Impact of mitochondrial reactive oxygen species and apoptosis signal-regulating kinase 1 on insulin signaling
Impact of mitochondrial reactive oxygen species and apoptosis signal-regulating kinase 1 on insulin signaling
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DOI：
10.2337/db05-1187
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发表时间：
2006-05-01
期刊：
影响因子：
7.7
通讯作者：
Araki, E
中科院分区：
文献类型：
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作者：
Imoto, K;Kukidome, D;Araki, E
肿瘤坏死因子(TNF) α抑制胰岛素作用；然而，确切的机制尚不清楚。据报道，tnf - α可以增加线粒体活性氧（ROS）的产生，凋亡信号调节激酶1（凋亡信号调节激酶1，ASK1）被报道为tnf - α诱导的细胞凋亡所必需。在这里，我们研究了线粒体ROS和ASK1在培养的人肝癌（Huh7）细胞中tnf α诱导的胰岛素信号通路受损中的作用。使用减少的MitoTracker Red探针，我们证实tnf - α增加了线粒体ROS的产生，这被解偶联蛋白-1 (UCP)-1或锰超氧化物歧化酶（MnSOD）的过表达所抑制。tnf - α显著激活ASK1，增加胰岛素受体底物(IRS)-1的丝氨酸磷酸化，降低胰岛素刺激的IRS-1的酪氨酸磷酸化和Akt的丝氨酸磷酸化，所有这些作用都被UCP-1或MnSOD过表达抑制。与TNF-a类似，野生型ASK1的过表达增加了IRS-1的丝氨酸磷酸化，降低了胰岛素刺激的酪氨酸磷酸化。而过表达显性阴性ASK1可改善这些tnf -a诱导的事件。此外，tnf - α激活了c-jun nh2末端激酶（JNKs），这一观察结果被UCP-1、MnSOD或显性阴性ASK1的过表达部分抑制。这些结果表明，tnf - α增加线粒体ROS并激活Huh7细胞中的ASK1，这些tnf - α诱导的现象至少在一定程度上导致胰岛素信号传导受损。
Tumor necrosis factor (TNF)-alpha inhibits insulin action; however, the precise mechanisms are unknown. It was reported that TNF-alpha could increase mitochondrial reactive oxygen species (ROS) production, and apoptosis signal-regulating kinase 1 (ASK1) was reported to be required for TNF-alpha-induced apoptosis. Here, we examined roles of mitochondrial ROS and ASK1 in TNF-alpha-induced impaired insulin signaling in cultured human hepatoma (Huh7) cells. Using reduced MitoTracker Red probe, we confirmed that TNF-alpha: increased mitochondrial ROS production, which was suppressed by overexpression of either uncoupling protein-1 (UCP)-1 or manganese superoxide dismutase (MnSOD). TNF-alpha significantly activated ASK1, increased serine phosphorylation of insulin receptor substrate (IRS)-1, and decreased insulin-stimulated tyrosine phosphorylation of IRS-1 and serine phosphorylation of Akt, and all of these effects were inhibited by overexpression of either UCP-1 or MnSOD. Similar to TNF-a, overexpression of wild-type ASK1 increased serine phosphorylation of IRS-1 and decreased insulin-stimulated tyrosine phosphorylation. of IRS-1, whereas overexpression of dominant-negative ASK1 ameliorated these TNF-a-induced events. In addition, TNF-alpha activated c-jun NH2-terminal kinases (JNKs), and this observation was partially inhibited by overexpression of UCP-1, MnSOD, or dominant-negative ASK1. These results suggest that TNF-alpha increases mitochondrial ROS and activates ASK1 in Huh7 cells and that these TNF-alpha-induced phenomena contribute, at least in part, to impaired insulin signaling.