Inhibition of insulin signaling by oxidized low density lipoprotein. Protective effect of the antioxidant Vitamin E.
Oxidative stress is involved in several pathological conditions, including diabetes. Reactive oxygen species (ROS) have been demonstrated to act as second messengers for several hormones and cytokines, including insulin (INS). The effect of Cu(2+)-oxidized LDL (CuLDL) on INS-induced generation of ROS and on INS signaling was investigated on cultured human fibroblasts. Intracellular ROS generation was observed either in CuLDL- or in INS-treated cells. Moreover, CuLDL and INS had an additive effect on ROS formation in human fibroblasts. CuLDL by itself increased the phosphorylation of ERK without affecting the PKB/Akt phosphorylation. CuLDL also stimulated the DNA binding activities of the transcription factors AP1 and NFkappaB. However, CuLDL dose-dependently prevented the INS-signaling pathway, by inhibiting the INS-induced phosphorylation of the signaling kinases ERK and PKB/Akt and the INS-induced activation of the transcription factors AP1 and NFkappaB. Finally, the lipophilic antioxidant Vitamin E (Vit E) partially restored all the studied signaling events initiated by INS and impaired after pretreatment with CuLDL. These studies demonstrate that the oxidative stress generated by CuLDL has a negative effect on the INS-signaling pathway, independently of the INS-induced generation of ROS. Thus, oxidized LDL might be involved not only in atherosclerosis, as it is commonly admitted, but also in the INS-resistance observed in type 2 diabetes mellitus.
Mazière
Cécile
C
Laboratoire de Biochimie EA 2087, CHU Amiens, Université de Picardie Jules Verne, Hôpital Nord, Place Victor Pauchet, 80054 Amiens Cedex 1, France. maziere.cecile@chu-amiens.fr
Morlière
Patrice
P
Santus
René
R
Marcheux
Virginie
V
Louandre
Christophe
C
Conte
Marie-Alix
MA
Mazière
Jean-Claude
JC
D000975:Antioxidants / Q000494:pharmacology*; D002478:Cells, Cultured; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation; D014810:Vitamin E / Q000494:pharmacology*
D000975:Antioxidants; D007328:Insulin; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; C099252:oxidized low density lipoprotein; D014810:Vitamin E; D048049:Extracellular Signal-Regulated MAP Kinases