title: Lipid profiling following intake of the omega 3 fatty acid DHA identifies the peroxidized metabolites F4-neuroprostanes as the best predictors of atherosclerosis prevention.
abstract: The anti-atherogenic effects of omega 3 fatty acids, namely eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) are well recognized but the impact of dietary intake on bioactive lipid mediator profiles remains unclear. Such a profiling effort may offer novel targets for future studies into the mechanism of action of omega 3 fatty acids. The present study aimed to determine the impact of DHA supplementation on the profiles of polyunsaturated fatty acids (PUFA) oxygenated metabolites and to investigate their contribution to atherosclerosis prevention. A special emphasis was given to the non-enzymatic metabolites knowing the high susceptibility of DHA to free radical-mediated peroxidation and the increased oxidative stress associated with plaque formation. Atherosclerosis prone mice (LDLR(-/-)) received increasing doses of DHA (0, 0.1, 1 or 2% of energy) during 20 weeks leading to a dose-dependent reduction of atherosclerosis (R(2) = 0.97, p = 0.02), triglyceridemia (R(2) = 0.97, p = 0.01) and cholesterolemia (R(2) = 0.96, p<0.01). Targeted lipidomic analyses revealed that both the profiles of EPA and DHA and their corresponding oxygenated metabolites were substantially modulated in plasma and liver. Notably, the hepatic level of F4-neuroprostanes, a specific class of DHA peroxidized metabolites, was strongly correlated with the hepatic DHA level. Moreover, unbiased statistical analysis including correlation analyses, hierarchical cluster and projection to latent structure discriminate analysis revealed that the hepatic level of F4-neuroprostanes was the variable most negatively correlated with the plaque extent (p<0.001) and along with plasma EPA-derived diols was an important mathematical positive predictor of atherosclerosis prevention. Thus, oxygenated n-3 PUFAs, and F4-neuroprostanes in particular, are potential biomarkers of DHA-associated atherosclerosis prevention. While these may contribute to the anti-atherogenic effects of DHA, further in vitro investigations are needed to confirm such a contention and to decipher the molecular mechanisms of action.
authors.affiliation: UMR1019 Unité de Nutrition Humaine (UNH), INRA, CRNH Auvergne, Clermont Université, Université d'Auvergne, Clermont-Ferrand, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Gladine
authors.affiliation: Obesity and Metabolism Research Unit, USDA, ARS, Western Human Nutrition Research Center, Davis, California, United States of America ; Department of Nutrition, University of California, Davis, California, United States of America.
authors.forename: John W
authors.initials: JW
authors.lastname: Newman
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR CNRS 5247, Universités de Montpellier I et II, France, Montpellier, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Durand
authors.affiliation: Obesity and Metabolism Research Unit, USDA, ARS, Western Human Nutrition Research Center, Davis, California, United States of America.
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Pedersen
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR CNRS 5247, Universités de Montpellier I et II, France, Montpellier, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Galano
authors.affiliation: EA 4267 Fonctions et Dysfonctions epithéliales, University of Franche-Comté, Besançon, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Demougeot
authors.affiliation: UMR6265 Centre des Sciences du Goût et de l'Alimentation, CNRS, Dijon, France ; UMR1324 Centre des Sciences du Goût et de l'Alimentation, INRA, Dijon, France ; UMR Centre des Sciences du Goût et de l'Alimentation, Université de Bourgogne, Dijon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Berdeaux
authors.affiliation: UMR1019 Unité de Nutrition Humaine (UNH), INRA, CRNH Auvergne, Clermont Université, Université d'Auvergne, Clermont-Ferrand, France ; UMR 1019, Plateforme d'Exploration du Métabolisme, INRA, Clermont-Ferrand, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Pujos-Guillot
authors.affiliation: UMR1019 Unité de Nutrition Humaine (UNH), INRA, CRNH Auvergne, Clermont Université, Université d'Auvergne, Clermont-Ferrand, France.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Mazur
authors.affiliation: UMR1019 Unité de Nutrition Humaine (UNH), INRA, CRNH Auvergne, Clermont Université, Université d'Auvergne, Clermont-Ferrand, France.
authors.forename: Blandine
authors.initials: B
authors.lastname: Comte
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D050197:Atherosclerosis / Q000517:prevention & control*; D015415:Biomarkers / Q000378:metabolism*; D001794:Blood Pressure; D002853:Chromatography, Liquid; D016000:Cluster Analysis; D004281:Docosahexaenoic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D006339:Heart Rate; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D058632:Neuroprostanes / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics; D053719:Tandem Mass Spectrometry
chemical_list: D015415:Biomarkers; D005231:Fatty Acids, Unsaturated; D058632:Neuroprostanes; D011973:Receptors, LDL; D004281:Docosahexaenoic Acids