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- Title
TNF-α Induces IRS-1 Serine Phosphorylation in Liver Cells by a Redox-Sensitive p38MAPK Mediated Cross-Talk with ErbB Receptors.
- Authors
Hemi, Rina; Rachminov, Yafit; Barhurdar, Ehud; Kasher-Meron, Michal; Kanety, Hannah
- Abstract
TNF is a key mediator of insulin resistance in infection, obesity and diabetes. Previously, we demonstrated that TNF-dependent ErbB2/3 transactivation in Fao hepatoma cells mediates IRS-1 serine (Ser) phosphorylation leading to impaired insulin signaling. Here, we further examined the relevance of ErbB receptors transactivation in inflammatory and stress-induced liver insulin resistance and studied the cellular pathways involved in this novel mechanism. Similar to our findings in Fao cells, we demonstrate that TNF-stimulated ErbB1 activation underlines IRS-1 Ser phosphorylation in HepG2 hepatoma cells, supporting the notion that ErbBs signaling pathways are involved in stress-induced insulin resistance. Activation of ErbBs in Fan and HepG2 cells by TNF, but not by their cognate ligands, was suppressed by inhibiting the p38MAPK (p38) pathway, either by pharmacological inhibitors or by infection with a dominant-negative p38 adenovirus. This led to a decrease in IRS-1 Ser phosphorylation on specific residues (307, 612, 632) and improved its ability to undergo insulin-stimulated Tyr phosphorylation. Modulation of ErbBs expression or activity attenuated TNF-dependent IRS-1 phosphorylation, without affecting p38 activation, indicating that under stress conditions p38 activation occurs upstream to ErbBs. The role of p38 in insulin resistance induction was further supported by in vivo experiments. Liver p38 activity was enhanced in C57B1/6 mice fed a HFD, while insulin-induced IRS-1 Tyr phosphorylation was impaired in mice injected with the wild type p38 adenovirus. Recent studies indicate that reactive oxygen species (ROS) may have a causal role in TNF-induced insulin resistance. Indeed, we found that TNF increased ROS production in Fan cells, and exposure of the cells to oxidative stress promoted p38 and ErbB2/3 activation, concomitantly with increased IRS-1 Ser phosphorylation and reduced insulin-dependent IRS-1 Tyr phosphorylation and Akt activation. Various antioxidants like NAC, GSH and DPI attenuated these effects and improved insulin action. Our data identify p38 as a cytokine- and oxidative stress-induced protein kinase responsible for transactivation of ErbB receptors, and strongly suggests that their signaling networks are playing a pivotal role in TNF-induced insulin resistance. This paradigm points to potential sites for therapeutic intervention using either antioxidants or kinase inhibitors to remedy insulin-resistance.
- Publication
Diabetes, 2007, Vol 56, pA334
- ISSN
0012-1797
- Publication type
Academic Journal