Work

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

Year: 2013

Type: article

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.

Source: Antioxidants and Redox Signaling

DOI: 10.1089/ars.2012.5157

Authors: Sarit Anavi, Michal Hahn-Obercyger, Raanan Margalit, Zecharia Madar, Oren Tirosh

Institution: Hebrew University of Jerusalem

Language: English

Topic: Liver Disease Diagnosis and Treatment

Subfield: Hepatology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funder: Israel Science Foundation