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J. Biol. Chem., Vol. 278, Issue 28, 25517-25525, July 11, 2003
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NPC1 and NPC2 Regulate Cellular Cholesterol Homeostasis through Generation of Low Density Lipoprotein Cholesterol-derived Oxysterols*
**
From the
Center for Cardiovascular Research,
Department of Internal Medicine, and the ¶Mass
Spectrometry Facility, Department of Internal Medicine,
**Department of Molecular Biology and Pharmacology,
and the Department of Cell Biology and
Physiology, Washington University School of Medicine, St. Louis, Missouri
63110-1010
Mutations in the Niemann-Pick disease genes cause lysosomal cholesterol accumulation and impaired low density lipoprotein (LDL) cholesterol esterification. These findings have been attributed to a block in cholesterol movement from lysosomes to the site of the sterol regulatory machinery. In this study we show that Niemann-Pick type C1 (NPC1) and Niemann-Pick type C2 (NPC2) mutants have increased cellular cholesterol, yet they are unable to suppress LDL receptor activity and cholesterol biosynthesis. Cholesterol overload in both NPC1 and NPC2 mutants results from the failure of LDL cholesterol tobothsuppresssterolregulatoryelement-bindingprotein-dependent gene expression and promote liver X receptor-mediated responses. However, the severity of the defect in regulation of sterol homeostasis does not correlate with endoplasmic reticulum cholesterol levels, but rather with the degree to which NPC mutant fibroblasts fail to appropriately generate 25-hydroxycholesterol and 27-hydroxycholesterol in response to LDL cholesterol. Moreover, we demonstrate that treatment with oxysterols reduces cholesterol in NPC mutants and is able to correct the NPC1I1061T phenotype, the most prevalent NPC1 disease genotype. Our findings support a role for NPC1 and NPC2 in the regulation of sterol homeostasis through generation of LDL cholesterol-derived oxysterols and have important implications for the treatment of NPC disease.
Received for publication, March 13, 2003 , and in revised form, April 23, 2003.
* 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 an American Heart Association Scientist Development Grant.
|| Supported by National Institutes of Health Grants DK56341 and P41-RR-00954.
Supported by grants from the National Niemann-Pick Disease Foundation, the Ara
Parseghian Medical Research Foundation, and by National Institutes of Health
Grants HL04482 and HL67773. To whom correspondence should be addressed: Center
for Cardiovascular Research, Washington University School of Medicine, Box
8086, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-8737; Fax:
314-362-0186; E-mail:
dory{at}im.wustl.edu.
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