title: Omega-3 fatty acids cause dramatic changes in TLR4 and purinergic eicosanoid signaling.
abstract: Dietary fish oil containing ω3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), elicit cardioprotective and anti-inflammatory effects through unresolved mechanisms that may involve competition and inhibition at multiple levels. Here, we report the effects of arachidonic acid (AA), EPA, and DHA supplementation on membrane incorporation, phospholipase A(2) catalyzed release, and eicosanoid production in RAW264.7 macrophages. Using a targeted lipidomics approach, we observed that Toll-like receptor 4 and purinergic receptor activation of supplemented cells leads to the release of 22-carbon fatty acids that potently inhibit cyclooxygenase pathways. This inhibition was able to shunt metabolism of AA to lipoxygenase pathways, augmenting leukotriene and other lipoxygenase mediator synthesis. In resident peritoneal macrophages, docosapentaenoic acid (DPA) was responsible for cyclooxygenase inhibition after EPA supplementation, offering fresh insights into how EPA exerts anti-inflammatory effects indirectly through elongation to 22-carbon DPA.
authors.affiliation: Department of Chemistry/Biochemistry, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Norris
authors.forename: Edward A
authors.initials: EA
authors.lastname: Dennis
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004281:Docosahexaenoic Acids / Q000378:metabolism / Q000494:pharmacology; D015777:Eicosanoids / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000378:metabolism / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry; D008070:Lipopolysaccharides / Q000494:pharmacology; D008084:Lipoxygenase / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D054467:Phospholipases A2 / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism*
chemical_list: D015777:Eicosanoids; D015525:Fatty Acids, Omega-3; D005231:Fatty Acids, Unsaturated; C506188:Kdo2-lipid A; D008070:Lipopolysaccharides; D008563:Membrane Lipids; D058486:Receptors, Purinergic P2X7; D051197:Toll-Like Receptor 4; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D000255:Adenosine Triphosphate; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D054467:Phospholipases A2; C026219:docosapentaenoic acid