Novel n-3 fatty acid oxidation products activate Nrf2 by destabilizing the association between Keap1 and Cullin3.

Gao L, Wang J, Sekhar KR, Yin H, Yared NF, Schneider SN, Sasi S, Dalton TP, Anderson ME, Chan JY, Morrow JD, Freeman ML
J Biol Chem. 2007 282 (4): 2529-37

PMID: 17127771 · DOI:10.1074/jbc.M607622200

Consumption of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can mitigate the progression of diseases in which oxidative stress represents a common underlying biochemical process. Nrf2-regulated gene expression regulates detoxification of reactive oxygen species. EPA and DHA were subjected to an in vitro free radical oxidation process that models in vivo conditions. Oxidized n-3 fatty acids reacted directly with the negative regulator of Nrf2, Keap1, initiating Keap1 dissociation with Cullin3, thereby inducing Nrf2-directed gene expression. Liquid chromatography-tandem mass spectrometry analyses of oxidized EPA demonstrated the presence of novel cyclopentenone-containing molecules termed J3-isoprostanes in vitro and in vivo and were shown to induce Nrf2-directed gene expression. These experiments provide a biochemical basis for the hypothesis that formation of J-ring compounds generated from oxidation of EPA and DHA in vivo can reach concentrations high enough to induce Nrf2-based cellular defense systems.

MeSH Terms (16)

Animals Cell Cycle Proteins Cell Line Cullin Proteins Fatty Acids, Omega-3 Gene Expression Regulation Genes, Reporter Humans Intracellular Signaling Peptides and Proteins Kelch-Like ECH-Associated Protein 1 Mice Molecular Structure NF-E2-Related Factor 2 Oxidation-Reduction Oxidative Stress Transcriptional Activation

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