J Nutr. , 2021., Mar 11;151(3):513-522. doi: 10.1093/jn/nxaa294.

Time Course and Sex Effects of α-Linolenic Acid-Rich and DHA-Rich Supplements on Human Plasma Oxylipins: A Randomized Double-Blind Crossover Trial.

Gabbs M Zahradka P Taylor CG Aukema HM


Background: Differences in health effects of dietary α-linolenic acid (ALA) and DHA are mediated at least in part by differences in their effects on oxylipins. Objectives: Time course and sex differences of plasma oxylipins in response to ALA- compared with DHA-rich supplements were examined. Methods: Healthy men and women, aged 19-34 y and BMI 18-28 kg/m2, were provided with capsules containing ∼4 g/d of ALA or DHA in a randomized double-blind crossover study with >6-wk wash-in and wash-out phases. Plasma PUFA and oxylipin (primary outcome) concentrations at days 0, 1, 3, 7, 14, and 28 of supplementation were analyzed by GC and HPLC-MS/MS, respectively. Sex differences, supplementation and time effects, and days to plateau were analyzed. Results: ALA supplementation doubled ALA concentrations, but had no effects on ALA oxylipins after 28 d, whereas DHA supplementation tripled both DHA and its oxylipins. Increases in DHA oxylipins were detected as early as day 1, and a plateau was reached by days 5-7 for 11 of 12 individual DHA oxylipins and for total DHA oxylipins. Nine individual DHA oxylipins reached a plateau in females with DHA supplementation, compared with only 4 in males. A similar time course and sex difference pattern occurred with EPA and its oxylipins with DHA supplementation. DHA compared with ALA supplementation also resulted in higher concentrations of 4 individual arachidonic acids, 1 linoleic acid, and 1 dihomo-γ-linolenic acid oxylipin, despite not increasing the concentrations of these fatty acids, further demonstrating that oxylipins do not always reflect their precursor PUFA. Conclusions: DHA compared with a similar dose of ALA has greater effects on both n-3 and n-6 oxylipins in young, healthy adults, with differences in response to DHA supplementation occurring earlier and being greater in females. These findings can help explain differences in dietary effects of ALA and DHA.

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Key Points

The objective of the current study was to systematically examine the time course and sex effects of plasma oxylipins in response to a direct comparison of a similar dose of ALA- and DHA-rich supplements in healthy young men and women. The data provide several examples of oxylipin concentrations that do not reflect precursor PUFAs, and demonstrate differing effects of ALA compared with DHA-rich supplements on the time course of plasma oxylipin changes and on sex differences in their concentrations. In this study with similar amounts of ALA and DHA provided over a 28-d phase, DHA supplementation had much greater effects on the appearance of plasma n–3 oxylipins than ALA supplementation. Although ∼4 g/d of supplemented DHA rapidly increased EPA and DHA oxylipins, a similar dose of ALA had no effects on ALA oxylipins and did not alter EPA or DHA oxylipins in men and women consuming a typical Canadian diet. Supplementation with ALA increased plasma ALA ∼2-fold, but did not increase ALA oxylipins. However, DHA concentrations were already approximately twice as high as ALA at baseline, and supplementation with DHA resulted in ∼3-fold increase of both plasma DHA and DHA oxylipins. These differences in their effects on oxylipins and PUFAs could be due in part to the fact that relative to the background dietary intake, the amount of supplemented PUFA was proportionally much greater for DHA than for ALA; for ALA the background intake was ∼1.5 g/d whereas for DHA it was less than ∼0.1 g/d. This suggests that the amount of ALA in the typical diet is sufficient to saturate ALA oxylipin levels, whereas dietary amounts of DHA are low enough that both DHA and its oxylipins are increased by DHA supplementation. However, it cannot be ruled that out increased turnover of ALA or its oxylipins as a potential explanation for the lack of change in ALA and ALA oxylipins, as has been suggested for DHA by carbon-13 studies of DHA turnover.

EPA and DHA oxylipins reached a plateau in <1 wk of DHA supplementation, although a plateau was not detected for all oxylipins. Nevertheless, it shows that the increase in oxylipins is rapid and largely complete by 1 wk with DHA supplementation. In contrast, with ALA supplementation a plateau was detected for only 2 ALA oxylipins, and no plateau was reached for total ALA oxylipins.

The current study also demonstrated that whereas the effects of n–3 PUFA supplementation over time occur rapidly (within days) for n–3 oxylipins, the effects on n–6 oxylipins are subtler. DHA compared with ALA supplementation resulted in higher concentrations of several individual AA-, LA-, and DGLA derived oxylipins, as well as total LA oxylipins and total n– 6 PUFA–derived oxylipins. In contrast, ALA supplementation did not alter AA-derived oxylipins. The current study therefore demonstrates a greater and more rapid human plasma oxylipin response to DHA compared with ALA supplementation.

In summary, this side-by-side comparison demonstrates that ∼4 g/d DHA compared with ALA has greater effects on increasing plasma n–3 PUFA oxylipins and altering n–6 oxylipins. It also demonstrates that n–3 PUFA supplementation increases n–3 PUFA–derived oxylipins sooner in females, reaching a plateau by 1 wk of supplementation with the doses used in this study. However, effects on n–6 PUFA oxylipins are much subtler, and do not necessarily follow PUFA patterns, confirming that PUFA data alone are insufficient to predict oxylipin changes. These findings can help explain the differing effects of dietary ALA and DHA on health, and indicate that the responses to these PUFAs can be greater for females.