Regulation of the expression of platelet-activating factor (PAF) receptor by atherogenic lipoproteins might contribute to atherogenesis. We show that progressive oxidation of low-density lipoprotein (LDL) gradually inhibits PAF 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 γ (PPARγ), a nuclear receptor activated by oxLDL. OxLDL decreased by 50% (P ⩽0.001) and by 29% (P⩽0.05) the binding of PAF and the expression of PAF receptor mRNA respectively. Next we demonstrated that progressive oxidation of LDLs significantly activated PPARα-dependent transcription in transfected mouse aortic endothelial cells. Finally we demonstrated, in mature macrophages, that fenofibrate (20µM), a specific PPARα agonist, but not the specific PPARγ agonist BRL49653 (20nM), significantly decreased both PAF binding and PAF receptor mRNA expression, by 65% and 40% (P⩽0.001) respectively. Additionally, another PPARα agonist, Wy14,643, decreased PAF receptor promoter activity by 70% (P⩽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)-κB motifs. Thus PPARα might be involved in the down-regulation of PAF receptor gene expression by oxLDLs in human monocytes/macrophages. The oxidation of one or more lipid components of LDLs might result in the formation of natural activators of PPARα. It is hypothesized that such activators might modulate inflammation and apoptosis upon atherogenesis by decreasing the expression of PAF receptor.
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February 2001
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Research Article|
February 08 2001
Oxidized low-density lipoprotein and peroxisome-proliferator-activated receptor α down-regulate platelet-activating-factor receptor expression in human macrophages
Delphine HOURTON;
Delphine HOURTON
*INSERM U321, Bâtiment d'Anatomopathologie, Groupe Hôspitalier Pitié-Salpêtrière, 83 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France
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Philippe DELERIVE;
Philippe DELERIVE
†INSERM U325, Département d'Athérosclérose, Institut Pasteur de Lille, Faculte de Pharmacie, Université de Lille II, 1 rue du Professor Calmette, 59019 Lille, Lille, France
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Jana STANKOVA;
Jana STANKOVA
‡Immunology Division, Département de Pédiatrie, Faculte de Médecine, Université de Sherbrooke, Sherbrooke, QC, J1H 5N4, Canada.
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Bart STAELS;
Bart STAELS
†INSERM U325, Département d'Athérosclérose, Institut Pasteur de Lille, Faculte de Pharmacie, Université de Lille II, 1 rue du Professor Calmette, 59019 Lille, Lille, France
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M. John CHAPMAN;
M. John CHAPMAN
*INSERM U321, Bâtiment d'Anatomopathologie, Groupe Hôspitalier Pitié-Salpêtrière, 83 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France
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Ewa NINIO
*INSERM U321, Bâtiment d'Anatomopathologie, Groupe Hôspitalier Pitié-Salpêtrière, 83 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France
1To whom correspondence should be addressed (e-mail eninio@infobiogen.fr).
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Publisher: Portland Press Ltd
Received:
July 27 2000
Revision Received:
September 29 2000
Accepted:
October 26 2000
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 2001
2001
Biochem J (2001) 354 (1): 225–232.
Article history
Received:
July 27 2000
Revision Received:
September 29 2000
Accepted:
October 26 2000
Citation
Delphine HOURTON, Philippe DELERIVE, Jana STANKOVA, Bart STAELS, M. John CHAPMAN, Ewa NINIO; Oxidized low-density lipoprotein and peroxisome-proliferator-activated receptor α down-regulate platelet-activating-factor receptor expression in human macrophages. Biochem J 15 February 2001; 354 (1): 225–232. doi: https://doi.org/10.1042/bj3540225
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