Effect of Paraquat-Induced Oxidative Stress on Insulin Regulation of Insulin-Like Growth Factor-Binding Protein-1 Gene Expression
Effect of Paraquat-Induced Oxidative Stress on Insulin Regulation of Insulin-Like Growth Factor-Binding Protein-1 Gene Expression
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DOI：
10.3164/jcbn.09-97
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发表时间：
2010-03-01
影响因子：
2.4
通讯作者：
Takenaka, Asako
中科院分区：
文献类型：
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作者：
Kimura, Kumi;Katsumata, Yoshihito;Takenaka, Asako
氧化应激被认为在胰岛素抵抗的发展过程中发挥了作用。为了阐明氧化应激在肝脏胰岛素信号转导中的分子作用，我们分析了百草枯(1，1-二甲基-4，4-联吡啶；PQ)来源的氧化应激对胰岛素依赖基因表达和肝脏胰岛素信号通路激活的影响。原代培养的大鼠肝细胞与2 mM PQ孵育6h后，胰岛素对胰岛素样生长因子结合蛋白-1(IGFBP-1)基因表达的抑制作用减弱，但不影响葡萄糖-6-磷酸酶基因的表达。PQ治疗不影响横纹肌肉瘤胰岛素依赖的胰岛素受体、胰岛素受体底物-1和-2、磷脂酰肌醇3-激酶、Akt和Forkhead的磷酸化或激活。相反，PQ治疗削弱了哺乳动物雷帕霉素靶点(MTOR)的胰岛素依赖的磷酸化。这些结果表明，PQ诱导的氧化应激损伤了胰岛素依赖的mTOR激活，这种损伤可能导致了对胰岛素依赖的IGFBP-1表达的抑制。
Oxidative stress is thought to play a role in the development of insulin resistance. In order to elucidate the molecular effect of oxidative stress on liver insulin signaling, we analyzed the effect of paraquat (1,1-dimethy1-4,4-dipyridynium; PQ)-derived oxidative stress on the expression of insulin-dependent genes and activation of liver insulin signaling pathway. Incubation of primary cultured rat hepatocytes with 2 mM PQ for 6 h impaired the suppressive effect of insulin on insulin-like growth factor-binding protein-1 (IGFBP-1) gene expression, but did not influence glucose-6-phosphatase gene expression. Insulin-dependent phosphorylation or activation of insulin receptor, insulin receptor substrate-1 and -2, phosphatidylinositol 3-kinase, Akt and forkhead in rhabdomyosarcoma were not affected by PQ pre-treatment. In contrast, PQ treatment impaired insulin-dependent phosphorylation of mammalian target of rapamycin (mTOR). These results indicate that PQ-induced oxidative stress impairs insulin-dependent mTOR activation and that this impairment probably causes inhibition of insulin-dependent repression of IGFBP-1 expression.