The intake of omega-3 fatty acids and the inhibition of their mitochondrial metabolism increase EPA and DHA levels in healthy volunteers

Omega-3 polyunsaturated fatty acids (PUFAs) are widely recognised for their beneficial effects on cardiometabolic health. However, the efficacy of omega-3 PUFA supplementation has recently been questioned, potentially because of limited PUFA exposure caused by rapid mitochondrial oxidation. The objective of this study was to determine whether pharmacological inhibition of carnitine-dependent mitochondrial fatty acid metabolism with meldonium enhances the plasma response to n-3 PUFA supplementation by increasing EPA and DHA levels and decreasing PUFA-derived acylcarnitine formation. In this study, 50 participants were randomly divided into 3 cohorts, which received an omega-3 PUFA supplement containing 930 mg eicosapentaenoic acid (C20:5n-3, EPA) and 750 mg docosahexaenoic acid (C22:6n-3, DHA), either alone or in combination with 1 g/day meldonium. The study included healthy volunteers (70% female) with a median age of 39.5 years (IQR 30.0–49.0) and a median BMI of 25.6 kg/m² (IQR 23.0–27.2). The levels of EPA, DHA, their acylcarnitines, and PUFA-containing lipids, as well as markers of the carnitine‒acylcarnitine pathway, were measured in plasma at baseline and after 4 and 8 weeks of intervention. In the study participants, the plasma levels of EPA were 4–5 times lower than those of DHA; therefore, a markedly greater relative increase in EPA levels was achieved by PUFA supplement intake. The levels of EPA and DHA acylcarnitines gradually increased after 4 and 8 weeks of treatment, suggesting stimulated PUFA metabolism after prolonged intake of PUFA supplements. Meldonium treatment decreased the concentrations of acylcarnitines, which indicates a lower fatty acid oxidation rate in the treatment groups. In turn, meldonium treatment combined with PUFA supplementation resulted in a significantly higher increase in EPA, DHA and derived lipid levels than PUFA supplementation alone. Our findings provide evidence that the inhibition of mitochondrial PUFA metabolism represents a promising strategy to increase EPA and DHA levels in humans.