Defective removal of cellular cholesterol and phospholipids by apolipoprotein A-I in Tangier Disease.

TitleDefective removal of cellular cholesterol and phospholipids by apolipoprotein A-I in Tangier Disease.
Publication TypeJournal Article
Year of Publication1995
AuthorsFrancis, GA, Knopp, RH, Oram, JF
JournalJ Clin Invest
Volume96
Issue1
Pagination78-87
Date Published1995 Jul
ISSN0021-9738
KeywordsApolipoprotein A-I, Cell Line, Cholesterol, Cholesterol Esters, Fibroblasts, Humans, Lipoproteins, HDL, Lipoproteins, LDL, Phospholipids, Tangier Disease
Abstract

Tangier disease is a rare genetic disorder characterized by extremely low plasma levels of HDL and apo A-I, deposition of cholesteryl esters in tissues, and a high prevalence of cardiovascular disease. We examined the possibility that HDL apolipoprotein-mediated removal of cellular lipids may be defective in Tangier disease. With fibroblasts from normal subjects, purified apo A-I cleared cells of cholesteryl esters, depleted cellular free cholesterol pools available for esterification, and stimulated efflux of radiolabeled cholesterol, phosphatidylcholine, and sphingomyelin. With fibroblasts from two unrelated Tangier patients, however, apo A-I had little or no effect on any of these lipid transport processes. Intact HDL also was unable to clear cholesteryl esters from Tangier cells even though it promoted radiolabeled cholesterol efflux to levels 50-70% normal. Passive desorption of radiolabeled cholesterol or phospholipids into medium containing albumin or trypsinized HDL was normal for Tangier cells. Binding studies showed that the interaction of apo A-I with high-affinity binding sites on Tangier fibroblasts was abnormal. These results indicate that apo A-I has an impaired ability to remove cholesterol and phospholipid from Tangier fibroblasts, possibly because of a defective interaction of apo A-I with cell-surface binding sites. Failure of apo A-I to acquire cellular lipids may account for the rapid catabolism of nascent HDL particles and the low plasma HDL levels in Tangier disease.

DOI10.1172/JCI118082
Alternate JournalJ. Clin. Invest.
PubMed ID7615839
PubMed Central IDPMC185175
Grant ListDK02456 / DK / NIDDK NIH HHS / United States
HL-18645 / HL / NHLBI NIH HHS / United States
HL-31194 / HL / NHLBI NIH HHS / United States