Hepatic nNOS impaired hepatic insulin sensitivity through the activation of p38 MAPK

Abstract

Neuronal nitric oxide synthase (nNOS) interacts with its adaptor protein NOS1AP through its PZD domain in the neurons. Previously, we had reported that NOS1AP enhanced hepatic insulin sensitivity through its PZD-binding domain, which suggested that nNOS might mediate the effect of NOS1AP. This study aimed to examine the role and underlying mechanisms of nNOS in regulating hepatic insulin sensitivity. nNOS co-localized with NOS1AP in mouse liver. The overexpression of NOS1AP in mouse liver decreased the level of phosphorylated nNOS (p-nNOS (Ser1417)), the active form of nNOS. Conversely, the liver-specific deletion of NOS1AP increased the level of p-nNOS (Ser1417). The overexpression of nNOS in the liver of high-fat diet-induced obese mice exacerbated glucose intolerance, enhanced intrahepatic lipid accumulation, decreased glycogen storage, and blunted insulin-induced phosphorylation of IRβ and Akt in the liver. Similarly, nNOS overexpression increased triglyceride production, decreased glucose utilization, and downregulated insulin-induced expression of p-IRβ, p-Akt, and p-GSK3β in the HepG2 cells. In contrast, treatment with Nω-propyl-L-arginine (L-NPA), a selective nNOS inhibitor, improved glucose tolerance and upregulated insulin-induced phosphorylation of IRβ and Akt in the liver of ob/ob mice. Furthermore, overexpression of nNOS increased p38MAPK phosphorylation in the HepG2 cells. In contrast, inhibition of p38MAPK with SB203580 significantly reversed the nNOS-induced inhibition of insulin signaling activity (all P < 0.05). This indicated that hepatic nNOS inhibited the insulin-signaling pathway through the activation of p38MAPK. These findings suggest that nNOS is involved in the development of hepatic insulin resistance and that nNOS might be a potential therapeutic target for diabetes.

The metabolic phenotype of the patient influences the reduction in carotid intima-media thickness achieved following metabolic surgery

“…Consistent with this, the expression of neuronal nitric oxide synthase has been shown to be related to hepatic insulin resistance and the concentrations of pro-fibrotic factors, such as platelet-derived growth factor, in experimental models. 20,21 In addition, hyperinsulinemia has been shown to significantly reduce the production of NO and alter the concentrations of vasomotor regulators, including endothelin-1 and NO, as well as the vasodilatory response, particularly in individuals with more serious metabolic disorders. 22 Mechanistic insight into the influence of the cardiometabolic phenotype on blood vessels following BMS may help identify specific therapeutic targets and aid risk stratification.…”

Role of Mitogen-Activated Protein (MAP) Kinase Pathways in Metabolic Diseases

“…This results in hepatic insulin resistance and diabetes, with further metabolic related pathological correlates to hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). [ 133 ] However, in another study, when 3T3-L1 adipocytes are isolated from type II diabetic patients, it was observed that there is an increased level of MAPKs signalling as well as p38 activation. This was responsible for the downregulation of GLUT4 expression on the plasma membrane eventually leading to insulin resistance and decreased glucose transport.…”

The Physiological Function of nNOS-Associated CAPON Proteins and the Roles of CAPON in Diseases

“…Higher nNOS activity leads to lower insulin sensitivity and upregulates the phosphorylation level of p38 MAPK. nNOS expression in the liver is negatively correlated with CAPON level and decreases p38 MAPK activity [93]. Therefore, CAPON may act through the inactivation of nNOS in liver (Table 1).…”