Mechanisms
EPA, but not DHA, significantly lowers CETP activity in a crossover trial of omega-3 fatty acid supplementation (J Clin Lipidol 2022)
Original title: Ethyl EPA and ethyl DHA cause similar and differential changes in plasma lipid concentrations and lipid metabolism in subjects with low-grade chronic inflammation
In a randomised, double-blind, crossover study, 21 older adults (over 50 years) with metabolic syndrome features and low-grade chronic inflammation received 10 weeks of 3 g per day pure ethyl-ester EPA and, separately, pure ethyl-ester DHA, with plasma lipids and activities of lipoprotein lipase, CETP and LCAT measured. Both EPA and DHA lowered plasma triglycerides and raised LDL-C to apoB and HDL-C to apoA-I ratios, but only DHA raised LDL cholesterol concentrations, and triglyceride reductions correlated inversely with lipoprotein lipase activity changes for both fatty acids. Notably, EPA specifically lowered CETP activity, while DHA specifically lowered LCAT activity, and DHA increased lipoprotein lipase activity and LDL cholesterol only in women, demonstrating that EPA and DHA act through distinct, sex-specific enzymatic pathways despite similar effects on triglycerides.
Original abstract
Background: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to similarly lower plasma TG concentrations but differentially regulate plasma LDL-C and HDL-C concentrations.
Objective: The aim of this study was to evaluate the common and differential effects of these ω-3 fatty acids on plasma lipids and lipoproteins and to assess the metabolic mechanisms of the effects.
Methods: In a randomized, double-blind, crossover study, we assessed the effect of 10-week supplementation with 3 g/d pure EPA and pure DHA (both as ethyl ester, ≥97% purity) on plasma lipid and lipoprotein concentrations and activities of lipoprotein lipase (LPL), cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyl transferase (LCAT) in 21 older (>50 y) men and postmenopausal women with some characteristics of metabolic syndrome and low-grade chronic inflammation.
Results: Both EPA and DHA lowered plasma TG concentrations and increased LDL-C/apoB and HDL-C/apoA-I ratios, but only DHA increased LDL-C concentrations. The reductions in plasma TG were inversely associated with the changes in LPL activity after both EPA and DHA supplementation. EPA lowered CETP, while DHA lowered LCAT activity. EPA and DHA worked differently in men and women, with DHA increasing LPL activity and LDL-C concentrations in women, but not in men.
Conclusions: EPA and DHA exerted similar effects on plasma TG, but differences were observed in LDL-C concentrations and activities of some enzymes involved in lipoprotein metabolism. It was also noted that EPA and DHA worked differently in men and women, supporting sex-specific variations in lipoprotein metabolism.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.