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      Transcriptome-based identification of antioxidative gene expression after fish oil supplementation in normo- and dyslipidemic men

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          Abstract

          Background

          The beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs), especially in dyslipidemic subjects with a high risk of cardiovascular disease, are widely described in the literature. A lot of effects of n-3 PUFAs and their oxidized metabolites are triggered by regulating the expression of genes. Currently, it is uncertain if the administration of n-3 PUFAs results in different expression changes of genes related to antioxidative mechanisms in normo- and dyslipidemic subjects, which may partly explain their cardioprotective effects. The aim of this study was to investigate the effects of n-3 PUFA supplementation on expression changes of genes involved in oxidative processes.

          Methods

          Ten normo- and ten dyslipidemic men were supplemented for twelve weeks with fish oil capsules, providing 1.14 g docosahexaenoic acid and 1.56 g eicosapentaenoic acid. Gene expression levels were determined by whole genome microarray analysis and quantitative real-time polymerase chain reaction (qRT-PCR).

          Results

          Using microarrays, we discovered an increased expression of antioxidative enzymes and a decreased expression of pro-oxidative and tissue enzymes, such as cytochrome P450 enzymes and matrix metalloproteinases, in both normo- and dyslipidemic men. An up-regulation of catalase and heme oxigenase 2 in both normo- and dyslipidemic subjects and an up-regulation of cytochrome P450 enzyme 1A2 only in dyslipidemic subjects could be observed by qRT-PCR analysis.

          Conclusions

          Supplementation of normo- and dyslipidemic subjects with n-3 PUFAs changed the expression of genes related to oxidative processes, which may suggest antioxidative and potential cardioprotective effects of n-3 PUFAs. Further studies combining genetic and metabolic endpoints are needed to verify the regulative effects of n-3 PUFAs in antioxidative gene expression to better understand their beneficial effects in health and disease prevention.

          Trial registration

          ClinicalTrials.gov (ID: NCT01089231)

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          Most cited references65

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          GenMAPP, a new tool for viewing and analyzing microarray data on biological pathways.

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            Polyunsaturated fatty acids and inflammatory processes: New twists in an old tale.

            The n-6 fatty acid arachidonic acid (AA; 20:4n-6) gives rise to eicosanoid mediators that have established roles in inflammation and AA metabolism is a long recognised target for commonly used anti-inflammatory therapies. It has generally been assumed that all AA-derived eicosanoids are pro-inflammatory. However this is an over-simplification since some actions of eicosanoids are anti-inflammatory (e.g. prostaglandin (PG) E(2) inhibits production of some inflammatory cytokines) and it has been discovered quite recently that PGE(2) inhibits production of inflammatory leukotrienes and induces production of inflammation resolving lipoxin A(4). The n-3 fatty acids from oily fish and "fish oils", eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3), are incorporated into inflammatory cell phospholipids in a time- and dose-dependent manner. They are incorporated partly at the expense of AA, but also of other n-6 fatty acids. EPA and DHA inhibit AA metabolism. Thus production of AA-derived eicosanoids is decreased by these n-3 fatty acids; this occurs in a dose-dependent manner. EPA gives rise to an alternative family of eicosanoids (e.g. PGE(3)), which frequently, but not always, have lower potency than those produced from AA. Recently a new family of EPA- and DHA-derived lipid mediators called resolvins (E- and D-series) has been described. These have potent anti-inflammatory and inflammation resolving properties in model systems. It seems likely that these mediators will explain many of the antiinflammatory actions of n-3 fatty acids that have been described. In addition to modifying the profile of lipid-derived mediators, fatty acids can also influence peptide mediator (i.e. cytokine) production. To a certain extent this action may be due to the altered profile of regulatory eicosanoids, but it seems likely that eicosanoid-independent actions are a more important mechanism. Indeed effects on transcription factors that regulate inflammatory gene expression (e.g. nuclear factor kappaB) seem to be important.
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              Polyunsaturated fatty acids as antioxidants.

              The susceptibility of fatty acids to oxidation is thought to be directly dependent on their degree of unsaturation. However, some in vitro and in vivo studies suggest that the relation between chemical structure and susceptibility to oxidation is not as straightforward as hypothesized from theoretical viewpoints. Indeed, long chain polyunsaturated fatty acids (LC-PUFAs) might be less oxidizable than others under specific experimental conditions. We investigated the free radical-scavenging potential of PUFA and the production of reactive oxygen/nitrogen (ROS/RNS) species by human aortic endothelial cells (HAECs) supplemented with different fatty acids. Fatty acid micelles scavenged superoxide in an unsaturation-dependent manner, up to eicosapentaenoic acid, which was the most effective fatty acid. Supplementation of HAEC with polyunsaturated fatty acids of the omega 3 series resulted in lower formation of ROS, as compared with cells supplemented with saturates, monounsaturates, or polyunsaturates of the omega 6 series. This effect was maximal at concentrations of 10muM. The effects of omega 3 fatty acids on reactive species production appear to be stronger when ROS were evaluated, as a milder, albeit significant effect was observed on RNS generation. Based on in vivo data showing reduced excretion of lipid peroxidation products after omega 3 intake and our data on ROS production and direct superoxide scavenging by LC-PUFAs, notably those of the omega 3 series, we propose that this series of fatty acid might act as indirect anti- rather than pro-oxidant in vascular endothelial cells, hence diminishing inflammation and, in turn, the risk of atherosclerosis and cardiovascular disease.
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                Author and article information

                Journal
                Nutr Metab (Lond)
                Nutr Metab (Lond)
                Nutrition & Metabolism
                BioMed Central
                1743-7075
                2012
                23 May 2012
                : 9
                : 45
                Affiliations
                [1 ]Faculty of Natural Sciences at the Leibniz University of Hannover, Institute of Food Science and Human Nutrition, Am Kleinen Felde 30, 30167, Hannover, Germany
                [2 ]Faculty of Natural Sciences at the Leibniz University of Hannover, Institute of Technical Chemistry, Callinstr 5, 30167, Hannover, Germany
                Article
                1743-7075-9-45
                10.1186/1743-7075-9-45
                3408332
                22621246
                40d80a51-91f9-4a9c-bdd8-9efe9b9a1574
                Copyright ©2012 Schmidt et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 5 March 2012
                : 23 May 2012
                Categories
                Research

                Nutrition & Dietetics
                oxylipines,omega-3 fatty acids,glutathione,dyslipidemia,cytochrome p450 enzyme,matrix metalloproteinase,catalase,heme oxygenase,antioxidative defence

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