ABC1 gene expression and ApoA-I-mediated cholesterol efflux are regulated by LXR.
ATP-binding cassette transporter 1 (ABC1) mediates the active efflux of cholesterol from cells to apolipoproteins. To study the mechanisms of regulation of ABC1 gene expression, RAW 264.7 macrophages were transiently transfected with ABC1 promoter-luciferase reporter gene-fusion constructs. Transcription from a 1.64 kb fragment was induced by cholesterol loading but was not responsive to cAMP. Treatment of the cells with 9-cis retinoic acid or 20(S)-hydroxycholesterol, ligands for the nuclear receptors LXR and RXR, resulted in a marked induction of luciferase expression. The responsible control element was mapped to an imperfect direct repeat of the nuclear receptor half-site TGACCT separated by four bases (DR-4) that binds LXR/RXR heterodimers. Endogenous ABC1 gene expression in RAW cells and apolipoprotein A-I mediated cholesterol efflux were also upregulated by both receptor ligands. These findings raise the possibility that ligands that activate the LXR-RXR heterodimer may be useful for the therapeutic modulation of the ABC1 pathway.
CV Therapeutics Inc., 3172 Porter Drive, Palo Alto, California, 94304, USA.
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D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D016632:Apolipoprotein A-I / Q000502:physiology*; D001483:Base Sequence; D001692:Biological Transport / Q000502:physiology; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins; D017930:Genes, Reporter; D006023:Glycoproteins / Q000502:physiology*; D008024:Ligands; D000071518:Liver X Receptors; D008156:Luciferases / Q000235:genetics; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D004268:DNA-Binding Proteins; D006023:Glycoproteins; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D002784:Cholesterol; D008156:Luciferases