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J. Biol. Chem., Vol. 279, Issue 39, 41197-41207, September 24, 2004

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Deficiency of ABCA1 Impairs Apolipoprotein E Metabolism in Brain^*

Veronica Hirsch-Reinshagen, Steven Zhou, Braydon L. Burgess, Lise Bernier¶, Sean A. McIsaac, Jeniffer Y. Chan, Gavin H. Tansley, Jeffrey S. Cohn¶||, Michael R. Hayden**, and Cheryl L. Wellington

From the Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver V5Z 4H4, Canada, the ^¶Clinical Research Institute of Montreal, Montreal H2W 1R7, Canada, and the ^**Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver V5Z 4H4, Canada

ABCA1 is a cholesterol transporter that is widely expressed throughout the body. Outside the central nervous system (CNS), ABCA1 functions in the biogenesis of high-density lipoprotein (HDL), where it mediates the efflux of cholesterol and phospholipids to apolipoprotein (apo) A-I. Deficiency of ABCA1 results in lack of circulating HDL and greatly reduced levels of apoA-I. ABCA1 is also expressed in cells within the CNS, but its roles in brain lipid metabolism are not yet fully understood. In the brain, glia synthesize the apolipoproteins involved in CNS lipid metabolism. Here we demonstrate that glial ABCA1 is required for cholesterol efflux to apoA-I and plays a key role in facilitating cholesterol efflux to apoE, which is the major apolipoprotein in the brain. In both astrocytes and microglia, ABCA1 deficiency reduces lipid efflux to exogenous apoE. The impaired ability to efflux lipids in ABCA1-/- glia results in lipid accumulation in both astrocytes and microglia under normal culture conditions. Additionally, apoE secretion is compromised in ABCA1-/- astrocytes and microglia. In vivo, deficiency of ABCA1 results in a 65% decrease in apoE levels in whole brain, and a 75-80% decrease in apoE levels in hippocampus and striatum. Additionally, the effect of ABCA1 on apoE is selective, as apoJ levels are unchanged in brains of ABCA1-/- mice. Taken together, these results show that glial ABCA1 is a key influence on apoE metabolism in the CNS.

Received for publication, July 14, 2004

^* 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.

Supported by the British Columbia Research Institute for Children's and Women's Health (BCRICWH).

^|| Supported by an operating grant from the Canadian Institutes of Health Research (CIHR) and by a CIHR/Pfizer Investigator Salary Award.

Holds a Canada Research Chair in Human Genetics and is supported by grants from the Heart and Stroke Foundation of BC and Yukon (HSFBCY) and CIHR.

Supported by a CIHR New Investigator Salary Award and by operating grants from CIHR and from the Alzheimer's Society of Canada/CIHR/AstraZeneca. To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, University of British Columbia, 980 W. 28th Ave., Vancouver, BC V5Z 4H4, Canada. Tel.: 604-875-2000 (ext. 6825); Fax: 604-875-3819; E-mail: cheryl{at}cmmt.ubc.ca.

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