Updates to the n-3 polyunsaturated fatty acid biosynthesis pathway: DHA synthesis rates, tetracosahexaenoic acid and (minimal) retroconversion

N-3 polyunsaturated fatty acids (PUFA) and the numerous families of lipid mediators derived from them collectively regulate numerous biological processes. The mechanisms by which n-3 PUFA regulate biological processes begins with an understanding of the n-3 biosynthetic pathway that starts with alpha-linolenic acid (18:3n-3) and is commonly thought to end with the production of docosahexaenoic acid (DHA, 22:6n-3). However, our understanding of this pathway is not as complete as previously believed. In the current review we provide a background of the evidence supporting the pathway as currently understood and provide updates from recent studies challenging three central dogma of n-3 PUFA metabolism. By building on nearly three decades of research primarily in cell culture and oral dosing studies, recent evidence presented focuses on in vivo kinetic modelling and compound-specific isotope abundance studies in rodents and humans that have been instrumental in expanding our knowledge of the pathway. Specifically, we highlight three main updates to the n-3 PUFA biosynthesis pathway: (1) DHA synthesis rates cannot be as low as previously believed, (2) DHA is both a product and a precursor to tetracosahexaenoic acid (24:6n-3) and (3) increases in EPA in response to DHA supplementation are not the result of increased retroconversion.