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

Ling Gao, Jiakun Wang, Konjeti R. Sekhar, Huiyong Yin, Nicholas F. Yared, Scott N. Schneider, Soumya Sasi, Timothy P. Dalton, Mark E. Anderson, Jefferson Y. Chan, Jason D. Morrow, Michael L. Freeman

Research output: Contribution to journalArticle

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 DHAwere 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.

Original languageEnglish (US)
Pages (from-to)2529-2537
Number of pages9
JournalJournal of Biological Chemistry
Volume282
Issue number4
DOIs
StatePublished - Jan 26 2007
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Gao, L., Wang, J., Sekhar, K. R., Yin, H., Yared, N. F., Schneider, S. N., Sasi, S., Dalton, T. P., Anderson, M. E., Chan, J. Y., Morrow, J. D., & Freeman, M. L. (2007). Novel n-3 fatty acid oxidation products activate Nrf2 by destabilizing the association between Keap1 and Cullin3. Journal of Biological Chemistry, 282(4), 2529-2537. https://doi.org/10.1074/jbc.M607622200