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J. Biol. Chem., Vol. 282, Issue 4, 2529-2537, January 26, 2007

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Novel n-3 Fatty Acid Oxidation Products Activate Nrf2 by Destabilizing the Association between Keap1 and Cullin3^*

Ling Gao¹, Jiakun Wang^¶1, Konjeti R. Sekhar^¶, Huiyong Yin, Nicholas F. Yared^¶, Scott N. Schneider^||, Soumya Sasi^¶, Timothy P. Dalton^||, Mark E. Anderson^**2, Jefferson Y. Chan, Jason D. Morrow³, and Michael L. Freeman^¶4

From the Departments of Medicine and Pharmacology, Division of Clinical Pharmacology, Department of Radiation Oncology, ^¶Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, the ^||Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, the ^**Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, and the Department of Pathology, University of California, Irvine, California 92697

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.

Received for publication, August 10, 2006 , and in revised form, October 23, 2006.

^* This work was supported in part by NCI, National Institutes of Health (NIH) Grants CA38079, CA104590, T32 CA093240, DK26657, ES012463, DK48831, CA77839, GM15431, and ES13125 and by NHLBI, NIH Grants HL070250, HL62494, and HL046681. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental "Experimental Procedures" and Figs. S1 and S2.

¹ Both authors contributed equally to this work.

² An Established Investigator of the American Heart Association.

³ To whom correspondence may be addressed: Division of Clinical Pharmacology, Dept. of Medicine and Pharmacology, Vanderbilt University School of Medicine, 526 RRB, 23rd and Pierce Aves., Nashville, TN 37232. Tel.: 615-322-4785; Fax: 615-322-3669; E-mail: jason.morrow{at}vanderbilt.edu. ⁴ To whom correspondence may be addressed: B902 TVC Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN 37232. Tel.: 615-322-3606; Fax: 615-343-3061; E-mail: michael.freeman{at}vanderbilt.edu.

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