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A novel antihypoglycemic role of inducible nitric oxide synthase in liver inflammatory response induced by dietary cholesterol and endotoxemia.
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ABSTRACT: 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) (5 mg/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.
SUBMITTER: Anavi S
PROVIDER: S-EPMC3852347 | biostudies-literature | 2013 Dec
REPOSITORIES: biostudies-literature
Publications
A novel antihypoglycemic role of inducible nitric oxide synthase in liver inflammatory response induced by dietary cholesterol and endotoxemia.
Antioxidants & redox signaling 20130724 16
<h4>Aims</h4>The current study aim was to elucidate the antihypoglycemic role and mechanism of inducible nitric oxide synthase (iNOS) under inflammatory stress.<h4>Methods</h4>Liver inflammatory stress was induced in wild-type (WT) and iNOS-knockout (iNOS(-/-)) mice by lipopolysaccharide (LPS) (5 mg/kg) with and without the background of nonalcoholic steatohepatitis (NASH)-Induced by high cholesterol diet (HCD, 6 weeks).<h4>Results</h4>HCD led to steatohepatitis in WT and iNOS(-/-) mice. LPS adm ...[more]
