Abstract

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.