Abstract
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n-3 polyunsaturated fatty acids (PUFAs) consumed in low abundance in the Western diet. Increased consumption of n-3 PUFAs may have beneficial effects for a wide range of physiological outcomes including chronic inflammation. However, considerable mechanistic gaps in knowledge exist about EPA versus DHA, which are often studied as a mixture. We suggest the novel hypothesis that EPA and DHA may compete against each other through overlapping mechanisms. First, EPA and DHA may compete for residency in membrane phospholipids and thereby differentially displace n-6 PUFAs, which are highly prevalent in the Western diet. This would influence biosynthesis of downstream metabolites of inflammation initiation and resolution. Second, EPA and DHA exert different effects on plasma membrane biophysical structure, creating an additional layer of competition between the fatty acids in controlling signaling. Third, DHA regulates membrane EPA levels by lowering its rate of conversion to EPA's elongation product n-3 docosapentaenoic acid. Collectively, we propose the critical need to investigate molecular competition between EPA and DHA in health and disease, which would ultimately impact dietary recommendations and precision nutrition trials.