Dietary docosahexaenoic acid (DHA) downregulates liver DHA synthesis by inhibiting eicosapentaenoic acid elongation.

DHA is abundant in the brain where it regulates cell survival, neurogenesis, and neuroinflammation. DHA can be obtained from the diet or synthesized from alpha-linolenic acid (ALA; 18:3n-3) via a series of desaturation and elongation reactions occurring in the liver. Tracer studies suggest that dietary DHA can downregulate its own synthesis, but the mechanism remains undetermined and is the primary objective of this manuscript. First, we show by tracing 13C content (δ13C) of DHA via compound-specific isotope analysis, that following low dietary DHA, the brain receives DHA synthesized from ALA. We then show that dietary DHA increases mouse liver and serum EPA, which is dependant on ALA. Furthermore, by compound-specific isotope analysis we demonstrate that the source of increased EPA is slowed EPA metabolism, not increased DHA retroconversion as previously assumed. DHA feeding alone or with ALA lowered liver elongation of very long chain (ELOVL2, EPA elongation) enzyme activity despite no change in protein content. To further evaluate the role of ELOVL2, a liver-specific Elovl2 KO was generated showing that DHA feeding in the presence or absence of a functional liver ELOVL2 yields similar results. An enzyme competition assay for EPA elongation suggests both uncompetitive and noncompetitive inhibition by DHA depending on DHA levels. To translate our findings, we show that DHA supplementation in men and women increases EPA levels in a manner dependent on a SNP (rs953413) in the ELOVL2 gene. In conclusion, we identify a novel feedback inhibition pathway where dietary DHA downregulates its liver synthesis by inhibiting EPA elongation.

Blood and tissue docosahexaenoic acid (DHA, 22:6n-3) turnover rates from Ahiflower® oil are not different than from DHA ethyl ester oil in a diet switch mouse model.

Ahiflower® oil is high in α-linolenic and stearidonic acids, however, tissue/blood docosahexaenoic acid (DHA, 22:6n-3) turnover from dietary Ahiflower oil has not been investigated. In this study, we use compound-specific isotope analysis to determine tissue DHA synthesis/turnover from Ahiflower, flaxseed and DHA oils. Pregnant BALB/c mice (13-17 days) were placed on a 2 % algal DHA oil diet of high carbon-13 content (δ13C) and pups (n = 132) were maintained on the diet until 9 weeks old. Mice were then randomly allocated to a low δ13C-n-3 PUFA diet of either: 1) 4 % Ahiflower oil, 2) 4.35 % flaxseed oil or 3) 1 % fish DHA ethyl ester oil for 1, 3, 7, 14, 30, 60 or 120 days (n = 6). Serum, liver, adipose and brains were collected and DHA levels and δ13C were determined. DHA concentrations were highest (p < 0.05) in the liver and adipose of DHA-fed animals with no diet differences in serum or brain (p > 0.05). Based on the presence or absence of overlapping 95 % C.I.'s, DHA half-lives and synthesis/turnover rates were not different between Ahiflower and DHA diets in the liver, adipose or brain. DHA half-lives and synthesis/turnover rates from flaxseed oil were significantly slower than from the DHA diet in all serum/tissues. These findings suggest that the distinct Ahiflower oil n-3 PUFA composition could support tissue DHA needs at a similar rate to dietary DHA, making it a unique plant-based dietary option for maintaining DHA turnover comparably to dietary DHA.