。NOS1AP 的胰岛素增敏作用可以通过在 ob/ob 小鼠中过表达 NOS1AP 的 C 端结构域来模拟。此外，肝脏中 NOS1AP 的过表达显著抑制了 p38 MAPK 的磷酸化，并通过 p-eIF2a-ATF4-CHOP 通路维持内质网的稳态。NOS1AP 的 rsl2742393 发生突变的受试者发生肝脂肪变性的风险更高。
我们的数据表明 NOS1AP 在调节肥胖小鼠的肝胰岛素敏感性和 p38 MAPK 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。
本工作得到了中国国家自然科学基金（81670707，31340072）（王传）和中国国家重点基础研究发展计划（国家 973 计划）（2011CB504001）（贾伟）的支持。
