title: Novel n-3 fatty acid oxidation products activate Nrf2 by destabilizing the association between Keap1 and Cullin3.
abstract: 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.
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
authors.forename: Jiakun
authors.initials: J
authors.lastname: Wang
authors.forename: Konjeti R
authors.initials: KR
authors.lastname: Sekhar
authors.forename: Huiyong
authors.initials: H
authors.lastname: Yin
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Yared
authors.forename: Scott N
authors.initials: SN
authors.lastname: Schneider
authors.forename: Soumya
authors.initials: S
authors.lastname: Sasi
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Dalton
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.forename: Jefferson Y
authors.initials: JY
authors.lastname: Chan
authors.forename: Jason D
authors.initials: JD
authors.lastname: Morrow
authors.forename: Michael L
authors.initials: ML
authors.lastname: Freeman
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D044842:Cullin Proteins / Q000737:chemistry / Q000378:metabolism*; D015525:Fatty Acids, Omega-3 / Q000737:chemistry / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D015394:Molecular Structure; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics; D015533:Transcriptional Activation
chemical_list: C503645:CUL3 protein, human; D018797:Cell Cycle Proteins; D044842:Cullin Proteins; D015525:Fatty Acids, Omega-3; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2