A novel antihypoglycemic role of inducible nitric oxide synthase in liver inflammatory response induced by dietary cholesterol and endotoxemia.

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 HIF1α was expressed in the livers of iNOS(-/-) mice, and significantly ameliorated cholesterol and LPS-induced liver damage. WT mice overexpressing HIF1α exhibited higher blood glucose levels and lower glycogen contents after LPS injection. Conversely, induction of HIF1α 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-α (TNFα) and intrahepatic TNFα 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.

• Authors: Sarit Anavi, Michal Hahn-Obercyger, Raanan Margalit, Zecharia Madar, Oren Tirosh
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 19 Issue 16 Pg. 1889-901 (Dec 01 2013) ISSN: 1557-7716 [Electronic] United States
• PMID: 23697659 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cholesterol, Dietary
• Hypoxia-Inducible Factor 1
• Lipopolysaccharides
• Nitric Oxide Synthase Type II

Topics

• Animals
• Cholesterol, Dietary (pharmacology)
• Endotoxemia (chemically induced, metabolism)
• Hypoglycemia (metabolism)
• Hypoxia-Inducible Factor 1 (metabolism)
• Inflammation (chemically induced, metabolism)
• Lipopolysaccharides (pharmacology)
• Liver (drug effects, enzymology, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nitric Oxide Synthase Type II (deficiency, metabolism)
• Non-alcoholic Fatty Liver Disease (chemically induced, enzymology, metabolism, pathology)