title: PPAR-alpha and PPAR-gamma 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-alpha and PPAR-gamma are both expressed in human macrophages where they exert anti-inflammatory effects. The activation of PPAR-alpha 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-alpha and PPAR-gamma activators do not influence acetylated low density lipoprotein-induced foam-cell formation of human macrophages. In contrast, PPAR-alpha and PPAR-gamma 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 alpha, an oxysterol-activated nuclear receptor which induces ABCA1-promoter transcription. Moreover, PPAR-alpha and PPAR-gamma activators increase apoAI-induced cholesterol efflux from normal macrophages. In contrast, PPAR-alpha or PPAR-gamma 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-alpha and PPAR-gamma in the first steps of the reverse-cholesterol-transport pathway through the activation of ABCA1-mediated cholesterol efflux in human macrophages.
authors.affiliation: Institut Pasteur and U325 INSERM and Université de Lille 2, Lille, France.
authors.forename: G
authors.initials: G
authors.lastname: Chinetti
authors.forename: S
authors.initials: S
authors.lastname: Lestavel
authors.forename: V
authors.initials: V
authors.lastname: Bocher
authors.forename: A T
authors.initials: AT
authors.lastname: Remaley
authors.forename: B
authors.initials: B
authors.lastname: Neve
authors.forename: I P
authors.initials: IP
authors.lastname: Torra
authors.forename: E
authors.initials: E
authors.lastname: Teissier
authors.forename: A
authors.initials: A
authors.lastname: Minnich
authors.forename: M
authors.initials: M
authors.lastname: Jaye
authors.forename: N
authors.initials: N
authors.lastname: Duverger
authors.forename: H B
authors.initials: HB
authors.lastname: Brewer
authors.forename: J C
authors.initials: JC
authors.lastname: Fruchart
authors.forename: V
authors.initials: V
authors.lastname: Clavey
authors.forename: B
authors.initials: B
authors.lastname: Staels
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D001483:Base Sequence; D001692:Biological Transport; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D017931:DNA Primers; D005487:Foam Cells / Q000378:metabolism*; D006801:Humans; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D014157:Transcription Factors / Q000819:agonists*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D017931:DNA Primers; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D002784:Cholesterol