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Title:   Author  item
                                            SHEARER, GREGORY - STANFORD RES./USD, NUTR.item
                                            HARRIS, WILLIAM - STANFORD RES./USD, NUTR.item
                                            Pedersen, Theresaitem
                                            Newman, John
  Submitted to: Journal of Lipid Research
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 8/11/2009
                                    Publication  Date: 8/10/2010
                                    Citation: Shearer, G.C., Harris, W.S., Pedersen, T.L., Newman, J.W. 2010. DETECTION OF OMEGA-3 OXYLIPINS IN HUMAN PLASMA AND RESPONSE TO TREATMENT WITH OMEGA-3 ACID ETHYL ESTERS. Journal of Lipid Research. 51(8):2074-81.Interpretive Summary: Diets rich in long chain omega-3 fatty acids (n-3 FAs), eicosapentaenoic (EPA), and docosahexaenoic (DHA) acids have beneficial health effects, but the molecular mediators of these effects are not well-characterized. The addition of oxygen molecules to these and other unsaturated fatty acids produce a class of potent signaling molecules called oxylipins, which include epoxides, alcohols, diols, and ketones. The oxylipins derived from n-3 FAs may underlie some of the health effects of n-3 FA enriched diets, but are poorly studied to date. In fact, neither the presence of n-3 oxylipins in human plasma nor the effect of n-3 FA ingestion on their levels has been well documented. In this study, we measured plasma oxylipins derived from both the n-3 and n-6 FA classes, in healthy volunteers (n=10) before and after 4 weeks of treatment with a very pure form of n-3 FA ethyl esters (4 g/day). At baseline, EPA and DHA oxylipins were detected in low (1-50) nM range, with alcohols > epoxides and greater or equal to diols. Treatment increased n-3 oxylipin levels 2- to 5-fold and reduced selected n-6 oxylipins by ~20%. This is the first documentation that endogenous n-3 oxylipins levels can be modulated by n-3 FA treatment in humans.  The extent to which the beneficial cardiovascular effects of n-3 FAs are mediated by increased n-3 or reduced n-6 oxylipin levels remains to be explored. Moreover, this study highlights the fact that if a mechanistic understanding of dietary interventions is sought, a broad view of metabolic changes should be considered when nutritional interventions change the balance of multiple metabolic products.
                                Technical Abstract: The long chain omega-3 fatty acids (n-3 FAs), eicosapentaenoic (EPA), and docosahexaenoic (DHA) acids have beneficial health effects, but the molecular mediators of these effects are not well-characterized. Oxygenated n-3 FAs (oxylipins) may be an important class of mediators. Members of this chemical class include epoxides, alcohols, diols, and ketones many of which have bioactivity in vitro. Neither the presence of n-3 oxylipins in human plasma nor the effect of n-3 FA ingestion on their levels has been documented. We measured plasma oxylipins derived from both the n-3 and n-6 FA classes, in healthy volunteers (n=10) before and after 4 weeks of treatment with prescription n-3 FA ethyl esters (4 g/day). At baseline, EPA and DHA oxylipins were detected in low (1-50) nM range, with alcohols > epoxides and greater or equal to diols. Treatment increased n-3 oxylipin levels 2- to 5-fold and reduced selected n-6 oxylipins by ~20%. This is the first documentation that endogenous n-3 oxylipins metabolite levels can be modulated by n-3 FA treatment in humans. The extent to which the beneficial cardiovascular effects of n-3 FAs are mediated by increased n-3 or reduced n-6 oxylipin levels remains to be explored.


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