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PPAR-α and PPAR-γ activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway

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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Figure 1: PPAR-α and PPAR-γ activators do not influence foam-cell transformation of human macrophages.
Figure 2: PPAR-α and PPAR-γ activators induce ABCA1-gene expression in human primary and in differentiated THP-1 macrophages.
Figure 3: PPAR-α and PPAR-γ activators induce LXR-α gene expression in primary human macrophages.
Figure 4: PPAR- and LXR-agonists cooperatively induce ABCA1-gene expression in human macrophages.
Figure 5: PPAR-activators induce apoAI-mediated cholesterol efflux from human macrophages.
Figure 6: The ABCA1 transporter inhibitor DIDS inhibits the apoAI-mediated induction of cholesterol efflux by PPAR-activators from human macrophages.
Figure 7: PPAR-activators do not influence cholesterol efflux from Tangier macrophages.

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Acknowledgements

We thank the Etablissement Français du sang- Nord de France for buffy coats of healthy individuals; A. Shevelev for the pcDNA3-hLXR-α plasmid; A. Bril for rosiglitazone; and B. Derudas, P. Poulain, N. Tian and G. Searfoss for technical contribution. This work was supported by grants from the Fondation pour la Recherche Médicale (to G.C.), Aventis Pharma and ARCOL.

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Correspondence to Bart Staels.

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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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