Dietary docosahexaenoic acid (DHA) downregulates liver DHA synthesis by inhibiting eicosapentaenoic acid elongation.
Journal of Lipid Research. 2024-04-01; : 100548
DOI: 10.1016/j.jlr.2024.100548
Lire sur PubMed
1. J Lipid Res. 2024 Apr 20:100548. doi: 10.1016/j.jlr.2024.100548. Online ahead
of print.
Dietary docosahexaenoic acid (DHA) downregulates liver DHA synthesis by
inhibiting eicosapentaenoic acid elongation.
Metherel AH(1), Valenzuela R(2), Klievik BJ(3), Cisbani G(3), Rotarescu RD(3),
Gonzalez-Soto M(4), Cruciani-Guglielmacci C(5), Layé S(6), Magnan C(5), Mutch
DM(4), Bazinet RP(3).
Author information:
(1)Department of Nutritional Sciences, University of Toronto, Toronto, Ontario,
Canada. Electronic address: .
(2)Department of Nutrition, University of Chile, Santiago, Chile.
(3)Department of Nutritional Sciences, University of Toronto, Toronto, Ontario,
Canada.
(4)Department of Human Health and Nutritional Sciences, University of Guelph,
Guelph, Ontario, Canada.
(5)Université Paris Cité, BFA, UMR8251, CNRS, Paris, France.
(6)Université de Bordeaux, INRA, Bordeaux INP, NutriNeuro, Bordeaux, France.
DHA is abundant in 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 paper. First, we show by tracing 13C content
(δ13C) of DHA via compound-specific isotope analysis (CSIA), 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 CSIA 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 knockout 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 non-competitive 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.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jlr.2024.100548
PMID: 38649096