Impaired ABCA1-dependent lipid efflux and hypoalphalipoproteinemia in human Niemann-Pick type C disease.

TitleImpaired ABCA1-dependent lipid efflux and hypoalphalipoproteinemia in human Niemann-Pick type C disease.
Publication TypeJournal Article
Year of Publication2003
AuthorsChoi, HY, Karten, B, Chan, T, Vance, JE, Greer, WL, Heidenreich, RA, Garver, WS, Francis, GA
JournalJ Biol Chem
Volume278
Issue35
Pagination32569-77
Date Published2003 Aug 29
ISSN0021-9258
KeywordsAdolescent, Adult, Apolipoprotein A-I, ATP Binding Cassette Transporter 1, ATP-Binding Cassette Transporters, Blotting, Northern, Blotting, Western, Child, Child, Preschool, Cholesterol, Female, Fibroblasts, Humans, Lipid Metabolism, Lipoproteins, Lipoproteins, HDL, Lipoproteins, LDL, Male, Mutation, Niemann-Pick Diseases, Phosphatidylcholines, Phospholipids, Protein Binding, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Sex Factors, Sphingomyelins, Tangier Disease, Time Factors
Abstract

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.

DOI10.1074/jbc.M304553200
Alternate JournalJ. Biol. Chem.
PubMed ID12813037