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J. Biol. Chem., Vol. 281, Issue 48, 37081-37090, December 1, 2006

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Correction of Apolipoprotein A-I-mediated Lipid Efflux and High Density Lipoprotein Particle Formation in Human Niemann-Pick Type C Disease Fibroblasts^*

Emmanuel Boadu¹, Hong Y. Choi², Diana W. K. Lee, Emma I. Waddington¹, Teddy Chan, Bela Asztalos, Jean E. Vance, Alicia Chan^¶, Graciela Castro^||3, and Gordon A. Francis^**4

From the Departments of Medicine, ^¶Pediatrics and ^**Biochemistry and the Canadian Institutes of Health Research Group in Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada, the Jean Mayer United States Department of Agriculture Human Nutrition Center on Aging, Tufts University, Boston, Massachusetts 02111, and the ^||Institut Pasteur de Lille, UMR545 INSERM, Université de Lille II, 59019 Lille Cedex, France

Impaired cell cholesterol trafficking in Niemann-Pick type C (NPC) disease results in the first known instance of impaired regulation of the ATP-binding cassette transporter A1 (ABCA1), a lipid transporter mediating the rate-limiting step in high density lipoprotein (HDL) formation, as a cause of low plasma HDL-cholesterol in humans. We show here that treatment of human NPC1^-/- fibroblasts with the liver X receptor (LXR) agonist TO-901317 increases ABCA1 expression and activity in human NPC1^-/- fibroblasts, as indicated by near normalization of efflux of radiolabeled phosphatidylcholine and a marked increase in efflux of cholesterol mass to apoA-I. LXR agonist treatment prior to and during apoA-I incubation resulted in reduction in filipin staining of unesterified cholesterol in late endosomes/lysosomes, as well as cholesterol mass, in NPC1^-/- cells. HDL species in human NPC disease plasma showed the same pattern of diminished large, cholesterol-rich -1 HDL particles as seen in isolated heterozygous ABCA1 deficiency. Incubating NPC1^-/- fibroblasts with the LXR agonist normalized the pattern of HDL particle formation by these cells. ABCG1, another LXR target gene involved in cholesterol efflux to HDL, also showed diminished expression in NPC1^-/- fibroblasts and increased expression upon LXR agonist treatment. These results suggest that NPC1 mutations can be largely bypassed and that NPC1 protein function is non-essential for the trafficking and removal of cellular cholesterol if the down-stream defects in ABCA1 and ABCG1 regulation in NPC disease cells are corrected using an LXR agonist.

Received for publication, July 19, 2006 , and in revised form, September 29, 2006.

^* This work was supported in part by Canadian Institutes of Health Research Grants MOP-79532 (to G. A. F.), MGC-64520, and STR-63305. 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 Supported by a Canadian Institutes of Health Research/Heart and Stroke Foundation of Canada/Pfizer Canada Postdoctoral Training Fellowship in Stroke, Cardiovascular, Obesity, Lipid, and Atherosclerosis Research (SCOLAR).

² Supported by a Doctoral Research Award from the Heart and Stroke Foundation of Canada.

³ Supported by an INSERM/Canadian Institutes of Health Research International Scientific Exchange Bursary.

⁴ Senior 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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