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Journal of Lipid Research, Vol. 46, 2151-2167, October 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology
Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892
Published, JLR Papers in Press, July 16, 2005. DOI 10.1194/jlr.M500080-JLR200
2 To prevent confusion and to facilitate cross-species comparison, in this study, we number human ABCG1 exons and introns according to the table of Langmann et al. (38), which lists exons of the originally described and apparently major ABCG1 mRNA transcript (GenBank accessions BC029158, NM_004915, and NM_016818) initiated at the promoter shown in Fig. 2. Transcripts initiating at this promoter actually consist of two alternatively spliced isoforms differing by the presence or absence of 36 coding bases, because of the presence of two alternate splice donor sites at the end of exon 9 (4).
3 These intronic putative LXRE sequences are located at chr9:104,768,568-104,768,583 and chr9:104,710,952-104,710,967 in the May 2004 human genome assembly (UCSC Genome Browser). The LXRE in the regulatory promoter of ABCA1 is located at chr9:104,770,045-104,770,060.
1 To whom correspondence should be addressed. e-mail: slsabol{at}mail.nih.gov
The ABC transporter ABCG1 (ATP binding cassette transporter G1), 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 activators of liver X receptors (LXRs) and retinoid X receptors (RXRs) through genomic sequences that have not been fully characterized. Here we show that ABCG1 mRNA is induced by LXR agonists in RAW264.7 macrophage cells, HepG2 hepatoma cells, and primary mouse hepatocytes. We identify two evolutionarily highly conserved LXR response elements (LXREs), LXRE-A and LXRE-B, located in the first and second introns of the human ABCG1 gene. Each element conferred robust LXR-agonist responsiveness to ABCG1 promoter-directed luciferase gene constructs in RAW264.7 and HepG2 cells. Overexpression of LXR/RXR activated the ABCG1 promoter in the presence of LXRE-A or LXRE-B sequences. In gel-shift assays, LXR/RXR heterodimers bound to wild-type but not to mutated LXRE-A and LXRE-B sequences. In chromatin immunoprecipitation assays, LXR and RXR were detected at LXRE-A and -B regions of DNA of human THP-1 macrophages.
These studies clarify the mechanism of transcriptional upregulation of the ABCG1 gene by oxysterols in macrophages and liver, two key tissues where ABCG1 expression may affect cholesterol balance and atherogenesis.
Abbreviations: ABCG1, ATP-binding cassette transporter family G member 1; Ac-LDL, acetyl low density lipoprotein; 9cRA, 9-cis-retinoic acid; DR4, direct repeat with four intervening nucleotides; EMSA, electrophoretic mobility shift assay; LXR, liver X receptor; LXRE, LXR response element; 22-OH-cholesterol, 22(R)-hydroxycholesterol; RACE, rapid amplification of cDNA ends; RXR, retinoid X receptor; Nucleotide abbreviations: R, A or G; Y, C or T; M, A or C; K, G or T; n, any base
Supplementary key words ATP binding cassette transporter • liver X receptor • retinoid X receptor • cholesterol • hepatocyte • oxysterols • T-0901317 • promoter • transcription start site
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