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Impact of Mitochondrial Reactive Oxygen Species and Apoptosis Signal–Regulating Kinase 1 on Insulin Signaling

¹ Department of Metabolic Medicine, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
² Laboratory of Cell Signaling and Core Research for Evolutional Science and Technology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan

Address correspondence and reprint requests to Takeshi Nishikawa, Department of Metabolic Medicine, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan. E-mail: takeshi{at}kaiju.medic.kumamoto-u.ac.jp

Abbreviations: ASK1, apoptosis signal-regulating kinase 1; ASK1-KM, ASK1 dominant-negative mutant; ASK1-WT, ASK1 wild type; DMEM, Dulbecco’s modified Eagle’s medium; IRS, insulin receptor substrate; JNK, c-jun NH₂-terminal kinase; MnSOD, manganese superoxide dismutase; ROS, reactive oxygen species; TNF, tumor necrosis factor; Trx, thioredoxin; UCP, uncoupling protein

Tumor necrosis factor (TNF)- inhibits insulin action; however, the precise mechanisms are unknown. It was reported that TNF- could increase mitochondrial reactive oxygen species (ROS) production, and apoptosis signal–regulating kinase 1 (ASK1) was reported to be required for TNF-–induced apoptosis. Here, we examined roles of mitochondrial ROS and ASK1 in TNF-–induced impaired insulin signaling in cultured human hepatoma (Huh7) cells. Using reduced MitoTracker Red probe, we confirmed that TNF- increased mitochondrial ROS production, which was suppressed by overexpression of either uncoupling protein-1 (UCP)-1 or manganese superoxide dismutase (MnSOD). TNF- 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-, 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-–induced events. In addition, TNF- 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- increases mitochondrial ROS and activates ASK1 in Huh7 cells and that these TNF-–induced phenomena contribute, at least in part, to impaired insulin signaling.

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