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J. Biol. Chem., Vol. 278, Issue 35, 32569-32577, August 29, 2003
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Impaired ABCA1-dependent Lipid Efflux and Hypoalphalipoproteinemia in Human Niemann-Pick type C Disease*
¶
From the
Departments of Medicine and
Biochemistry and the Canadian
Institutes of Health Research Group on Molecular and Cell Biology of Lipids,
University of Alberta, Edmonton, Alberta T6G 2S2, the
||Department of Pathology, Dalhousie University,
Halifax, Nova Scotia B3H 1V8, Canada, and the
**Department of Pediatrics, University of Arizona,
Tucson, Arizona 85724
The cholesterol trafficking defect in Niemann-Pick type C (NPC) disease leads to impaired regulation of cholesterol esterification, cholesterol synthesis, and low density lipoprotein receptor activity. The ATP-binding cassette transporter A1 (ABCA1), which mediates the rate-limiting step in high density lipoprotein (HDL) particle formation, is also regulated by cell cholesterol content. To determine whether the Niemann-Pick C1 protein alters the expression and activity of ABCA1, we determined the ability of apolipoprotein A-I (apoA-I) to deplete pools of cellular cholesterol and phospholipids in human fibroblasts derived from NPC1+/+, NPC1+/–, and NPC1–/– subjects. Efflux of low density lipoprotein-derived, non-lipoprotein, plasma membrane, and newly synthesized pools of cell cholesterol by apoA-I was diminished in NPC1–/– cells, as was efflux of phosphatidylcholine and sphingomyelin. NPC1+/– cells showed intermediate levels of lipid efflux compared with NPC1+/+ and NPC1–/– cells. Binding of apoA-I to cholesterol-loaded and non-cholesterol-loaded cells was highest for NPC1+/– cells, with NPC1+/+ and NPC1–/– cells showing similar levels of binding. ABCA1 mRNA and protein levels increased in response to cholesterol loading in NPC1+/+ and NPC1+/– cells but showed low levels at base line and in response to cholesterol loading in NPC1–/– cells. Consistent with impaired ABCA1-dependent lipid mobilization to apoA-I for HDL particle formation, we demonstrate for the first time decreased plasma HDL-cholesterol levels in 17 of 21 (81%) NPC1–/– subjects studied. These results indicate that the cholesterol trafficking defect in NPC disease results in reduced activity of ABCA1, which we suggest is responsible for the low HDL-cholesterol in the majority of NPC subjects and partially responsible for the overaccumulation of cellular lipids in this disorder.
Received for publication, May 1, 2003 , and in revised form, June 6, 2003.
* This work was supported in part by the Heart and Stroke Foundation of Alberta, Northwest Territories, and Nunavut (to G. A. F.), Canadian Institutes of Health Research Grant MOP-12660 (to G. A. F.) and MOP-132321 (to J. E. V.), National Institutes of Health Grant DK56732 (to R. A. H.), and the Ara Parseghian Medical Research Foundation (to W. S. G. and J. E. V.). 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 a Doctoral Research Award from the Heart and Stroke Foundation
of Canada.
¶ Supported by a Postdoctoral Research award from the Alberta Heritage Foundation for Medical Research.
Scholar of the Alberta Heritage Foundation for Medical Research. To whom
correspondence should be addressed: 328 Heritage Medical Research Centre,
University of Alberta, Edmonton, Alberta T6G 2S2, Canada. Tel.: 780-492-9193;
Fax: 780-492-3383; E-mail:
gordon.francis{at}ualberta.ca.
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