PPAR-α and PPAR-γ activators induce cholesterol removal from human macrophage foam cells through sti

Abstract

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate lipid and glucose metabolism and cellular differentiation. PPAR-α and PPAR-γ are both expressed in human macrophages where they exert anti-inflammatory effects. The activation of PPAR-α 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-α and PPAR-γ activators do not influence acetylated low density lipoprotein-induced foam-cell formation of human macrophages. In contrast, PPAR-α and PPAR-γ 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 α, an oxysterol-activated nuclear receptor which induces ABCA1- promoter transcription. Moreover, PPAR-α and PPAR-γ activators increase apoAI-induced cholesterol efflux from normal macrophages. In contrast, PPAR-α or PPAR-γ 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-α and PPAR-γ in the first steps of the reverse-cholesterol-transport pathway through the activation of ABCA1-mediated cholesterol efflux in human macrophages.

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Chinetti, G., Lestavel, S., Bocher, V. et al. PPAR-α and PPAR-γ activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med 7, 53–58 (2001). https://doi.org/10.1038/83348

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