The aim of this study was to determine whether eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), or both, were responsible for the triglyceride (TG)-lowering effects of fish oil. EPA (91% pure) and DHA (83% pure), a fish oil concentrate (FOC; 41% EPA and 23% DHA) and an olive oil (OO) placebo (all ethyl esters) were tested. A total of 49 normolipidemic subjects participated. Each subject was given placebo for 2-3 wk and one of the n-3 supplements for 3 wk in randomized, blinded trials. The target n-3 fatty acid (FA) intake was 3 g/day in all studies. Blood samples were drawn twice at the end of each supplementation phase and analyzed for lipids, lipoproteins, and phospholipid FA composition. In all groups, the phospholipid FA composition changed to reflect the n-3 FA given. On DHA supplementation, EPA levels increased to a small but significant extent, suggesting that some retroconversion may have occurred. EPA supplementation did not raise DHA levels, however. FOC and EPA produced significant decreases in both TG and very low density lipoprotein (VLDL) cholesterol (C) levels (P < 0.01) and increases in low density lipoprotein (LDL) cholesterol levels (P < 0.05). DHA supplementation did not affect cholesterol, triglyceride, VLDL, LDL, or high density lipoprotein (HDL) levels, but it did cause a significant increase in the HDL2/HDL3 cholesterol ratio. We conclude that EPA appears to be primarily responsible for TG-lowering (and LDL-C raising) effects of fish oil.

The aim of these studies was to explore the possibility that enhanced triacylglycerol clearance may contribute to the hypotriacylglycerolemic effect of n-3 fatty acids in humans. Healthy subjects (n = 20) and hypertriacylglycerolemic patients (n = 6) were given a placebo (olive oil, OO) or a fish-oil concentrate (FOC; 41% eicosapentaenoic acid and 23% docosahexaenoic acid) in two, independent, randomized, blind trials. For the healthy subjects, the FOC treatment period was 3 wk long and FOC intakes were 5 g/d. For the patients, treatment periods were 4 wk long and dosages were 5 g.70 kg body wt-1.d-1. Washout periods were 2-4 wk for both groups. Blood samples were drawn at the end of each phase and analyzed for plasma lipids, lipoproteins, and endogenous (nonheparin-stimulated) activities of lipoprotein lipase (LPL) and hepatic lipase (HL). In the healthy subjects the FOC decreased plasma triacylglycerol concentrations by 18% (P < 0.01), whereas in the patients concentrations were reduced by 35% (P < 0.05). Low-density-lipoprotein-cholesterol concentrations increased by 25% in the latter group (P = 0.06). FOC increased the endogenous activities of LPL and HL by 62% and 68%, respectively (P < 0.0001), in the healthy subjects, but only LPL in the patients (65%, P < 0.005). These data suggest that endogenous lipase activities may be altered by nutritional interventions, and further, that accelerated lipolysis could contribute, at least in part, to the observed effects of n-3 fatty acids on human lipoprotein metabolism.

Fish oils rich in n-3 fatty acids have been shown to augment endothelium-dependent vasodilation in human peripheral and coronary arteries. This suggests that n-3 fatty acids may enhance arterial nitric oxide production. To explore this hypothesis we measured total urinary nitrate output in healthy volunteers supplemented with a fish oil concentrate (FOC; n = 15) or purified eicosapentaenoic acid (EPA; n = 14) in a placebo-controlled, parallel-group study. The FOC contained 41% EPA and 23% docosahexaenoic acid (DHA) ethyl esters, whereas EPA was 91% pure; the placebo contained olive oil ethyl esters. Doses were 5 g placebo, 5 g FOC, and 3 g EPA to keep the total n-3 fatty acid content equal in the latter two groups. The placebo period was 2 wk long and was followed by a 3-wk n-3 fatty acid phase. At the end of each period, 24-h urine collections and fasting blood samples were obtained. Serum and urinary nitrate concentrations were measured in a blinded fashion. The FOC produced a 43% increase in daily, creatinine-adjusted, nitrate excretion rates (P < 0.029). Because serum nitrate concentrations were not different, these findings suggest that FOC supplementation may stimulate systemic nitric oxide synthesis. The lack of effect with EPA supplementation suggests that this component of the FOC is not likely to be an active component. If confirmed, these observations suggest another mechanism whereby n-3 fatty acids may be antiatherogenic.

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