Oxidized phospholipids activate PPARα in a phospholipase A2-dependent manner

The peroxisome proliferator-activated receptor alpha (PPAR alpha) is a transcription factor belonging to the PPAR subfamily of nuclear receptors, Fatty acids and eicosanoids are natural PPAR alpha ligands. Here, me show using transient transfection assays that oxidized (oxLDL) but not native low-density lipoproteins (LDL) dose-dependently activate PPAR alpha in endothelial cells without affecting PPAR alpha protein espression, Fractioning of oxLDL lipids followed by transactivation experiments demonstrated that the oxidized phospholipid component in oxLDL is responsible for PPAR alpha activation, Using specific inhibitors, it is shown that oxLDL-mediated PPAR alpha activation requires phospholipase A2 activity and that the oxidized fatty acids 9- and 13-HODE activate PPAR alpha directly. Finally, we found that, similar to the synthetic PPAR alpha ligand Wy-14643, oxLDL induced espression of the fatty acid transport protein-1 in human primary endothelial cells. Our findings define a no,el group of PPAR alpha activators and provide a molecular basis for certain effects of these biologically active phospholipids on gene transcription. (C) 2000 Federation of European Biochemical Societies.