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FALDH REVERSES THE DELETERIOUS ACTION OF OXIDATIVE STRESS INDUCED BY THE LIPID PEROXIDATION PRODUCT, HNE, ON INSULIN SIGNALING IN 3T3-L1 ADIPOCYTES.

¹Institut National de la Santé et de la Recherche Médicale (INSERM) U145, IFR 50, Faculté de Médecine, Université de Nice Sophia-Antipolis, 28 Avenue de Valombrose, 06107 Nice Cedex 2, France

Objective: Oxidative stress is associated with insulin resistance and is thought to contribute to progression towards type 2 diabetes. Oxidation induces cellular damages through increased amounts of reactive aldehydes from lipid peroxidation. The aim of our study was to investigate (i) the effect of the major lipid peroxidation end-product, 4-hydroxynonenal (HNE), on insulin signaling in 3T3-L1 adipocytes, and (ii) whether Fatty Aldehyde Dehydrogenase (FALDH), which detoxifies HNE, protects cells and improves insulin action under oxidative stress conditions.

Research Design and Methods: 3T3-L1 adipocytes were exposed to HNE and/or infected with control adenovirus or adenovirus expressing FALDH.

Results: Treatment of 3T3-L1 adipocytes with HNE at nontoxic concentrations leads to a pronounced decrease in IRS-1/-2 proteins and in insulin-induced IRS and IRβ tyrosine-phosphorylation. Remarkably, we detect increased binding of HNE to IRS-1/-2 generating HNE-IRS adducts, which likely impair IRS function and favor their degradation. PI3-kinase and PKB activities are also downregulated upon HNE treatment resulting in blunted metabolic responses. Moreover, FALDH, by reducing adduct formation, partially restores HNE-generated decrease in insulin-induced IRS-1 tyrosine-phosphorylation and metabolic responses. Moreover, rosiglitazone could have an antioxidant effect as it blocks the noxious HNE action on IRS-1 by increasing FALDH gene expression. Collectively, our data show that FALDH improves insulin action in HNE-treated 3T3-L1 adipocytes.

Conclusion: Oxidative stress induced by reactive aldehydes, such as HNE, is implicated in the development of insulin resistance in 3T3-L1 adipocytes, which is alleviated by FALDH. Hence, detoxifying enzymes could play a crucial role in blocking progression of insulin resistance to diabetes.

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