Liver-Specific Overexpression of NOS1AP Alleviates Hepatic Insulin Resistance in Obese Mice

Abstract

Objective: Nitric oxide synthase 1 adaptor protein (NOS1AP) controls a number of different signaling complexes. We reported previously that the NOS1AP SNP rs12742393 was associated with type 2 diabetes (T2D). T2D and nonalcoholic fatty liver disease (NAFLD) are closely associated, in which NAFLD contributes to the development of liver insulin resistance in T2D. Thus, we investigated whether NOS1AP plays a role in regulating hepatic insulin sensitivity. Methods: Liver-specific NOS1AP overexpression and knockout mice were fed a high-fat diet (HFD). Results: NOS1AP protein is highly expressed in mouse liver. Its expression is downregulated in livers of obese rodents. Overexpression of NOS1AP in liver of ob/ob or HFD-induced obese mice improved pyruvate and/or glucose and insulin tolerance, and attenuated liver lipid accumulation in these mice. Conversely, liver specific deletion of NOS1AP impaired pyruvate, glucose and insulin tolerance in the mice, and increased lipid accumulation in the liver. Moreover, overexpression of NOS1AP resulted in reduced expression of Pck1 and increased insulin-induced p-Akt in HepG2 cells. Furthermore, the insulin sensitizing effect of NOS1AP could be mimicked by overexpression of C-terminal domain of NOS1AP in ob/ob mice. Conclusion: Our data demonstrate a novel role of NOS1AP in regulating hepatic insulin sensitivity and lipid accumulation in liver, which implicates NOS1AP a therapeutic target for treatment of NAFLD and prevention of T2D. Disclosure C. Wang: None. K. Mu: None. T. Zhao: None. H. Zhu: None. W. Jia: None.