© 1999 American Heart Association, Inc.
Original Contributions |
Cellular Cholesterol Transport and Efflux in Fibroblasts Are Abnormal in Subjects With Familial HDL Deficiency
From the Cardiovascular Genetics Laboratory (M.M., L.Y., L.K., B.B., J.S.C., J.G, Jr); the Clinical Research Institute of Montreal, Cardiology Services, Centre hospitalier de l'Université de Montréal (CHUM), Hôtel-Dieu Hospital (J.G., Jr); and the Montreal Heart Institute (M.M., J.G., Jr), Montréal, Québec, Canada, and from the Department of Medicine, University of Washington, Seattle (J.F.O.).
Correspondence to Jacques Genest, Jr, MD, Cardiovascular Genetics Laboratory, Clinical Research Institute of Montreal, Montréal, Québec, Canada H2W 1R7. E-mail genestj{at}ircm.umontreal.CA
Abstract—Familial high density
lipoprotein (HDL) deficiency (FHD) is a genetic lipoprotein
disorder characterized by a severe decrease in the plasma HDL
cholesterol (-C) level (less than the fifth percentile).
Unlike Tangier disease, FHD is transmitted as an autosomal dominant
trait. FHD subjects have none of the clinical manifestations of Tangier
disease (lymphoid tissue infiltration with cholesteryl esters and/or
neurological manifestations). Plasmas from FHD subjects contain
pre–ß-migrating HDLs but are deficient in 
-migrating HDLs. We
hypothesized that a reduced HDL-C level in FHD is due to abnormal
transport of cellular cholesterol to the plasma membrane,
resulting in reduced cholesterol efflux onto nascent HDL
particles, leading to lipid-depleted HDL particles that are rapidly
catabolized. Cellular cholesterol metabolism
was investigated in skin fibroblasts from FHD and control subjects.
HDL3- and apolipoprotein (apo) A-I–mediated cellular
cholesterol and phosphatidylcholine efflux was examined by
labeling cells with [3H]cholesterol and
[3H]choline, respectively, during growth and
cholesterol loading during growth arrest. FHD cells
displayed an 
25% reduction in HDL3-mediated cellular
cholesterol efflux and an 50% to 80% reduction in
apoA-I–mediated cholesterol and phosphatidylcholine efflux
compared with normal cells. Cellular cholesterol ester
levels were decreased when cholesterol-labeled cells were
incubated with HDL3 in normal cells, but
cholesterol ester mobilization was significantly reduced in
FHD cells. HDL3 binding to fibroblasts and the possible
role of the HDL binding protein/vigilin in FHD were also investigated.
No differences were observed in 125I-HDL3
binding to LDL-loaded cells between FHD and control cells. HDL binding
protein/vigilin mRNA levels and its protein expression were
constitutively expressed in FHD cells and could be modulated (2-fold
increase) by elevated cellular cholesterol in normal cells.
In conclusion, FHD is characterized by reduced HDL3- and
apoA-I–mediated cellular cholesterol efflux. It is not
associated with abnormal cellular HDL3 binding or a defect
in a putative HDL binding protein.
Key Words: apolipoprotein A-I • cholesterol efflux • HDL deficiency • coronary artery disease
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