Non-enzymatic cyclic oxygenated metabolites of adrenic, docosahexaenoic, eicosapentaenoic and α-linolenic acids; bioactivities and potential use as biomarkers

International audienceCyclic oxygenated metabolites are formed in vivo through non-enzymatic free radical reaction of n-6 and n-3 polyunsaturated fatty acids (PUFAs) such as arachidonic (ARA C20:4 n-6), adrenic (AdA 22:4 n-6), α-linolenic (ALA 18:3 n-3), eicosapentaenoic (EPA 20:5 n-3) and docosahexaenoic (DHA 22:6 n-3) acids. These cyclic compounds are known as isoprostanes, neuroprostanes, dihomo-isoprostanes and phytoprostanes. Evidence has emerged for their use as biomarkers of oxidative stress and, more recently, the n-3PUFA-derived compounds have been shown to mediate bioactivities as secondary messengers. Accordingly, this review will focus on the cyclic oxygenated metabolites generated from AdA, ALA, EPA and DHA. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance

Supplementary Material for: Eicosanoids and oxylipin signature in HH patients are similar to DIOS patients but are impacted by dietary iron absorption.

Introduction: Oxylipins are mediators of oxidative stress. To characterize the underlying inflammatory processes and phenotype the effect of iron metabolism disorders, we investigated the oxylipin profile in hereditary hemochromatosis (HH) and dysmetabolic iron overload syndrome (DIOS) patients. Methods: LC-MS/MS based method to quantify plasma oxylipins in 20 HH and 20 DIOS patients in fasting conditions and 3 hours after an iron-rich meal in HH patients. Results: Principal component analysis showed no separation between HH and DIOS, suggesting that the clinical phenotype has no direct impact on oxylipin metabolism. 20-HETE was higher in DIOS and correlated with hypertension (p = 0.03). Different oxylipin signatures were observed in HH before and after the iron-rich meal. Discriminant oxylipins include epoxy fatty acids derived from docosahexaenoic acid and arachidonic acid as well as 13-HODE and 9-HODE. Mediation analysis found no major contribution of dietary iron absorption for 16/22 oxylipins significantly affected by the meal. Discussion: The oxylipin profiles of HH and DIOS seemed similar except for 20-HETE, possibly reflecting different hypertension prevalence between the two groups. Oxylipins were significantly affected by the iron-rich meal but the specific contribution of iron was not clear. Although iron may contribute to oxidative stress and inflammation in HH and DIOS, this does not seem to directly affect oxylipin metabolism

Effet d’un polyphénol dans l’hémochromatose et l’hépatosidérose dysmétabolique : étude contrôlée randomisée

Effet d’un polyphénol dans l’hémochromatose et l’hépatosidérose dysmétabolique : étude contrôlée randomisée. 79. Congrès SNFM

Optimized rapeseed oil naturally enriched with healthy micronutrients: a relevant nutritional approach to prevent cardiovascular diseases. Results of the Optim’Oils randomized intervention trial

International audienc

DHA at nutritional doses restores insulin sensitivity in skeletal muscle by preventing lipotoxicity and inflammation

International audienceSkeletal muscle plays a major role in the control of whole body glucose disposal in response to insulin stimulus. Excessive supply of fatty acids to this tissue triggers cellular and molecular disturbances leading to lipotoxicity, inflammation, mitochondrial dysfunctions, impaired insulin response and decreased glucose uptake. This study was conducted to analyze the preventive effect of docosahexaenoic acid (DHA), a long-chain polyunsaturated n-3 fatty acid, against insulin resistance, lipotoxicity and inflammation in skeletal muscle at doses compatible with nutritional supplementation. DHA (30 muM) prevented insulin resistance in C2C12 myotubes exposed to palmitate (500 muM) by decreasing protein kinase C (PKC)-theta activation and restoring cellular acylcarnitine profile, insulin-dependent AKT phosphorylation and glucose uptake. Furthermore, DHA protected C2C12 myotubes from palmitate- or lipopolysaccharide-induced increase in Ptgs2, interleukin 6 and tumor necrosis factor-alpha mRNA level, probably through the inhibition of p38 MAP kinase and c-Jun amino-terminal kinase. In LDLR -/- mice fed a high-cholesterol-high-sucrose diet, supplementation with DHA reaching up to 2% of daily energy intake enhanced the insulin-dependent AKT phosphorylation and reduced the PKC-theta activation in skeletal muscle. Therefore, DHA used at physiological doses participates in the regulation of muscle lipid and glucose metabolisms by preventing lipotoxicity and inflammation

