EPA and DHA have divergent effects on serum triglycerides and lipogenesis, but similar effects on lipoprotein lipase activity: a randomized controlled trial

Abstract

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.

Higher Increase in Plasma DHA in Females Compared to Males Following EPA Supplementation May Be Influenced by a Polymorphism in ELOVL2: An Exploratory Study

“…Fatty acid synthase expression itself is similarly upregulated in aromatase‐KO mice that cannot synthesize estrogen (Hewitt et al, 2004) and further highlights the transcriptional role for estrogen and lipogenesis. Although we previously demonstrated that EPA supplementation for 12 weeks increases de novo lipogenesis (Klingel et al, 2019), there were no sex effects of EPA supplementation on the change in δ 13 C of any SFA or MUFA measured, but DHA supplementation did result in a larger decrease in the percentage of plasma 18:1n‐9 in males. Conversely, lower consumption of added sugars by females could also explain the lower δ 13 C‐16:0, 16:1n‐7, and 18:0 in females; however, diet records were not collected.…”

“…Despite generally higher levels of plasma 16:0, 18:0, and 18:1n‐9 in females at baseline, we found lower δ 13 C of 16:0, 16:1n‐7, and 18:0 in females compared with males. Variations in δ 13 C‐16:0 has been used as a marker for de novo lipogenesis (Klingel et al, 2019), and a higher δ 13 C content—likely derived from added sugars—suggests that de novo lipogenesis is a larger contributor to plasma 16:0 levels in males compared with females. Higher de novo lipogenesis has been reported in males compared with females (Pramfalk et al, 2015; Tran et al, 2010), and estrogen is thought to play a role in attenuating de novo lipogenesis in rodents (Diamant et al, 1975; Hewitt et al, 2004; Paquette et al, 2008).…”

“…Our study has limitations. In particular, this is an exploratory analysis of a randomized control trial in which the primary endpoint was the effect of 12 weeks of EPA or DHA supplementation on the omega‐3 index (Klingel et al, 2019). As a result, group sizes were relatively small for the genotype analysis, resulting in a higher risk of false positives or negatives, and as an exploratory analysis, we did not perform multiple comparison corrections that may again increase the likelihood of false discoveries.…”

“…Healthy individuals aged 18–30 years old were recruited from the University of Guelph (Guelph, Ontario, Canada) and provided written, informed consent. Exclusion criteria, block randomization, and protocols for double blinding have been reported previously (Klingel et al, 2019; Metherel et al, 2019a). The study was registered on http://clinicaltrials.gov (NCT03378232) with the primary outcome of omega‐3 index (proportion of EPA and DHA in erythrocytes) and secondary outcomes of heart rate, blood pressure, and muscle sympathetic nerve activity reported previously (Klingel et al, 2019; Lee et al, 2019).…”

Resolvin E1 derived from eicosapentaenoic acid prevents hyperinsulinemia and hyperglycemia in a host genetic manner

“…Therefore, major limitations in the field of EPA biology need to be addressed. Notably, most preventative studies use levels of EPA that are not achievable in humans; moreover, investigators routinely rely on impure fish oil mixtures of EPA/DHA despite strong evidence that these two fatty acids are structurally and functionally distinct 25,26 .…”