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

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.