Oxidized LDL downregulates ATP-binding cassette transporter-1 in human vascular endothelial cells via inhibiting liver X receptor (LXR).
OBJECTIVE
ATP-binding cassette transporter-1 (ABCA1) mediates the active efflux of cholesterol and phospholipids, playing an important role in cholesterol homeostasis and atherogenesis. Oxidized low density lipoprotein (oxLDL) is an atherogenic molecule associated with the vascular endothelial dysfunction and development of atherosclerotic plaque. This report describes the effect of copper-catalyzed oxLDL on the regulation of ABCA1 in human endothelial cells (ECs).


RESULTS
oxLDL downregulated ABCA1 at both mRNA and protein levels in a dose-dependent manner. This inhibitory effect of oxLDL was observed with both minimally and extensively oxLDL. Transfection of the ABCA1 promoter luciferase revealed oxLDL to substantially decrease ABCA1 promoter activity at basal conditions and after stimulation by overexpressing the liver X receptor LXRalpha and retinoid X receptor RXRalpha. oxLDL also attenuated LXR activation by blocking LXR ligand binding and interfering with the generation of 27-hydroxycholesterol, an LXR endogenous ligand. Furthermore, oxLDL inhibited exogenous cholesterol- and oxysterol-induced endothelial ABCA1 induction.


CONCLUSIONS
oxLDL downregulated ABCA1 by inhibiting LXR activation in endothelial cells. Such an effect may contribute to endothelial dysfunction and plaque formation.
Zhu
Yi
Y
Department of Physiology, Key Laboratory of Molecular Cardiovascular Sciences of Education Ministry, Health Science Center, Peking University, Beijing 100083, China. zhuyi@bjmu.edu.cn
Liao
Hailing
H
Xie
Xuefen
X
Yuan
Yuan
Y
Lee
Tzong-Shyuan
TS
Wang
Nanping
N
Wang
Xian
X
Shyy
John Y-J
JY
Stemerman
Michael B
MB
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000199:Actins / Q000235:genetics; D015415:Biomarkers / Q000032:analysis; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002460:Cell Line; D053493:Cholestanetriol 26-Monooxygenase; D002784:Cholesterol / Q000032:analysis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051127:Scavenger Receptors, Class E / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics; D014162:Transfection / Q000379:methods; D014841:von Willebrand Factor / Q000235:genetics
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000199:Actins; D015415:Biomarkers; D004268:DNA-Binding Proteins; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C495137:OLR1 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; D014841:von Willebrand Factor; D002784:Cholesterol; D013250:Steroid Hydroxylases; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase