PPAR- and PPAR- activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway
Giulia Chinetti1, Sophie Lestavel1, Virginie Bocher1, Alan T. Remaley2, Bernadette Neve1, Inés Pineda Torra1, Elisabeth Teissier1, Anne Minnich3, Michael Jaye3, Nicolas Duverger4, H. Bryan Brewer2, Jean-Charles Fruchart1, Véronique Clavey1
& Bart Staels1
1
Institut Pasteur and U325 INSERM and Université de Lille 2, Lille, France
2
National Institutes of Health, National Heart, Lung and Blood Institute, Bethesda, Maryland, USA
3
Aventis Pharma, Collegeville, Pennsylvania 19426, USA
4
Core Genomics and Cardiovascular Departments, Aventis Pharma, Vitry sur Seine, France
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate lipid and glucose metabolism and cellular differentiation. PPAR- and PPAR- are both expressed in human macrophages where they exert anti-inflammatory effects. The activation of PPAR- may promote foam-cell formation by inducing expression of the macrophage scavenger receptor CD36. This prompted us to investigate the influence of different PPAR- activators on cholesterol metabolism and foam-cell formation of human primary and THP-1 macrophages. Here we show that PPAR- and PPAR- activators do not influence acetylated low density lipoprotein-induced foam-cell formation of human macrophages. In contrast, PPAR- and PPAR- activators induce the expression of the gene encoding ABCA1, a transporter that controls apoAI-mediated cholesterol efflux from macrophages. These effects are likely due to enhanced expression of liver-x-receptor , an oxysterol-activated nuclear receptor which induces ABCA1- promoter transcription. Moreover, PPAR- and PPAR- activators increase apoAI-induced cholesterol efflux from normal macrophages. In contrast, PPAR- or PPAR- activation does not influence cholesterol efflux from macrophages isolated from patients with Tangier disease, which is due to a genetic defect in ABCA1. Here we identify a regulatory role for PPAR- and PPAR- in the first steps of the reverse-cholesterol-transport pathway through the activation of ABCA1-mediated cholesterol efflux in human macrophages.
and PPAR-
activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway
and PPAR-
are both expressed in human macrophages where they exert anti-inflammatory effects. The activation of PPAR-
