Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor.
A common feature of many metabolic pathways is their control by retinoid X receptor (RXR) heterodimers. Dysregulation of such metabolic pathways can lead to the development of atherosclerosis, a disease influenced by both systemic and local factors. Here we analyzed the effects of activation of RXR and some of its heterodimers in apolipoprotein E -/- mice, a well established animal model of atherosclerosis. An RXR agonist drastically reduced the development of atherosclerosis. In addition, a ligand for the peroxisome proliferator-activated receptor (PPAR)gamma and a dual agonist of both PPARalpha and PPARgamma had moderate inhibitory effects. Both RXR and liver X receptor (LXR) agonists induced ATP-binding cassette protein 1 (ABC-1) expression and stimulated ABC-1-mediated cholesterol efflux from macrophages from wild-type, but not from LXRalpha and beta double -/-, mice. Hence, activation of ABC-1-mediated cholesterol efflux by the RXR/LXR heterodimer might contribute to the beneficial effects of rexinoids on atherosclerosis and warrant further evaluation of RXR/LXR agonists in prevention and treatment of atherosclerosis.
Claudel
T
T
Département d'Athérosclérose, Institut National de la Santé et de la Recherché Médicale (INSERM) U325, Institut Pasteur de Lille, 59019 Lille, France.
Leibowitz
M D
MD
Fiévet
C
C
Tailleux
A
A
Wagner
B
B
Repa
J J
JJ
Torpier
G
G
Lobaccaro
J M
JM
Paterniti
J R
JR
Mangelsdorf
D J
DJ
Heyman
R A
RA
Auwerx
J
J
D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D001161:Arteriosclerosis / Q000235:genetics / Q000517:prevention & control*; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000378:metabolism*
D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D002784:Cholesterol