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J. Biol. Chem., Vol. 281, Issue 30, 21216-21224, July 28, 2006

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Reduction in ABCG1 in Type 2 Diabetic Mice Increases Macrophage Foam Cell Formation^*

Jeremy P. Mauldin^¶, Suseela Srinivasan^¶, Anny Mulya^||, Abraham Gebre^||, John S. Parks^||, Alan Daugherty^**, and Catherine C. Hedrick^¶1

From the Department of Pharmacology, Division of Endocrinology & Metabolism, and the ^¶Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia 22908, the ^||Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27106, and the ^**Gill Heart Institute, Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky 40506

Atherosclerosis development is accelerated severalfold in patients with Type 2 diabetes. In the initial stages of disease, monocytes transmigrate into the subendothelial space and differentiate into foam cells. Scavenger receptors and ATP binding cassette (ABC) Transporters play an important role in foam cell formation as they regulate the influx and efflux of oxidized lipids. Here, we show that peritoneal macrophages isolated from Type 2 diabetic db/db mice have decreased expression of the ABC transporter ABCG1 and increased expression of the scavenger receptor CD36. We found a 2-fold increase in accumulation of esterified cholesterol in diabetic db/db macrophages compared with wild-type control macrophages. Diabetic db/db macrophages also had impaired cholesterol efflux to high density lipoprotein but not to lipid-free apo A-I, suggesting that the increased esterified cholesterol in diabetic db/db macrophages was due to a selective loss of ABCG1-mediated efflux to high density lipoprotein. Additionally, we were able to confirm down-regulation of ABCG1 using C57BL/6J peritoneal macrophages cultured in elevated glucose in vitro (25 mM glucose for 7 days), suggesting that ABCG1 expression in diabetic macrophages is regulated by chronic exposure to elevated glucose. Diabetic KK^ay mice were also studied and were found to have decreased ABCG1 expression without an increase in CD36. These observations demonstrate that ABCG1 plays a major role in macrophage cholesterol efflux and that decreased ABCG1 function can facilitate foam cell formation in Type 2 diabetic mice.

Received for publication, October 6, 2005 , and in revised form, March 7, 2006.

^* This work was supported by National Institutes of Health Grants P01 HL55798 (to C. C. H.) and P01 HL49373 (to J. S. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Division of Endocrinology and Metabolism, University of Virginia, 415 Lane Rd., MR-5, Rm. G123, P. O. Box 801394, Charlottesville, VA 22908. Tel.: 434-982-4065; Fax: 434-924-9730; E-mail: cch6n{at}virginia.edu.

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