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Journal of Lipid Research, Vol. 47, 1915-1927, September 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

ABCA7 expression is regulated by cellular cholesterol through the SREBP2 pathway and associated with phagocytosis

Noriyuki Iwamoto^*, Sumiko Abe-Dohmae^*, Ryuichiro Sato and Shinji Yokoyama^*,1

^* Biochemistry, Cell Biology, and Metabolism 1, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan
Department of Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, University of Tokyo, Tokyo 113-8657, Japan

Published, JLR Papers in Press, June 20, 2006.

¹ To whom correspondence should be addressed. e-mail: syokoyam{at}med.nagoya-cu.ac.jp

ABCA7 is highly homologous to ABCA1 and mediates cellular cholesterol and phospholipid release by apolipoproteins when transfected in vitro. However, expression of ABCA7 was downregulated by increased cellular cholesterol while ABCA1 was upregulated, and the results were consistent by forced expression or downregulation of sterol-responsive/regulatory element (SRE) binding proteins (SREBPs). We analyzed the promoter of the ABCA7 gene and identified the new exon encoding 96 bp (mouse) and 95 bp (human) of the 5' untranslated region and the transcription start site at 1,122 bp (mouse) and 1,260 bp (human) upstream of the initiation methionine codon. At 5' upstream of this exon is the ABCA7 proximal promoter containing multiple binding sites of transcription factors for hematopoiesis and SRE of 9 bp at 212 bp (mouse) and 179 bp (human) upstream of the new exon. The apolipoprotein A-I-mediated lipid release was not influenced by suppression of the endogenous ABCA7 with small interfering RNA in mouse fibroblasts or by its increase in ABCA1-deficient mouse cells. In contrast, 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 decreased in this condition. We conclude that the ABCA7 gene is regulated by sterol in the opposite direction to ABCA1 through SRE/SREBP2 and that expression of ABCA7 by this regulation is associated with phagocytic activity.

Supplementary key words ATP binding cassette transporter A7 • ATP binding cassette transporter A1 • cholesterol • high density lipoprotein • sterol-responsive/regulatory element • sterol-responsive/regulatory element binding protein • promoter

Abbreviations: apoA-I, apolipoprotein A-I; ChIP, chromatin immunoprecipitation; DF medium, 1:1 mixture of Dulbecco's modified Eagle's medium and Ham's F12 medium; FCS, fetal calf serum; LPDS, lipoprotein-deficient serum; LXR, liver X receptor; 5'RACE, rapid amplification of 5' cDNA ends; siRNA, small interfering RNA; SRE, sterol-responsive/regulatory element; SREBP, sterol-responsive/regulatory element binding protein; UTR, untranslated region

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