Abstract
Omega-6 polyunsaturated fatty acid (n-6 PUFA) is the predominant polyunsaturated fatty acid (PUFA), especially in Western diet. A high omega-6/omega-3 ratio in Western diets is implicated in the development of cardiovascular diseases and inflammatory processes. Studies in animal models and in humans have demonstrated beneficial effects of omega-3 PUFA (n-3 PUFA) in a variety of diseases, including cardiac arrhythmias and inflammatory diseases, as well as breast and colon cancer. The molecular mechanisms underlying the effects of n-3 PUFA are still not well understood. Possible mechanisms include competition between n-3 and n-6 PUFAs at the cyclooxygenase (COX) and lipoxygenase (LOX) and cytochrome P450 levels, and subsequent formation of oxylipins with specific anti-inflammatory or anti-arrhythmic effects. In this study, we report the impact of routine long-term treatment with prescription-grade n-3 PUFA (either 840 mg or 1680 mg per day) on blood cell membrane fatty acid composition, as well as plasma oxylipin patterns, in a patient population with severe hyperlipidemia and cardiovascular disease who are on standard lipid-lowering and cardioprotective medications. Lipidomics analyses were performed by LC/ESI-MS/MS. Supplementation led to a dose-dependent increase in n-3 PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the blood cell fraction. We also observed a dose-dependent increase in EPA- and DHA-derived epoxy metabolites, whereas the effect of n-3 PUFA supplementation on LOX-dependent EPA- and DHA-derived hydroxy metabolites was less pronounced, with a tendency towards lower metabolites in subjects with higher n-3 PUFA levels. These data thus generally confirm effects of n-3 PUFA supplementation observed previously in healthy individuals. Additionally, they indicate a suppressive effect of high n-3 PUFA supplementation on the formation of LOX metabolites in the context of concomitant aspirin medication.
Highlights
Omega-6 polyunsaturated fatty acids (n-6 PUFAs) such as arachidonic acid (AA, 20:4 n-6) have been shown to enhance predominantly negative effects: pro-inflammatory [1], pro-thrombotic and pro-arrhythmogenic effects [2]
We report the impact of long-term treatment with prescription-grade n-3 PUFAs on blood cell fatty acid composition, as well as plasma oxylipin patterns in a patient population with severe atherosclerosis and hyperlipidemia who are on long-term treatment with aspirin and lipid-lowering drugs
D0.i0f5fe).rences between the groups are significant as indicated (* p < 0.05). This is the first study to investigate the impact of a routine medication with n-3 PUFA in two different doses on AA, docosahexaenoic acid (DHA)- and eicosapentaenoic acid (EPA)-derived lipid metabolites in severely hyperlipidemic patients with atherosclerotic disease and the full spectrum of concomitant medications most notably aspirin and statins
Summary
Omega-6 polyunsaturated fatty acids (n-6 PUFAs) such as arachidonic acid (AA, 20:4 n-6) have been shown to enhance predominantly negative effects: pro-inflammatory [1], pro-thrombotic and pro-arrhythmogenic effects [2]. Taken together with non-enzymatic pathways, a broad variety of bioactive lipid mediators can be generated, which are important for understanding the molecular mechanisms underlying the effects of n-3 PUFAs. Many of the EPA- and DHA-derived metabolites have been characterized and have been shown to have potent anti-inflammatory effects in a variety of inflammation models [7]. Many of the EPA- and DHA-derived metabolites have been characterized and have been shown to have potent anti-inflammatory effects in a variety of inflammation models [7] These include reduced platelet adherence and vasodilation by modulating transcription factors such as sterol regulatory-element binding protein (SREBP) [8] and the peroxisome proliferator-activated receptor (PPAR) [9]. Epoxydocosapentaenoic acids (EDPs) for instance, cytochrome P450 epoxygenase metabolites of DHA, have been reported to be more potent vasodilatory and anti-inflammatory compounds than AA-derived epoxyeicosatrienoic acids (EETs) [10]
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