Document Detail

NPC1 and NPC2 regulate cellular cholesterol homeostasis through generation of low density lipoprotein cholesterol-derived oxysterols.
MedLine Citation:
PMID:  12719428     Owner:  NLM     Status:  MEDLINE    
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.
Andrey Frolov; Sarah E Zielinski; Jan R Crowley; Nicole Dudley-Rucker; Jean E Schaffer; Daniel S Ory
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2003-04-28
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  278     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2003 Jul 
Date Detail:
Created Date:  2003-07-04     Completed Date:  2003-08-14     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  25517-25     Citation Subset:  IM    
Center for Cardiovascular Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110-1010, USA.
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MeSH Terms
Carrier Proteins / physiology*
Cells, Cultured
Cholesterol / metabolism*
Cholesterol, LDL / metabolism
DNA-Binding Proteins
Dose-Response Relationship, Drug
Endoplasmic Reticulum / metabolism
Fibroblasts / metabolism
Filipin / metabolism
Gas Chromatography-Mass Spectrometry
Genes, Reporter
Glycoproteins / physiology*
Hydroxycholesterols / metabolism,  pharmacology
Lipoproteins / metabolism
Lipoproteins, LDL / metabolism*
Luciferases / metabolism
Membrane Glycoproteins / physiology*
Microscopy, Fluorescence
Niemann-Pick Diseases / metabolism
Orphan Nuclear Receptors
Oxygen / metabolism
Receptors, Cytoplasmic and Nuclear / metabolism
Skin / metabolism
Sterols / metabolism*
Grant Support
Reg. No./Substance:
0/Carrier Proteins; 0/Cholesterol, LDL; 0/DNA-Binding Proteins; 0/Glycoproteins; 0/Hydroxycholesterols; 0/Lipoproteins; 0/Lipoproteins, LDL; 0/Membrane Glycoproteins; 0/NPC1 protein, human; 0/NPC2 protein, human; 0/Orphan Nuclear Receptors; 0/Receptors, Cytoplasmic and Nuclear; 0/Sterols; 0/liver X receptor; 20380-11-4/27-hydroxycholesterol; 2140-46-7/25-hydroxycholesterol; 480-49-9/Filipin; 57-88-5/Cholesterol; 7782-44-7/Oxygen; EC 1.13.12.-/Luciferases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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