PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway.
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.
Chinetti
G
G
Institut Pasteur and U325 INSERM and Université de Lille 2, Lille, France.
Lestavel
S
S
Bocher
V
V
Remaley
A T
AT
Neve
B
B
Torra
I P
IP
Teissier
E
E
Minnich
A
A
Jaye
M
M
Duverger
N
N
Brewer
H B
HB
Fruchart
J C
JC
Clavey
V
V
Staels
B
B
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*
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