Simultaneous quantitative profiling of 20 isoprostanoids from omega-3 and omega-6 polyunsaturated fatty acids by LC-MS/MS in various biological samples

This work was supported by the Fondation pour la Recherche Médicale (grant ING20121226373), the Agence Nationale de la Recherche, the Institut National de la Santé et de la Recherche Medical and the French National Infrastructure MetaboHUBANR-11-INBS-010International audienceIsoprostanoids are a group of non-enzymatic oxygenated metabolites of polyunsaturated fatty acids. It belongs to oxylipins group, which are important lipid mediators in biological processes, such as tissue repair, blood clotting, blood vessel permeability, inflammation and immunity regulation. Recently, isoprostanoids from eicosapentaenoic, docosahexaenoic, adrenic and α-linolenic namely F3-isoprostanes, F4-neuroprostanes, F2-dihomo-isoprostanes and F1-phytoprostanes, respectively have attracted attention because of their putative contribution to health. Since isoprostanoids are derived from different substrate of PUFAs and can have similar or opposing biological consequences, a total isoprostanoids profile is essential to understand the overall effect in the testing model. However, the concentration of most isoprostanoids range from picogram to nanogram, therefore a sensitive method to quantify 20 isoprostanoids simultaneously was formulated and measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The lipid portion from various biological samples was extracted prior to LC-MS/MS evaluation. For all the isoprostanoids LOD and LOQ, and the method was validated on plasma samples for matrix effect, yield of extraction and reproducibility were determined. The methodology was further tested for the isoprostanoids profiles in brain and liver of LDLR(-/-) mice with and without docosahexaenoic acid (DHA) supplementation. Our analysis showed similar levels of total F2-isoprostanes and F4-neuroprostanes in the liver and brain of non-supplemented LDLR(-/-) mice. The distribution of different F2-isoprostane isomers varied between tissues but not for F4-neuroprostanes which were predominated by the 4(RS)-4-F4t-neuroprostane isomer. DHA supplementation to LDLR(-/-) mice concomitantly increased total F4-neuroprostanes levels compared to F2-isoprostanes but this effect was more pronounced in the liver than brain

Profilage lipidomique des oxylipines pour mieux caractériser le syndrome cardiométabolique et ses liens avec l’alimentation

Session IV: Obésité (Modérateurs : K. Couturier et J.A. Nazare)Le syndrome cardiométabolique est un désordre complexe et progressif qui constitue un facteur de risque significatif de maladies cardiovasculaires et de diabète de type II. Il se caractérise par l’association d’au moins trois anomalies incluant un tour de taille élevé, une pression sanguine haute, une hyperglycémie, une hypertriglycéridémie et un taux faible de HDL-cholestérol. Le diagnostic et la prise en charge du syndrome cardiométabolique reste insatisfaisant car il est souvent trop tardif et pas assez intégratif. Les oxylipines, métabolites issus de l’oxygénation des acides gras polyinsaturés, sont des médiateurs lipidiques impliqués dans la régulation de nombreux processus biologiques en lien avec le développement du syndrome cardiométabolique. Par ailleurs, la synthèse des oxylipines est modulable par l’alimentation. Dans le cadre du projet JPI-HDHL OXYGENATE, nous avons émis l’hypothèse que la signature d’oxylipines pourrait permettre d’identifier des perturbations précoces du statut cardiométabolique et pourrait aider à suivre l’effet d’une intervention nutritionnelle sur la prise en charge du syndrome cardiométabolique. Le projet OXYGENATE a pour but d’identifier et valider les signatures d’oxylipines caractéristiques du statut cardiométabolique et de son évolution