Referenced in: none

Automatically associated channels: SK1

Title: Impact of mitochondrial reactive oxygen species and apoptosis signal-regulating kinase 1 on insulin signaling.

Authors: Koujiro Imoto, Daisuke Kukidome, Takeshi Nishikawa, Takako Matsuhisa, Kazuhiro Sonoda, Kazuo Fujisawa, Miyuki Yano, Hiroyuki Motoshima, Tetsuya Taguchi, Kaku Tsuruzoe, Takeshi Matsumura, Hidenori Ichijo, Eiichi Araki

Journal, date & volume: Diabetes, 2006 May , 55, 1197-204

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/16644673

Abstract
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-alpha, 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-alpha-induced events. In addition, TNF-alpha activated c-jun NH(2)-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.