Oxidized phospholipids activate PPARα in a phospholipase A2‐dependent manner

Abstract

The peroxisome proliferator-activated receptor K K (PPARK K) is a transcription factor belonging to the PPAR subfamily of nuclear receptors. Fatty acids and eicosanoids are natural PPARK K ligands. Here, we show using transient transfection assays that oxidized (oxLDL) but not native lowdensity lipoproteins (LDL) dose-dependently activate PPARK K in endothelial cells without affecting PPARK K protein expression. Fractioning of oxLDL lipids followed by transactivation experiments demonstrated that the oxidized phospholipid component in oxLDL is responsible for PPARK K activation. Using specific inhibitors, it is shown that oxLDL-mediated PPARK K activation requires phospholipase A2 activity and that the oxidized fatty acids 9-and 13-HODE activate PPARK K directly. Finally, we found that, similar to the synthetic PPARK K 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 PPARK K activators and provide a molecular basis for certain effects of these biologically active phospholipids on gene transcription.z 2000 Federation of European Biochemical Societies.

Paraoxonase 1‐treated oxLDL promotes cholesterol efflux from macrophages by stimulating the PPARγ–LXRα–ABCA1 pathway

“…Given that LysoPC is the major product of PON1 hydrolytic activity in the presence of oxLDL and that LysoPC can stimulate the PPARc-LXRa-ABCA1 pathway, this strengthens the notion that oxLDL-PON1 promotes cholesterol efflux by the activation of the PPARc-LXRa-ABCA1 pathway in J774 macrophages and that this effect is due to the LysoPC formed by the hydrolytic activity of PON1. Previous study of Delerive et al showed that oxLDL induced the activation of PPARa on human coronary endothelial cells in a phospholipase A2-dependent manner [53]. In the present study, we did not investigate the effect of oxLDL-PON1 on PPARa expression on macrophages; however, our results confirm that PON1, due to its PLA2-like activity, hydrolyzes oxLDL to induce the activation of PPARc.…”

Dual Roles for Lipolysis and Oxidation in Peroxisome Proliferation-Activator Receptor Responses to Electronegative Low Density Lipoprotein

“…4C). The oxidized molecules likely responsible for these effects have been identified as 9-and 13-HODE, both established PPAR␥ (27) and PPAR␣ activators (30). Such HODEs are released during LDL hydrolysis of LDL(Ϫ) (Fig.…”

“…Recently, PPAR␣ LBD activation by HODE has been reported (30). To evaluate the extent of PPAR␣ activation by HODE and HpODE, cell-free displacement and cell-based LBD assays were performed.…”

IAP Survivin Regulates Atherosclerotic Macrophage Survival

“…Alternatively, M-CSF-stimulated or adenovirus-transduced macrophages were incubated for 48 hours with 1 to 100 g/mL of human oxLDL prepared by complete CuSO 4 oxidation, as described (215.2Ϯ32 nmol peroxides/mg protein, 46Ϯ4 nmol TBARS/mg protein). 35 …”