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Lipid profiling following intake of the omega 3 fatty acid DHA identifies the peroxidized metabolites F4-neuroprostanes as the best predictors of atherosclerosis prevention.

Gladine C, Newman JW, Durand T, Pedersen TL, Galano JM, Demougeot C, Berdeaux O, Pujos-Guillot E, Mazur A, Comte B - PLoS ONE (2014)

Bottom Line: 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.Notably, the hepatic level of F4-neuroprostanes, a specific class of DHA peroxidized metabolites, was strongly correlated with the hepatic DHA level.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.

View Article: PubMed Central - PubMed

Affiliation: UMR1019 Unité de Nutrition Humaine (UNH), INRA, CRNH Auvergne, Clermont Université, Université d'Auvergne, Clermont-Ferrand, France.

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.

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Related in: MedlinePlus

A Spearman’s correlation heatmap.Variables rank from the most positive to most negative correlation with arteriosclerotic plaque area. The displayed variables are the 30 most significantly correlated with arteriosclerotic plaque area at p<0.001 with orange indicating positive and blue indicating negative correlations.
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pone-0089393-g005: A Spearman’s correlation heatmap.Variables rank from the most positive to most negative correlation with arteriosclerotic plaque area. The displayed variables are the 30 most significantly correlated with arteriosclerotic plaque area at p<0.001 with orange indicating positive and blue indicating negative correlations.

Mentions: Correlation analyses were used to assess the association of the measured variables with changes in atherosclerotic plaque area. Among the 131 variables assessed, the 30 most significantly correlated with plaque area at p<0.001 are represented in Figure 5. Positive correlations were seen with liver TG and TC, the diet-induced change in sBP and the initial dBP as well as plasma fatty acid and oxylipin levels including several n-6 PUFAs and 5-hydroxyeicosatetraenoic acid (5-HETE), a putative pro-inflammatory mediator derived from 5-lipoxygenase metabolism of AA. Surprisingly, plasma TC and TG did not belong to the 30 most significantly correlated variables. Negative correlations with plaque area first included the liver concentrations of the DHA-derived F4-NeuroPs which was also the variable most negatively correlated with plasma TC, a major cardiovascular risk factor (data not shown). It should be noted that the hepatic concentration of F4-NeuroPs was also negatively correlated with other cardiovascular risk factors (i.e. liver TC and TG, change in sBP). Interestingly, none of the DHA-derived oxylipins in plasma appeared in the list of the 9 variables most negatively correlated with plaque area. In contrast, liver EPA and two plasma EPA-derived oxylipins (15-HEPE, 14,15-DiHETE) belong to this list. Finally, other variables negatively correlated with plaque area at p<0.001 included the arachidonic acid derived 15-deoxyprostaglandin J2 (15-deoxyPGJ2) as well as the saturated fatty acid stearate (C18∶0).


Lipid profiling following intake of the omega 3 fatty acid DHA identifies the peroxidized metabolites F4-neuroprostanes as the best predictors of atherosclerosis prevention.

Gladine C, Newman JW, Durand T, Pedersen TL, Galano JM, Demougeot C, Berdeaux O, Pujos-Guillot E, Mazur A, Comte B - PLoS ONE (2014)

A Spearman’s correlation heatmap.Variables rank from the most positive to most negative correlation with arteriosclerotic plaque area. The displayed variables are the 30 most significantly correlated with arteriosclerotic plaque area at p<0.001 with orange indicating positive and blue indicating negative correlations.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928438&req=5

pone-0089393-g005: A Spearman’s correlation heatmap.Variables rank from the most positive to most negative correlation with arteriosclerotic plaque area. The displayed variables are the 30 most significantly correlated with arteriosclerotic plaque area at p<0.001 with orange indicating positive and blue indicating negative correlations.
Mentions: Correlation analyses were used to assess the association of the measured variables with changes in atherosclerotic plaque area. Among the 131 variables assessed, the 30 most significantly correlated with plaque area at p<0.001 are represented in Figure 5. Positive correlations were seen with liver TG and TC, the diet-induced change in sBP and the initial dBP as well as plasma fatty acid and oxylipin levels including several n-6 PUFAs and 5-hydroxyeicosatetraenoic acid (5-HETE), a putative pro-inflammatory mediator derived from 5-lipoxygenase metabolism of AA. Surprisingly, plasma TC and TG did not belong to the 30 most significantly correlated variables. Negative correlations with plaque area first included the liver concentrations of the DHA-derived F4-NeuroPs which was also the variable most negatively correlated with plasma TC, a major cardiovascular risk factor (data not shown). It should be noted that the hepatic concentration of F4-NeuroPs was also negatively correlated with other cardiovascular risk factors (i.e. liver TC and TG, change in sBP). Interestingly, none of the DHA-derived oxylipins in plasma appeared in the list of the 9 variables most negatively correlated with plaque area. In contrast, liver EPA and two plasma EPA-derived oxylipins (15-HEPE, 14,15-DiHETE) belong to this list. Finally, other variables negatively correlated with plaque area at p<0.001 included the arachidonic acid derived 15-deoxyprostaglandin J2 (15-deoxyPGJ2) as well as the saturated fatty acid stearate (C18∶0).

Bottom Line: 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.Notably, the hepatic level of F4-neuroprostanes, a specific class of DHA peroxidized metabolites, was strongly correlated with the hepatic DHA level.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.

View Article: PubMed Central - PubMed

Affiliation: UMR1019 Unité de Nutrition Humaine (UNH), INRA, CRNH Auvergne, Clermont Université, Université d'Auvergne, Clermont-Ferrand, France.

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.

Show MeSH
Related in: MedlinePlus