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Modification of erythrocyte membrane phospholipid composition in preterm newborns with retinopathy of prematurity: The omegaROP study

ABSTRACT:

N-3 polyunsaturated fatty acids (PUFAs) may prevent retinal vascular abnormalities observed in oxygen-induced retinopathy, a model of retinopathy of prematurity (ROP). In the OmegaROP prospective cohort study, we showed that preterm infants who will develop ROP accumulate the n-6 PUFA arachidonic acid (ARA) at the expense of the n-3 PUFA docosahexaenoic acid (DHA) in erythrocytes with advancing gestational age (GA). As mice lacking plasmalogens ―that are specific phospholipids considered as reservoirs of n-6 and n-3 PUFAs― display a ROP-like phenotype, the aim of this study was to determine whether plasmalogens are responsible for the changes observed in subjects from the OmegaROP study. Accordingly, preterm infants aged less than 29 weeks GA were recruited at birth in the Neonatal Intensive Care Unit of University Hospital Dijon, France. Blood was sampled very early after birth to avoid any nutritional influence on its lipid composition. The lipid composition of erythrocytes and the structure of phospholipids including plasmalogens were determined by global lipidomics using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). LC-HRMS data confirmed our previous observations by showing a negative association between the erythrocyte content in phospholipid esterified to n-6 PUFAs and GA in infants without ROP (rho = -0.485, p = 0.013 and rho = -0.477, p = 0.015 for ethanolamine and choline total phospholipids, respectively). Phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn) species with ARA, namely PtdCho16:0/20:4 (rho = -0.511, p < 0.01) and PtdEtn18:1/20:4 (rho = -0.479, p = 0.015), were the major contributors to the relationship observed. On the contrary, preterm infants developing ROP displayed negative association between PtdEtn species with n-3 PUFAs and GA (rho = -0.380, p = 0.034). They were also characterized by a positive association between GA and the ratio of ethanolamine plasmalogens (PlsEtn) with n-6 PUFA to PlsEtn with n-3 PUFAs (rho = 0.420, p = 0.029), as well as the ratio of PlsEtn with ARA to PlsEtn with DHA (rho = 0.843, p = 0.011). Altogether, these data confirm the potential accumulation of n-6 PUFAs with advancing GA in erythrocytes of infants developing ROP. These changes may be partly due to plasmalogens.

INSTRUMENT(S): Liquid Chromatography MS - alternating - hilic

SUBMITTER: Niyazi ACAR

PROVIDER: MTBLS4219 | MetaboLights | 2022-09-07

REPOSITORIES: MetaboLights

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Project description:Fish oil supplementation is generally seen as beneficial for human health, due to the presence of n-3 polyunsaturated fatty acids (n-3 PUFAs). These fatty acids can elicit their effect through changes in gene expression. Effects of n-3 PUFAs on gene expression of inflammatory and atherogenic markers have been shown in several in vitro and animal studies. However, little evidence is available on human in vivo studies on n-3 PUFA related gene expression. In the present study we investigate the effects of EPA and DHA supplementation for 6 months on gene expression profiles of peripheral blood mononuclear cells (PBMCs). Whole genome microarray analysis was performed on PBMC RNA from subjects who received 1.8 grams of EPA and DHA in capsules (n=23) or capsules containing high oleic acid sunflower oil (HOSF)(n=25). Intake of EPA and DHA resulted in a change of 1040 genes. We found a down-regulation in inflammatory and atherogenic related pathways, such as NF-ÎºB signaling, eicosanoid synthesis, scavenger receptors activity and cell adhesion. These results seem to point to an improvement in health status, in which lymphocytes are less prone to produce chemokines and adhesion molecules and monocytes show reduced susceptibility to differentiate into foam cells. Overall, beneficial effects of n-3 PUFAs that have been described in vitro and in animal studies, were shown in vivo in human subjects in this study. This not only confirms that EPA and DHA elicits beneficial effects on inflammatory and atherogenic processes of elderly subjects, but also shows that PBMC gene expression profiles can be used to show effects of nutrition on human health status. Fasting venous blood samples were collected at baseline and after 26 weeks of supplementation with either 1.8 g EPA and DHA or HOSF. 4 ml blood was collected for PBMC isolation, using BD Vacutainer Cell Preparation Tubes with sodium citrate (BD, Breda, The Netherlands). Immediately after blood collection PBMCs were isolated according to the manufacturerâs manual. PBMC RNA was isolated from all PBMC samples using Qiagen RNeasy Micro kit (Qiagen, Venlo, the Netherlands). Total RNA from PBMCs from 48 subjects was labeled using a one-cycle cDNA labeling kit (MessageAmpTM II-Biotin Enhanced Kit, Ambion, Inc.) and hybridized to custom designed NuGO GeneChip arrays.

Project description:Background & Aims: Non-alcoholic fatty liver disease accompanies obesity and is independently associated with cardiovascular disease. Omega-3 fatty acids, such as docosahexaenoic (DHA) and eicosapentaenoic (EPA) acid, reduce the risk of cardiovascular disease due to their anti-inflammatory and hypolipidemic effects. Recent data suggested that metabolic effects of EPA/DHA as marine phospholipids could be stronger than triglycerides (fish oil). We characterised the mechanisms underlying beneficial effects of EPA/DHA phospholipids alone or in combination with antidiabetic drugs on hepatosteatosis in dietary obese mice. Methods: Male C57BL/6N mice were fed for 7 weeks a corn oil-based high-fat diet (cHF) or subjected to cHF-based interventions: (i) cHF with DHA/EPA as phosphatidylcholine-rich concentrate replacing ~10 % of dietary lipids (PC); ii) cHF with a low-dose of thiazolidinedione rosiglitazone (10 mg/kg diet), which retains some of the beneficial effects but also potentiates hepatic lipid accumulation (R); and iii) PC+R. Metabolic profiling together with hepatic gene expression and lipidomic analyses were performed. Results: PC and PC+R prevented weight gain and glucose intolerance induced by cHF, while all interventions reduced abdominal fat and plasma triglycerides. In contrast to R, PC and PC+R lowered hepatic and plasma cholesterol and eliminated hepatosteatosis. Hepatic microarray analysis primarily revealed a complex downregulation of lipogenic and cholesterol biosynthesis pathways by PC. Lipidomic analysis identified arachidonic acid, DHA and EPA in hepatic phosphatidylcholine and phosphatidylethanolamine fractions as the most important variables. Importantly, down-regulation of genes within these pathways was enlarged by phospholipid versus triglyceride forms of EPA/DHA in an independent experiment. Conclusions: Obesity-associated hepatosteatosis and hypercholesterolemia were ameliorated by marine phospholipids in association with a complex inhibition of biosynthetic pathways in liver. Stronger effects of phospholipids versus triglyceride form of EPA/DHA suggest their preferential use in the prevention and possible treatment of obesity-associated metabolic hepatic dysfunctions.

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Modification of erythrocyte membrane phospholipid composition in preterm newborns with retinopathy of prematurity: The omegaROP study

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