Novel n-3 fatty acid oxidation products activate Nrf2 by destabilizing the association between Keap1 and Cullin3.
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.
Gao
Ling
L
Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Wang
Jiakun
J
Sekhar
Konjeti R
KR
Yin
Huiyong
H
Yared
Nicholas F
NF
Schneider
Scott N
SN
Sasi
Soumya
S
Dalton
Timothy P
TP
Anderson
Mark E
ME
Chan
Jefferson Y
JY
Morrow
Jason D
JD
Freeman
Michael L
ML
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
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