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 HIF1a was expressed in the livers of iNOS -/ -mice, and significantly ameliorated cholesterol and LPS-induced liver damage. WT mice overexpressing HIF1a exhibited higher blood glucose levels and lower glycogen contents after LPS injection. Conversely, induction of HIF1a was not effective in preventing LPSinduced 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-a (TNFa) and intrahepatic TNFa 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.

The role of iNOS in cholesterol-induced liver fibrosis

“…23,24 Consistent with previous findings, in the current study HIF-1α was significantly increased in HCD-fed WT mice and was higher than in iNOS-deficient mice (Figure 3a). The elevated HIF-1 induction in HCD-fed WT mice was concomitant with a greater increase in the expression of profibrotic genes, ie, platelet-derived growth factor (PDGF)-A, PDGF-B, fibroblast growth factor-2 (FGF-2), and a trend toward higher plasminogen activator inhibitor-1 (PAI-1) expression, all of which were previously shown to be regulated in HIF-1α-dependent manner (Figure 3b-e).…”

“…This result is in accordance with our previous findings in which cholesterol induced the HIF-1 pathway in the liver and was iNOS dependant. 23,24 Recent data suggest an important role for HIF-1 in the pathogenesis of fibrotic diseases, including liver fibrosis. Indeed, many genes under the regulation of HIF-1 have been implicated in the pathogenesis of liver fibrosis as well as in ECM modifications.…”

High Fat Diets Composed of Palm Stearin and Olive Oil Equally Exacerbate Liver Inflammatory Damage and Metabolic Stress in Mice

“…[34] Previously, it was shown by us and others that LPS treatment induces hypoglycemia by inhibiting gluconeogenesis. [35][36][37][38][39] Indeed, in the current study LPS treatment downregulated gluconeogenesis response. The potency of LPS to induce hypoglycemia in the different animal treated groups was tested in the current study.…”

Intestinally derived bacterial products stimulate development of nonalcoholic steatohepatitis

“…receptor alpha-mediated transrepression of signaling pathways that involve adipose triglyceride lipase [71,72]. As a result, MCD diet and LPS causes steatohepatitis with enhanced role of hepatic pro-inflammatory mediators [73,74].…”