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A more recent version of this article appeared on September 1, 2006

Papers In Press, published online ahead of print June 20, 2006
J. Lipid Res., doi:10.1194/jlr.M600127-JLR200
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Submitted on March 16, 2006
Revised on June 14, 2006
Accepted on June 19, 2006

ATP-binding cassette transporter A7 expression is regulated by cellular cholesterol through the sterol responsive/regulatory element 2 pathway and associated with phagocytic activity

Noriyuki Iwamoto, Sumiko Abe-Dohmae, Ryuichiro Sato, and Shinji Yokoyama

Biochemistry, Cell Biology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601

Corresponding Author: syokoyam{at}med.nagoya-cu.ac.jp

ATP-binding cassette transporter (ABC) A7 is highly homologous to ABCA1 and mediates cellular cholesterol and phospholipid release by apolipoproteins when transfected in vitro. However, expression of ABCA7 was down-regulated by increase of cellular cholesterol while ABCA1 was up-regulated, and the results were consistent by forced expression or down-regulation of sterol responsive/regulatory element (SRE) binding proteins (SREBPs). We analyzed the promoter of the ABCA7 gene and identified the new exon encoding 96bp (mouse) and 95bp (human) of the 5’-untranslated region and the transcription-starting site at 1122bp (mouse) and 1260bp (human) upstream of the initiation methionine codon. The 5’ upstream of this exon is the ABCA7 proximal promoter containing multiple binding sites of transcription factors for hematopoiesis, and SRE of 9bp at 212bp (mouse) and 179bp (human) upstream of the new exon. The apoA-I-mediated lipid release was not influenced by suppression of the endogenous ABCA7 with siRNA in mouse fibroblasts or by its increase in the ABCA1-deficient mouse cells. In contrast, the phagocytic activity was altered in parallel to the ABCA7 expression in these cells. When phagocytosis was induced, the messages increased for SREBP2, ABCA7 and other SREBP2-regulated proteins. The ABCA1 message rather decreased in this condition. We concluded that the ABCA7 gene was regulated by sterol in the opposite direction to ABCA1 through SRE/SREBP2 and expression of ABCA7 by this regulation was associated with the phagocytic activity.


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