Oxidized low-density lipoprotein and peroxisome-proliferator-activated receptor alpha down-regulate platelet-activating-factor receptor expression inhuman macrophages

Citation
D. Hourton et al., Oxidized low-density lipoprotein and peroxisome-proliferator-activated receptor alpha down-regulate platelet-activating-factor receptor expression inhuman macrophages, BIOCHEM J, 354, 2001, pp. 225-232
Citations number
50
Categorie Soggetti
Biochemistry & Biophysics
Journal title
BIOCHEMICAL JOURNAL
ISSN journal
02646021 → ACNP
Volume
354
Year of publication
2001
Part
1
Pages
225 - 232
Database
ISI
SICI code
0264-6021(20010215)354:<225:OLLAPR>2.0.ZU;2-0
Abstract
Regulation of the expression of platelet-activating factor (PAF) receptor b y atherogenic lipoproteins might contribute to atherogenesis. We show that progressive oxidation of low-density lipoprotein (LDL) gradually inhibits P AF receptor expression on the macrophage cell surface. We tested the effect of oxidized LDL (oxLDL) on PAF receptor expression in human monocytes that do not contain peroxisome-proliferator-activated receptor gamma (PPAR gamm a), a nuclear receptor activated by oxLDL. OxLDL decreased by 50% (P less t han or equal to 0.001) and by 29% (P less than or equal to 0.05) the bindin g of PAF and the expression of PAF receptor mRNA respectively. Next we demo nstrated that progressive oxidation of LDLs significantly activated PPAR al pha -dependent transcription in transfected mouse aortic endothelial cells. Finally we demonstrated, in mature macrophages, that fenofibrate (20 muM), a specific PPAR alpha agonist, but not the specific PPAR gamma agonist BRL 49653 (20 nM), significantly decreased both PAF binding and PAF receptor mR NA expression, by 65% and 40% (P less than or equal to 0.001) respectively. Additionally, another PPAR alpha agonist, Wy14,643, decreased PAF receptor promoter activity by 70% (P less than or equal to 0.05) in transfected THP -1 cells, suggesting the involvement of the proximal promoter region (-980 to -500) containing a series of four nuclear factor (NF)-kappaB motifs. Thu s PPAR alpha might be involved in the down-regulation of PAF receptor gene expression by oxLDLs in human monocytes/macrophages. The oxidation of one o r more lipid components of LDLs might result in the formation of natural ac tivators of PPAR alpha. It is hypothesized that such activators might modul ate inflammation and apoptosis upon atherogenesis by decreasing the express ion of PAF receptor.