Background It has long been believed that DHA supplementation increases plasma EPA via the retroconversion pathway in mammals. However, in rodents this increase in EPA is likely due to a slower metabolism of EPA, but this has never been tested directly in humans. Objective The aim of this study was to use the natural variations in 13C:12C ratio (carbon-13 isotopic abundance [δ13C]) of n–3 PUFA supplements to assess n–3 PUFA metabolism following DHA or EPA supplementation in humans. Methods Participants (aged 21.6 ± 2.2 y) were randomly assigned into 1 of 3 supplement groups for 12 wk: 1) olive oil control, 2) ∼3 g/d DHA, or 3) ∼3 g/d EPA. Blood was collected before and after the supplementation period, and concentrations and δ13C of plasma n–3 PUFA were determined. Results DHA supplementation increased (P < 0.05) plasma EPA concentrations by 130% but did not affect plasma δ13C-EPA (−31.0 ± 0.30 to −30.8 ± 0.19, milliUrey ± SEM, P > 0.05). In addition, EPA supplementation did not change plasma DHA concentrations (P > 0.05) but did increase plasma δ13C-DHA (−27.9 ± 0.2 to −25.6 ± 0.1, P < 0.05) toward δ13C-EPA of the supplement (−23.5 ± 0.22). EPA supplementation increased plasma concentrations of EPA and docosapentaenoic acid (DPAn–3) by 880% and 200%, respectively, and increased plasma δ13C-EPA (−31.5 ± 0.2 to −25.7 ± 0.2) and δ13C-DPAn–3 (−28.9 ± 0.3 to −25.0 ± 0.1) toward δ13C-EPA of the supplement. Conclusions In this study, we show that the increase in plasma EPA following DHA supplementation in humans does not occur via retroconversion, but instead from a slowed metabolism and/or accumulation of plasma EPA. Furthermore, substantial amounts of supplemental EPA can be converted into DHA. δ13C of n–3 PUFA in humans is a powerful and underutilized tool that can track dietary n–3 PUFA and elucidate complex metabolic questions. This trial was registered at clinicaltrials.gov as NCT03378232.

Background Comparative studies suggest that DHA may have stronger serum triglyceride–lowering effects than EPA; however, the molecular basis for this differential effect remains unexplored in humans. Differential regulation of lipogenesis and triglyceride clearance are 2 possible mechanisms of action. Objectives We compared the effects of EPA and DHA supplementation on serum triglycerides, markers of lipogenesis, and lipoprotein lipase (LPL) activity in adults participating in a double-blind, multiarm, placebo-controlled parallel-group randomized trial. Lipogenesis was assessed with the lipogenic index and compound specific isotope analysis (CSIA). Methods Young, healthy normolipidemic men and women (n = 89; 21.6 ± 0.23 y; mean ± SEM) were randomly allocated into 1 of 3 supplement groups for 12 wk: 1) olive oil, 2) ∼3 g EPA/d, and 3) ∼3 g DHA/d. Omega-3 supplements were provided in triglyceride form. Blood was collected before and after supplementation for the analysis of fatty acids and preheparin LPL activity. Variations in the 13C:12C ratio (δ13C) of palmitate (16:0) and linoleate (18:2n–6) were measured by CSIA. Results DHA supplementation reduced blood triglycerides (0.85 ± 0.04 mmol/L to 0.65 ± 0.03 mmol/L; P < 0.01), with no change seen with EPA supplementation. DHA supplementation did not change the lipogenic index or δ13C-16:0, whereas EPA supplementation increased the lipogenic index by 11% (P < 0.01) and δ13C-16:0 (P = 0.03) from −23.2 ± 0.2 to −22.8 ± 0.2 milliUrey ± SEM. Conclusions Reduced triglyceride concentrations after DHA supplementation are associated with increased LPL activity, whereas the null effect of EPA supplementation on blood triglycerides may stem from the concomitant increases in lipogenesis and LPL activity. Further investigation of the differential triglyceride-lowering effects of EPA and DHA is warranted in both normolipidemic and hyperlipidemic individuals. This trial was registered at clinicaltrials.gov as NCT03378232.

