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- Title
Impact of Mitochondrial Reactive Oxygen Species and Apoptosis Signal-Regulating Kinase 1 on Insulin Signaling.
- Authors
Imoto, Koujiro; Kukidome, Daisuke; Nishikawa, Takeshi; Matsuhisa, Takako; Sonoda, Kazuhiro; Fujisawa, Kazuo; Yano, Miyuki; Motoshima, Hiroyuki; Taguchi, Tetsuya; Tsuruzoe, Kaku; Matsumura, Takeshi; Ichijo, Hidenori; Araki, Eiichi
- Abstract
Tumor necrosis factor (TNF)-α inhibits insulin action; however, the precise mechanisms are unknown. It was reported that TNF-α could increase mitochondrial reactive oxygen species (ROS) production, and apoptosis signal-regulating kinase 1 (ASK1) was reported to be required for TNF-α-induced apoptosis. Here, we examined roles of mitochondrial ROS and ASK1 in TNF-α-induced impaired insulin signaling in cultured human hepatoma (Huh7) cells. Using reduced MitoTracker Red probe, we confirmed that TNF-α increased mitochondrial ROS production, which was suppressed by overexpression of either uncoupling protein-1 (UCP)-1 or manganese superoxide dismutase (MnSOD). TNF-α 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-α, 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-α-induced events. In addition, TNF-α 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-α increases mitochondrial ROS and activates ASK1 in Huh7 cells and that these TNF-α-induced phenomena contribute, at least in part, to impaired insulin signaling. Diabetes 55:1197-1204, 2006
- Subjects
TUMOR necrosis factors; INSULIN receptors; REACTIVE oxygen species; APOPTOSIS; PHOSPHORYLATION; TYROSINE
- Publication
Diabetes, 2006, Vol 55, Issue 5, p1197
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db05-1187