A Novel Antihypoglycemic Role of Inducible Nitric Oxide Synthase in Liver Inflammatory Response Induced by Dietary Cholesterol and Endotoxemia
A Novel Antihypoglycemic Role of Inducible Nitric Oxide Synthase in Liver Inflammatory Response Induced by Dietary Cholesterol and Endotoxemia
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DOI：
10.1089/ars.2012.5157
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发表时间：
2013-12-01
影响因子：
6.6
通讯作者：
Tirosh, Oren
中科院分区：
文献类型：
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作者：
Anavi, Sarit;Hahn-Obercyger, Michal;Tirosh, Oren
目的：探讨诱导型一氧化氮合酶(INOS)在炎症应激下的降血糖作用及其机制。方法：给野生型(WT)和诱导型一氧化氮合酶基因敲除(iNOS(-/-))小鼠注射脂多糖(5 mg/kg)诱导肝脏炎症应激反应，同时给予高脂饮食诱导的非酒精性脂肪性肝炎(NASH)小鼠(6周)。结果：HCD可致WT和iNOS(-/-)小鼠脂肪性肝炎。脂多糖只在胆固醇喂养的小鼠中引起显著的肝脏炎症损伤，而在没有iNOS的情况下，这种损伤进一步加剧。血糖动态平衡明显受损，包括致命性低血糖和糖原分解抑制。在iNOS(-/-)低氧诱导因子-1(HIF1)组，与对照组相比，信号转导受损。采用流体力学基因转移方法，在iNOS(-/-)小鼠的肝脏中表达HIF1，并显著减轻胆固醇和内毒素诱导的肝损伤。高表达HIF1的WT小鼠注射脂多糖后血糖升高，糖原含量降低。相反，诱导HIF1不能有效阻止内毒素诱导的iNOS(-/-)小鼠的降糖效应。体外实验也证实了NO信号在HIF1途径介导的肝细胞葡萄糖输出中的重要作用。结果还显示，iNOS(-/-)小鼠肝脏中的氧化应激增加，血红素加氧酶-1mRNA减少。此外，在不加iNOS的情况下，血浆和肝组织中肿瘤坏死因子-1(TNF-1)和肝组织中的肿瘤坏死因子-1(TNF-1)的含量显著升高。创新和结论：这些数据强调了iNOS在NASH条件下对内毒素的血糖反应中的重要作用，并证明了iNOS的有益作用。抗氧化剂。氧化还原信号。191889-1901年。
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) (5mg/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. Antioxid. Redox Signal. 19, 1889-1901.