Background Eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) recommendations are frequently stated at 500 mg/d; however, adherence to these recommendations would result in a large global commercial EPA/DHA production deficit. Previously, our laboratory demonstrated that acute DHA intake in rats can increase the capacity for synthesis-secretion of n–3 (ω-3) polyunsaturated fatty acids (PUFAs). Objective We aimed to investigate the utility of a dietary DHA cycling strategy that employs 2 wk of repeated DHA feeding for a total of 3 cycles over 12 wk. Methods Male Long–Evans rats were fed a 10% fat diet by weight comprised of either 1) a 2-wk, 2% α-linolenic acid (ALA, DHA-ALA group 18:3n–3) diet followed by a 2-wk, 2% DHA + 2% ALA diet over 3 consecutive 4-wk periods (“DHA cycling,” DHA-ALA group); 2) a 2% DHA + 2% ALA diet (DHA group) for 12 wk; or 3) a 2% ALA-only diet (ALA group) for 12 wk. At 15 wk old, blood and tissue fatty acid concentrations and liver mRNA expression and 13C-DHA natural abundances were determined. Results DHA concentrations in plasma, erythrocytes, and whole blood between the DHA-ALA group and the DHA groups were not different (P ≥ 0.05), but were 72–110% higher (P < 0.05) than in the ALA group. Similarly, DHA concentrations in liver, heart, adipose, and brain were not different (P ≥ 0.05) between the DHA-fed groups, but were at least 62%, 72%, 320%, and 68% higher (P < 0.05) than in the ALA group in liver, heart, adipose, and skeletal muscle, respectively. Compound-specific isotope analysis indicated that 310% more liver DHA in the DHA-ALA group compared with the DHA group is derived from dietary ALA, and this was accompanied by a 123% and 93% higher expression of elongation of very long-chain (Elovl)2 and Elovl5, respectively, in the DHA-ALA group compared with the ALA group. Conclusions DHA cycling requires half the dietary DHA while achieving equal blood and tissue DHA concentrations in rats. Implementation of such dietary strategies in humans could reduce the gap between global dietary n–3 PUFA recommendations and commercial production.

Young adult females have higher blood docosahexaenoic acid (DHA), 22:6n‐3 levels than males, and this is believed to be due to higher DHA synthesis rates, although DHA may also accumulate due to a longer half‐life or a combination of both. However, sex differences in blood fatty acid responses to eicosapentaenoic acid (EPA), 20:5n‐3 or DHA supplementation have not been fully investigated. In this exploratory analysis, females and males (n = 14–15 per group) were supplemented with 3 g/day EPA, 3 g/day DHA, or olive oil control for 12 weeks. Plasma was analyzed for sex effects at baseline and changes following 12 weeks' supplementation for fatty acid levels and carbon‐13 signature (δ13C). Following EPA supplementation, the increase in plasma DHA in females (+23.8 ± 11.8, nmol/mL ± SEM) was higher than males (−13.8 ± 9.2, p < 0.01). The increase in plasma δ13C‐DHA of females (+2.79 ± 0.31, milliUrey (mUr ± SEM) compared with males (+1.88 ± 0.44) did not reach statistical significance (p = 0.10). The sex effect appears driven largely by increased plasma DHA in the AA genotype of females (+58.8 ± 11.5, nmol/mL ± SEM, n = 5) compared to GA + GG in females (+4.34 ± 13.5, n = 9) and AA in males (−29.1 ± 17.2, n = 6) for rs953413 in the ELOVL2 gene (p < 0.001). In conclusion, EPA supplementation increases plasma DHA levels in females compared to males, which may be dependent on the AA genotype for rs953413 in ELOVL2.

Fish oil feeding, and to a lesser extent the fat-1 transgene, enhances the astrocyte activation phenotype in response to amyloid-β 1-40. Astrocytes in mice fed fish oil were more activated in response to amyloid-β than in fat-1 mice despite similar levels of hippocampal n-3 PUFA, which suggests that other fatty acids or dietary factors contribute to this effect.