Oxidized phospholipids activate PPARalpha in a phospholipase A2-dependent manner.
The peroxisome proliferator-activated receptor alpha (PPARalpha) is a transcription factor belonging to the PPAR subfamily of nuclear receptors. Fatty acids and eicosanoids are natural PPARalpha ligands. Here, we show using transient transfection assays that oxidized (oxLDL) but not native low-density lipoproteins (LDL) dose-dependently activate PPARalpha in endothelial cells without affecting PPARalpha protein expression. Fractioning of oxLDL lipids followed by transactivation experiments demonstrated that the oxidized phospholipid component in oxLDL is responsible for PPARalpha activation. Using specific inhibitors, it is shown that oxLDL-mediated PPARalpha activation requires phospholipase A2 activity and that the oxidized fatty acids 9- and 13-HODE activate PPARalpha directly. Finally, we found that, similar to the synthetic PPARalpha ligand Wy-14643, oxLDL induced expression of the fatty acid transport protein-1 in human primary endothelial cells. Our findings define a novel group of PPARalpha activators and provide a molecular basis for certain effects of these biologically active phospholipids on gene transcription.
Delerive
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P
INSERM U.325, Département d'Athérosclérose, Institut Pasteur de Lille, 1 Rue Calmette, P.O. Box 245, 59019, Lille, France.
Furman
C
C
Teissier
E
E
Fruchart
J
J
Duriez
P
P
Staels
B
B
D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D050612:Fatty Acid Transport Proteins; D005786:Gene Expression Regulation; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D026901:Membrane Transport Proteins; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D010743:Phospholipids / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
D002352:Carrier Proteins; D050612:Fatty Acid Transport Proteins; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D010743:Phospholipids; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C099252:oxidized low density lipoprotein; D010741:Phospholipases A; D054467:Phospholipases A2