Document Detail

Impaired ABCA1-dependent lipid efflux and hypoalphalipoproteinemia in human Niemann-Pick type C disease.
MedLine Citation:
PMID:  12813037     Owner:  NLM     Status:  MEDLINE    
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.
Hong Y Choi; Barbara Karten; Teddy Chan; Jean E Vance; Wenda L Greer; Randall A Heidenreich; William S Garver; Gordon A Francis
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Publication Detail:
Type:  Journal Article     Date:  2003-06-16
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  278     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2003 Aug 
Date Detail:
Created Date:  2003-08-25     Completed Date:  2003-10-02     Revised Date:  2005-11-17    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  32569-77     Citation Subset:  IM    
Department of Medicine and the Canadian Institutes of Health Research Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
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MeSH Terms
ATP-Binding Cassette Transporters / genetics,  metabolism*
Apolipoprotein A-I / metabolism
Blotting, Northern
Blotting, Western
Child, Preschool
Cholesterol / metabolism
Fibroblasts / metabolism
Lipid Metabolism*
Lipoproteins / metabolism
Lipoproteins, HDL / metabolism
Lipoproteins, LDL / metabolism
Niemann-Pick Diseases / metabolism*
Phosphatidylcholines / metabolism
Phospholipids / metabolism
Protein Binding
RNA, Messenger / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Sex Factors
Sphingomyelins / metabolism
Tangier Disease / metabolism*
Time Factors
Reg. No./Substance:
0/ATP binding cassette transporter 1; 0/ATP-Binding Cassette Transporters; 0/Apolipoprotein A-I; 0/Lipoproteins; 0/Lipoproteins, HDL; 0/Lipoproteins, LDL; 0/Phosphatidylcholines; 0/Phospholipids; 0/RNA, Messenger; 0/Sphingomyelins; 57-88-5/Cholesterol

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

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