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Papers In Press, published online ahead of print July 16, 2005
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Molecular Disease Branch, National Heart, Lung, and Blood Inst., National Institutes of Health, Bethesda, MD 20892-1666
Corresponding Author: SLSABOL{at}MAIL.NIH.GOV
The ATP binding cassette transporter G1 (ABCG1), expressed in macrophages, liver, and other tissues, has been implicated in the efflux of cholesterol to high density lipoprotein. The ABCG1 gene is transcriptionally activated by cholesterol loading and oxysterol activators of liver X receptors (LXR); however, the DNA sequences mediating this activation have not been fully characterized. Here we show that ABCG1 mRNA is induced by LXR agonists not only in RAW264.7 macrophage cells but also in primary mouse hepatocytes and HepG2 hepatoma cells. We identify two evolutionarily highly conserved LXR response elements, LXRE-A and LXRE-B, located in the first and second introns at approximately 1250 bp and 14,500 bp, respectively, from the major human ABCG1 transcription start site determined in this study. LXRE-A and LXRE-B conferred robust orientation- and position-independent responsiveness of ABCG1 promoter-directed luciferase gene constructs to LXR agonists (3-8-fold stimulation) or LXR plus RXR agonists (10-18-fold stimulation) in both RAW264.7 and HepG2 cells. Similarly, cotransfection of plasmids expressing LXRa/RXRa and LXRß/RXRa activated the ABCG1 promoter in the presence of LXRE-A or LXRE-B. Mutations in the DR4 core motif of LXRE-A or LXRE-B abolished LXR-agonist activation. In gel shift assays, LXRa/RXRa and LXRß/RXRa heterodimers bound to the LXRE-A and LXRE-B sequences but not to mutated sequences. Chromatin immunoprecipitation assays confirmed that LXR and RXR are bound to LXRE-A and -B regions in THP-1 macrophages. These studies identify DNA sequences responsible for the transcriptional upregulation of the ABCG1 gene by oxysterols in macrophages and liver, two key tissues where changes in ABCG1 gene expression may markedly affect cholesterol balance and atherogenesis.
Revised on July 7, 2005
Accepted on July 8, 2005
The human ABCG1 gene: Identification of LXR response elements that modulate expression in macrophages and liver
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