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
Date Published2003 Aug 29
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

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.

Alternate JournalJ. Biol. Chem.
PubMed ID12813037