Linked Life Data

12813037

Source:http://linkedlifedata.com/resource/pubmed/id/12813037

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
35
pubmed:dateCreated
2003-8-25
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
29
pubmed:volume
278
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
32569-77
pubmed:dateRevised
2005-11-17
pubmed:meshHeading
pubmed-meshheading:12813037-ATP-Binding Cassette Transporters, pubmed-meshheading:12813037-Adolescent, pubmed-meshheading:12813037-Adult, pubmed-meshheading:12813037-Apolipoprotein A-I, pubmed-meshheading:12813037-Blotting, Northern, pubmed-meshheading:12813037-Blotting, Western, pubmed-meshheading:12813037-Child, pubmed-meshheading:12813037-Child, Preschool, pubmed-meshheading:12813037-Cholesterol, pubmed-meshheading:12813037-Female, pubmed-meshheading:12813037-Fibroblasts, pubmed-meshheading:12813037-Humans, pubmed-meshheading:12813037-Lipid Metabolism, pubmed-meshheading:12813037-Lipoproteins, pubmed-meshheading:12813037-Lipoproteins, HDL, pubmed-meshheading:12813037-Lipoproteins, LDL, pubmed-meshheading:12813037-Male, pubmed-meshheading:12813037-Mutation, pubmed-meshheading:12813037-Niemann-Pick Diseases, pubmed-meshheading:12813037-Phosphatidylcholines, pubmed-meshheading:12813037-Phospholipids, pubmed-meshheading:12813037-Protein Binding, pubmed-meshheading:12813037-RNA, Messenger, pubmed-meshheading:12813037-Reverse Transcriptase Polymerase Chain Reaction, pubmed-meshheading:12813037-Sex Factors, pubmed-meshheading:12813037-Sphingomyelins, pubmed-meshheading:12813037-Tangier Disease, pubmed-meshheading:12813037-Time Factors
pubmed:year
2003
pubmed:articleTitle
Impaired ABCA1-dependent lipid efflux and hypoalphalipoproteinemia in human Niemann-Pick type C disease.
pubmed:affiliation
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.
pubmed:publicationType
Journal Article