Activation of the antioxidant response element by specific oxidized metabolites of linoleic acid

Wang, Rui; Kern, Jonathan T.; Goodfriend, Theodore L.; Ball, Dennis L.; Luesch, Hendrik

doi:10.1016/j.plefa.2009.04.008

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Volume 81, Issue 1 , Pages 53-59, July 2009

Activation of the antioxidant response element by specific oxidized metabolites of linoleic acid

Rui Wang
- Department of Medicinal Chemistry, University of Florida, 1600 SW Archer Road, Gainesville, FL, USA
Jonathan T. Kern
- Molecular and Environmental Toxicology, School of Pharmacy, University of Wisconsin, Madison, WI, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin, Madison, WI, USA
Theodore L. Goodfriend
- William S. Middleton Memorial Veterans Hospital, and Departments of Medicine and Pharmacology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
Dennis L. Ball
- William S. Middleton Memorial Veterans Hospital, and Departments of Medicine and Pharmacology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
Hendrik Luesch
- Department of Medicinal Chemistry, University of Florida, 1600 SW Archer Road, Gainesville, FL, USA
- Corresponding author. Tel.: +13522737738; fax: +13522737741.

Received 19 September 2008; received in revised form 24 April 2009; accepted 27 April 2009. published online 25 August 2009.

Abstract

Linoleic acid is required for normal mammalian health and development, but is also prone to oxidation, yielding metabolites with biological effects. We screened linoleic acid, other fatty acids, and some of their derivatives and found that an epoxy-keto derivative of linoleic acid (but neither linoleic acid itself nor others of its oxidation products) strongly activates the antioxidant response element (ARE) in IMR-32 neuroblastoma cells and cerebro-cortical neurons. The active compound, 12,13-epoxy-9-keto-10(trans)-octadecenoic acid (EKODE), induces the expression of ARE-regulated cytoprotective genes such as NQO1 at the transcript and protein levels. EKODE requires transcription factor NRF2 and PI3-kinase for ARE activity. The results suggest that specific oxidation products of linoleic acid may initiate responses that lessen damage caused by oxidative stress.

Keywords: Polyunsaturated fatty acids, Fatty acid oxidation, Fatty acid epoxides, EKODE, Antioxidants, Antioxidant response element