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Journal of Lipid Research, Vol. 42, 1717-1726, November 2001
Copyright © 2001 by Lipid Research, Inc.
Pivotal role of ABCA1 in reverse cholesterol transport influencing HDL levels and susceptibility to atherosclerosis
Alan D. Attiea,
John P. Kasteleinb, and
Michael R. Haydenc
a Departments of Biochemistry and Comparative Biosciences, University of Wisconsin-Madison, Madison, WI 53706
b Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
c Centre for Molecular Medicine and Therapeutics, University of British Columbia, 980 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada, and Xenon Genetics, Inc., Vancouver BC, Canada V6T 1Z3
Correspondence to:
Michael R. Hayden, To whom correspondence should be addressed., mrh{at}cmmt.ubc.ca (E-mail)
The identification of mutations in ABCA1 in patients with Tangier disease and familial HDL deficiency demonstrated that inadequate transport of phospholipid and cholesterol to the extracellular space results in the hypercatabolism of lipid-poor nascent HDL particles. However, the relationship between changes in ABCA1 activity and HDL levels is not clear. To address this question directly in vivo, we have used bacterial artificial chromosome transgenic approaches, which allow for appropriate developmental and cellular localization of human ABCA1 in mouse tissues. Increased expression of ABCA1 is directly associated with an increase in HDL levels, and the relationship between the increase in efflux and HDL is completely linear (r2 = 0.87). Preliminary data have suggested that coronary artery disease (CAD) is increased in heterozygotes for ABCA1 deficiency. These results may have been biased by clinical sampling, and CAD end points are insensitive markers. We have now used surrogate end points of intima-media complex thickness (IMT) and have shown that mean IMT in ABCA1 heterozygotes is indeed increased. A strong correlation between adjusted IMT and HDL cholesterol values and apolipoprotein A-I-driven efflux has been established.
These studies suggest that compromised ABCA1 activity leads to accelerated and early atherogenesis and provides a link between the cholesterol deposition in macrophages within the arterial wall and cholesterol efflux in humans. Attie, A. D., J. P. Kastelein, and M. R. Hayden. Pivotal role of ABCA1 in reverse cholesterol transport influencing HDL levels and susceptibility to atherosclerosis. J. Lipid Res. 2001. 42: 17171726.
Supplementary key words:
animal models, genetics, lipids, mutations, transgenics

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Copyright © 2001 by the American Society for Biochemistry and Molecular Biology.
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