Metabolic aging in diabetes: The glucoliptoxic connection

The study was designed to elucidate the role of nitric oxide generated by inducible nitric oxide synthase (iNOS) during high cholesterol diet (HCD)-induced steatohepatitis with and without LPS treatment. Herein, wild type (WT) and iNOS-knockout (iNOS-/-) mice were fed with a HCD for 6 weeks. Following diet period, some of the mice were injected with LPS (5 mg/Kg). Results: Chronic consumption of HCD led to steatohepatitis WT and iNOS-/mice. LPS administration caused marked liver damage only in cholesterol-fed mice, which was further exacerbated in the absence of iNOS. Metabolic effect: Enhanced liver injury by HCD and LPS in iNOS-/mice was associated with a fatal hypoglycemia. Glycogen contents were significantly retained in iNOS-/mice while hypoxia inducible factor 1 (HIF1) signaling was markedly attenuated compared to control WT. Results also demonstrated increased oxidative stress and reduced heme oxygenase-1 (HO-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. These data highlight the essential role of iNOS axis in the glycemic response to LPS in NASH and argues for beneficial effects of acute NO production under chronic and acute liver stress.