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Journal of Lipid Research, Vol. 44, 1251-1255, June 2003
Copyright © 2003 by Lipid Research, Inc.

The role of the ABCA1 transporter and cholesterol efflux in familial hypoalphalipoproteinemia

G. Kees Hovingh^*, Michel J. A. van Wijland, Alison Brownlie, Radjesh J. Bisoendial^*, Michael R. Hayden^**, John J. P. Kastelein^* and Albert K. Groen^1,

^* Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
Department of Experimental Hepatology, Academic Medical Center, Amsterdam, The Netherlands
Xenon Genetics Inc., Vancouver, British Columbia, Canada
^** Center for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada

¹ To whom correspondence should be addressed. e-mail: a.k.groen{at}amc.uva.nl

Defects in the gene encoding for the ATP binding cassette (ABC) transporter A1 (ABCA1) were shown to be one of the genetic causes for familial hypoalphalipoproteinemia (FHA). We investigated the role of ABCA1-mediated cholesterol efflux in Dutch subjects suffering from FHA. Eighty-eight subjects (mean HDL cholesterol levels 0.63 ± 0.21 mmol/l) were enrolled. Fibroblasts were cultured and loaded with [³H]cholesterol. ABCA1 and non-ABCA1-mediated efflux was studied by using apolipoprotein A-I (apoA-I), HDL, and methyl-ß-cyclodextrin as acceptors. Efflux to apoA-I was decreased in four patients (4/88, 4.5%), and in all cases, a mutation in the ABCA1 gene was found. In the remaining 84 subjects, no correlation between efflux and apoA-I or HDL cholesterol was found. Efflux to both HDL and cyclodextrin, in contrast, did correlate with HDL cholesterol plasma levels (r = 0.34, P = 0.01; and r = 0.27, P = 0.008, respectively). The prevalence of defects in ABCA1-dependent cholesterol efflux in Dutch FHA patients is low.

The significant correlation between plasma HDL cholesterol levels and methyl-ß-cyclodextrin-mediated efflux in the FHA patients with normal ABCA1 function suggests that non-ABCA1-mediated efflux might also be important for plasma HDL cholesterol levels in these individuals.

Supplementary key words high density lipoprotein • ATP binding cassette transporter A1 • methyl-ß-cyclodextrin

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