Iron depletion by deferoxamine up-regulates glucose uptake and insulin signaling in hepatoma cells and in rat liver
Iron depletion by deferoxamine up-regulates glucose uptake and insulin signaling in hepatoma cells and in rat liver
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DOI：
10.2353/ajpath.2008.070097
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发表时间：
2008-03-01
影响因子：
6
通讯作者：
Fargion, Silvia
中科院分区：
文献类型：
--
作者：
Dongiovanni, Paola;Valenti, Luca;Fargion, Silvia
铁耗尽改善非酒精性脂肪性肝病和糖尿病患者的胰岛素抵抗，并稳定缺氧诱导因子(HIF)-1，导致体外葡萄糖摄取增加。本研究探讨了去铁胺对HepG2肝细胞和大鼠肝脏胰岛素信号传导和葡萄糖摄取的影响。在HepG2细胞中，去铁胺稳定11117-1 α并诱导葡萄糖转运蛋白Glut1和胰岛素受体。去铁胺对胰岛素受体的上调作用可被囊泡内铁螯合剂去铁铁和缺氧诱导剂CoCl模拟，并且需要HIF-1的专性伴侣ARNT/HIF-1 β。缺铁会增加胰岛素受体的活性，而补充铁则会产生相反的效果。去铁胺持续增加磷酸化。Akt/PKB及其靶点fox01和Gsk3 β的状态。这些基因介导胰岛素对糖异生和糖原合成的影响，并上调参与葡萄糖摄取和利用的基因。铁缺失使sd大鼠11117-1 α表达增加，葡萄糖清除率提高，并与胰岛素受体和Akt/PKB水平上调以及肝组织葡萄糖转运相关。相反，糖异生基因不受影响。在高热量和高脂肪饮食导致脂肪肝的大鼠中，缺铁增加了葡萄糖清除率，补铁降低了葡萄糖清除率。因此，去铁胺导致的铁消耗上调了葡萄糖摄取，并增加了肝细胞中的胰岛素受体活性和信号传导；在体外和体内。
Iron depletion improves insulin resistance in patients with nonalcoholic fatty liver disease and diabetes and also stabilizes the hypoxia-inducible factor (HIF)-1 resulting in increased glucose uptake in vitro. This study investigated the effect of iron depletion by deferoxamine on insulin signaling and glucose uptake in HepG2 hepatocytes and in rat liver. In HepG2 cells, deferoxamine stabilized 11117-1 alpha and induced the constitutive glucose transporter Glut1 and the insulin receptor. Up-regulation of insulin receptor by deferoxamine was mimicked by the intraceffular iron chelator deferasirox and the hypoxia inducer CoCl, and required the HIF-1 obligate partner ARNT/HIF-1 beta. iron depletion increased insulin receptor activity, whereas iron supplementation had the opposite effect. Deferoxamine consistently increased the phosphorylation. status of Akt/PKB and its targets FoxO1 and Gsk3 beta., which mediate the effect of insulin on gluconeogenesis and glycogen synthesis, and up-regulated genes involved in glucose uptake and utilization. iron depletion of Sprague-Dawley rats increased 11117-1 alpha expression, improved glucose clearance, and was associated with up-regulation of insulin receptor and Akt/PKB levels and of glucose transport in hepatic tissue. Conversely, gluconeogenic genes were not affected. in rats with fatty liver because of a high-calorie and high-fat diet, glucose clearance was increased by iron depletion and decreased by iron supplementation. Thus, iron depletion by deferoxamine up-regulates glucose uptake, and increases insulin receptor activity and signaling in hepatocytes; in vitro and in vivo.