17-Oxo-Docosahexaenoic acid induces Nrf2-mediated expression of heme oxygenase-1 and NAD(P)H:quinone oxidoreductase in mouse skin

Abstract

Dietary omega-3 polyunsaturated fatty acids (PUFAs) have been shown to have therapeutic and preventive potential in the management of oxidative stress- and inflammation-associated ailments, such as diabetes mellitus, neurodegenerative disorders and various types of cancers. Docosahexaenoic acid (DHA), a representative omega-3 PUFA, is capable of activating multiple anti-oxidant and cytoprotective signaling pathways. Nrf2 plays a key role in cellular stress responses. In the present study, the effects of DHA on Nrf2-mediated expression of anti-oxidative enzymes were examined in mouse skin. Topical application of DHA significantly activated Nrf2 and upregulated expression of its target proteins, namely heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase (NQO-1). According to the recent studies, DHA undergoes metabolism to produce electrophilic oxo-derivatives that modulate several cellular redox signaling pathways more efficiently than the parent compound. One such metabolite is 17-oxo-DHA. Topical application of 17-oxo-DHA markedly elevated the expression of Nrf2-mediated expression of HO-1 and NQO-1 in hairless mouse skin apparently by stimulating the degradation of cytosolic Keap1, a negative regulator of Nrf2. Notably, 17-oxo-DHA even at a lower dose (20 nmol), robustly upregulated the expression of aforementioned cytoprotective proteins as compared to DHA (10 µmol). In contrast to 17-oxo-DHA, 17-Hydroxy-DHA lacking the α,β-unsaturated carbonyl moiety was a much weaker inducer of Nrf2 activation and its target protein expression.