Oxidized omega-3 fatty acids in fish oil inhibit leukocyte-endothelial interactions through activation of PPAR alpha.
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 alpha (PPAR alpha), 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 alpha-dependent mechanism because oxidized EPA had no such effect in LPS-treated PPAR alpha-deficient mice. Therefore, the beneficial effects of omega-3 fatty acids may be explained by a PPAR alpha-mediated anti-inflammatory effect of oxidized EPA.
Sethi
Sanjeev
S
Vascular Research Division, Department of Pathology, Brigham and Women's Hospital and Center for Blood Research, Harvard Medical School, Boston, MA 02130, USA.
Ziouzenkova
Ouliana
O
Ni
Heyu
H
Wagner
Denisa D
DD
Plutzky
Jorge
J
Mayadas
Tanya N
TN
D000818:Animals; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects*; D002478:Cells, Cultured; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage / Q000494:pharmacology*; D005395:Fish Oils / Q000737:chemistry*; D015200:Fluoroimmunoassay; D006801:Humans; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D010084:Oxidation-Reduction; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014471:Umbilical Veins
D015525:Fatty Acids, Omega-3; D005395:Fish Oils; D008070:Lipopolysaccharides; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D015118:Eicosapentaenoic Acid