A Novel Antihypoglycemic Role of Inducible Nitric Oxide Synthase in Liver Inflammatory Response Induced by Dietary Cholesterol and Endotoxemia

Aims: The current study aim was to elucidate the antihypoglycemic role and mechanism of inducible nitric oxide synthase (iNOS) under inflammatory stress. Methods: Liver inflammatory stress was induced in wild-type (WT) and iNOS-knockout (iNOS(-/-)) mice by lipopolysaccharide (LPS) (5mg/kg) with and without the background of nonalcoholic steatohepatitis (NASH)-Induced by high cholesterol diet (HCD, 6 weeks). Results: HCD led to steatohepatitis in WT and iNOS(-/-) mice. LPS administration caused marked liver inflammatory damage only in cholesterol-fed mice, which was further exacerbated in the absence of iNOS. Glucose homeostasis was significantly impaired and included fatal hypoglycemia and inhibition of glycogen decomposition. In iNOS(-/-) hypoxia-inducible factor-1 (HIF1), signaling was impaired compared to control WT. Using hydrodynamic gene transfer method HIF1 was expressed in the livers of iNOS(-/-) mice, and significantly ameliorated cholesterol and LPS-induced liver damage. WT mice overexpressing HIF1 exhibited higher blood glucose levels and lower glycogen contents after LPS injection. Conversely, induction of HIF1 was not effective in preventing LPS-induced glucose lowering effect in iNOS(-/-) mice. The critical role of NO signaling in hepatocytes glucose output mediated by HIF1 pathway was also confirmed in vitro. Results also demonstrated increased oxidative stress and reduced heme oxygenase-1 mRNA in the livers of iNOS(-/-) mice. Furthermore, the amounts of plasma tumor necrosis factor- (TNF) and intrahepatic TNF mRNA were significantly elevated in the absence of iNOS. Innovation and Conclusion: These data highlight the essential role of iNOS in the glycemic response to LPS in NASH conditions and argues for the beneficial effects of iNOS. Antioxid. Redox Signal. 19, 1889-1901.