Decreased reverse cholesterol transport from Tangier disease fibroblasts. Acceptor specificity and effect of brefeldin on lipid efflux.
Tangier disease is characterized by HDL hypercatabolism and increased deposition of cholesterol in tissues. Tangier disease skin fibroblasts have decreased apoA-I-mediated cholesterol and phospholipid efflux, which may lead to the excess accumulation of cellular cholesterol. The mechanism of apolipoprotein-mediated cholesterol efflux and the apolipoprotein acceptor specificity for cholesterol efflux from normal and Tangier disease fibroblasts was investigated. Normal cells readily effluxed cholesterol and phospholipid to apoA-I and to all of the other apolipoproteins tested (apoA-II, AIV, C-I, C-II, C-III). In contrast, Tangier cells were almost completely defective in cholesterol efflux to apoA-I and to all of the other apolipoproteins tested. HDL was also less effective, by approximately 50%, in stimulating cholesterol efflux from Tangier cells compared with normal cells. In addition, Tangier cells also showed significantly reduced phospholipid efflux to both apolipoproteins and HDL. A similar rate of cholesterol efflux, however, was observed from normal and Tangier cells when phospholipid vesicles or cyclodextrin were used as acceptors. In contrast to normal cells, only phospholipid vesicles and cyclodextrin and not apoA-I or HDL depleted intracellular cholesteryl esters from Tangier cells. Brefeldin, an inhibitor of intracellular vesicular trafficking, decreased HDL-mediated cholesterol efflux by approximately 40% but almost completely blocked both cholesterol and phospholipid efflux to apoA-I from normal cells. Brefeldin also inhibited cholesteryl ester depletion by apoA-I and HDL from normal cells. Brefeldin, however, had no significant effect on cholesterol efflux from Tangier cells to HDL. In summary, Tangier cells were found to be defective in both cholesterol and phospholipid efflux to HDL and apoA-I. The defect in apolipoprotein-mediated lipid efflux was not specific for apoA-I but also occurred for other apolipoproteins, and brefeldin blocked HDL-mediated lipid efflux from normal but not Tangier disease cells. On the basis of these results, a model is proposed whereby decreased cholesterol efflux by apolipoproteins in Tangier cells is the result of a defect in a brefeldin-sensitive pathway of lipid efflux.
Remaley
A T
AT
National Institutes of Health, Clinical Pathology Department, Bethesda, Maryland 20892, USA. aremaley nih.gov
Schumacher
U K
UK
Stonik
J A
JA
Farsi
B D
BD
Nazih
H
H
Brewer
H B
HB
D000328:Adult; D016632:Apolipoprotein A-I / Q000378:metabolism; D001053:Apolipoproteins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D001693:Biological Transport, Active; D020126:Brefeldin A; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000494:pharmacology; D003517:Cyclopentanes / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D010743:Phospholipids / Q000037:antagonists & inhibitors / Q000378:metabolism; D012016:Reference Values; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D013631:Tangier Disease / Q000378:metabolism* / Q000473:pathology
D016632:Apolipoprotein A-I; D001053:Apolipoproteins; D008076:Cholesterol, HDL; D003517:Cyclopentanes; D010743:Phospholipids; D020126:Brefeldin A; D002784:Cholesterol