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The intake of long-chain n3-polyunsaturated fatty acids (PUFA), which are associated with beneficial health effects, is low in the Western diet, while the portion of dietary n6-PUFA and hence the n6/n3-PUFA ratio is high. Strategies to improve the n3-PUFA status are n3-PUFA supplementation and/or lowering n6-PUFA intake. In the present study, mice were fed with two different sunflower oil-based control diets rich in linoleic (n6-high) or oleic acid (n6-low), either with low n3-PUFA content (∼0.02%) as control or with ∼0.6% eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA). The n6-low diet had only little or no effect on levels of arachidonic acid (ARA) and its free oxylipins in liver tissue. Supplementation with EPA or DHA lowered ARA levels with an effect size of n6-high < n6-low. Blood cell %EPA + DHA reached >8% and >11% in n6-high and n6-low groups, respectively. Elevation of EPA levels and EPA derived oxylipins was most pronounced in n6-low groups in liver tissue, while levels of DHA and DHA derived oxylipins were generally unaffected by the background diet. While the n6-low diet alone had no effect on blood and liver tissue ARA levels or n3-PUFA status, a supplementation of EPA or DHA was more effective in combination with an n6-low diet. Thus, supplementation of long-chain n3-PUFA combined with a reduction of dietary n6-PUFA is the most effective way to improve the endogenous n3-PUFA status.

Background: The health effects of long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) are partly mediated by their oxidized metabolites, i.e., eicosanoids and other oxylipins. Some intervention studies have demonstrated that eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) increase systemic concentrations of n-3 PUFA-derived oxylipins and moderately decrease arachidonic acid-derived oxylipins. There is no information on the dose-response of oxylipin concentrations after n-3 PUFA intake., Objective: The aim of this study was to quantify oxylipins in human plasma samples from an intervention study in which participants were randomly assigned to different daily intakes of EPA and DHA for 12 mo., Methods: Healthy adult men and women with low habitual fish consumption (n = 121) were randomly assigned to receive capsules providing doses of n-3 PUFAs reflecting 3 patterns of consumption of oily fish [1, 2, or 4 portions/wk with 3.27 g EPA + DHA (1:1.2, wt:wt) per portion] or placebo. Oxylipins were quantified in plasma after 3 and 12 mo. Relative and absolute changes of individual oxylipins were calculated and concentrations were correlated with the dose and the content of EPA and DHA in blood lipid pools., Results: Seventy-three oxylipins, mostly hydroxy-, dihydroxy-, and epoxy-PUFAs, were quantified in the plasma samples. After 3 and 12 mo a linear increase with dose was observed for all EPA- and DHA-derived oxylipins. Cytochrome-P450-derived anti-inflammatory and cardioprotective epoxy-PUFAs increased linearly with n-3 PUFA dose and showed low interindividual variance (r2 > 0.95). Similarly, 5, 12-, and 15-lipoxygenase-derived hydroxy-PUFAs as well as those formed autoxidatively increased linearly. These include the precursors of so-called specialized pro-resolving lipid mediators (SPMs), e.g., 17-hydroxy-DHA and 18-hydroxy-EPA., Conclusions: Plasma concentrations of biologically active oxylipins derived from n-3 PUFAs, including epoxy-PUFAs and SPM-precursors, increase linearly with elevated intake of EPA and DHA. Interindividual differences in resulting plasma concentrations are low. This trial was registered at controlled-trials.com as ISRCTN48398526., (Copyright © American Society for Nutrition 2019.)