Native LDL upregulation of ATP-binding cassette transporter-1 in human vascular endothelial cells.
ATP-binding cassette transporter-1 (ABCA1) mediates the lipid efflux from cells to apolipoproteins. In studying the gene expression and regulation of ABCA1 in human vascular endothelial cells (ECs), we found that native low density lipoprotein (LDL) elevates ABCA1 in both protein and mRNA levels in a time- and dose-dependent fashion. Transfection of full-length human ABCA1 in ECs lowers cellular cholesterol content and increases apolipoprotein (apo) A-I-mediated cholesterol efflux. Transfection of the ABCA1 promoter-luciferase reporter results in a 2-fold induction after LDL exposure. The responsive element was mapped within -116 to -54 of the promoter region with use of promoter deletion constructs, as reported in other cells. A mutation of the DR4 site greatly diminished the LDL effect. Results showing that LDL increases the liver X receptor responsive element (LXRE)-driven luciferase activity demonstrate the effect of LDL on LXR activation. Furthermore, ligands of the retinoid X receptor and LXR activate ABCA1 in ECs at levels of both promoter activation and mRNA induction. Therefore, ABCA1 is expressed in vascular ECs and is transcriptionally upregulated by LDL. Overexpression of ABCA1 in these cells prevents overloading of cholesterol by increasing the efflux of cholesterol. Thus, ABCA1 plays an important role in the homeostasis of cholesterol in the vascular endothelium.
Liao
Hailing
H
Division of Biomedical Sciences, University of California, Riverside 92521, USA.
Langmann
Thomas
T
Schmitz
Gerd
G
Zhu
Yi
Y
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D016632:Apolipoprotein A-I / Q000378:metabolism*; D002478:Cells, Cultured / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000494:pharmacology*; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D000071518:Liver X Receptors; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008078:Cholesterol, LDL; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D002784:Cholesterol; D008156:Luciferases