Omega-3 fatty acids, which are abundant in fish oil, improve the prognosis of several chronic inflammatory diseases although the mechanism for such effects remains unclear. These fatty acids, such as eicosapentaenoic acid (EPA), are highly polyunsaturated and readily undergo oxidation. We show that oxidized, but not native unoxidized, EPA significantly inhibited human neutrophil and monocyte adhesion to endothelial cells in vitro by inhibiting endothelial adhesion receptor expression. In transcriptional coactivation assays, oxidized EPA potently activated the peroxisome proliferator-activated receptor ␣ (PPAR␣), a member of the nuclear receptor family. In vivo, oxidized, but not native, EPA markedly reduced leukocyte rolling and adhesion to venular endothelium of lipopolysaccharide (LPS)-treated mice. This occurred via a PPAR␣-dependent mechanism because oxidized EPA had no such effect in LPS-treated PPAR␣-deficient mice. Therefore, the beneficial effects of omega-3 fatty acids may be explained by a PPAR␣-mediated anti-inflammatory effect of oxidized EPA.
IntroductionConsumption of omega-3 fatty acids in fish oil has been reported to improve the prognosis of several chronic inflammatory diseases characterized by leukocyte accumulation, including atherosclerosis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, and rheumatoid arthritis. [1][2][3][4] Fish oil is also recommended for treatment of IgA nephropathy, the most common form of primary renal disease worldwide. 5,6 Several studies suggest that omega-3 fatty acid supplementation may reduce the inflammatory response by attenuating leukocyte adhesion to the vessel wall. [7][8][9] However, the primary mechanism for the anti-inflammatory effects of fish oil remains unclear. 10 Omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are highly polyunsaturated and readily undergo oxidation. 11 This suggests the possibility that oxidized omega-3 fatty acids may be an important component of the observed anti-inflammatory effects of fish oil. Indeed, Sethi and colleagues showed that oxidized EPA and DHA are more potent than native fatty acids in reducing RNA levels of leukocyte adhesion receptors and the adhesion of leukocyte cell lines to endothelial cells in vitro. 12 Polyunsaturated fatty acids may exert their effects in cells by activation of peroxisome proliferatoractivated receptors (PPARs). PPARs are ligand-activated transcription factors that regulate genes important in cell differentiation and various metabolic processes. Known PPAR isoforms include PPAR␥, important in lipoprotein metabolism, adipogenesis, and insulin sensitivity; PPAR␣, implicated in fatty acid metabolism; and PPAR␦, about which the least is known. 13,14 Synthetic PPAR␣ ligands such as fibrates (eg, fenofibric acid) are used in patients to lower triglyceride-rich lipoproteins. Synthetic PPAR␥ ligands such as thiazolidinediones (eg, rosiglitazone) are insulin-sensitizing drugs used in the treatment of diabetes. Polyunsaturated fatty acids...