© 1997 American Heart Association, Inc.
Articles |
Decreased Reverse Cholesterol Transport from Tangier Disease Fibroblasts
Acceptor Specificity and Effect of Brefeldin on Lipid Efflux
From the National Institutes of Health, Clinical Center, Clinical Pathology Department, Bethesda, Maryland (A.T.R.); and National Institutes of Health, National Heart, Lung and Blood Institute, Bethesda, Maryland (U.K.S., J.A.S., B.D.F., H.N., H.B.B.).
Correspondence to: A.T. Remaley, National Institutes of Health, Clinical Center, Clinical Pathology Department, Building 10/2C-431, Bethesda, Maryland 20892.
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Abstract |
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Abstract 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. (Arterioscler Thromb Vasc Biol. 1997;17:1813-1821.)
Key Words: Tangier disease • high-density lipoprotein • cholesterol • atherosclerosis • brefeldin
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Introduction |
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Tangier disease, an autosomal recessive disorder of unknown origin, is characterized by cholesteryl ester accumulation in various tissues, most notably the tonsils, liver, spleen, and intestinal mucosa.1 2 The excess cellular cholesterol in Tangier disease has been proposed to be the result of reduced reverse cholesterol transport,2 3 because of the markedly decreased plasma level of high density lipoproteins, which is a hallmark of the disease.1 2 Typically, HDL cholesterol levels in Tangier disease are below 5% of normal,2 which is coupled with a commensurate reduction of apolipoprotein A-I (apoA-I), the principal protein of HDL. Although many individuals with Tangier disease do not develop clinically apparent atherosclerosis,1 2 there is an overall increased incidence of cardiovascular disease in Tangier disease.4
The low level of HDL in Tangier disease is not the result of a mutation in the gene for apoA-I5 or of a defect in the biosynthesis of apoA-I.6 Although the biochemical basis is not known, patients with Tangier disease have been shown to have low plasma HDL because of hypercatabolism.6 Several studies have demonstrated abnormalities in the interaction of HDL with Tangier cells.3 7 8 9 10 11 12 Recently, Tangier disease skin fibroblasts have been described to have a defect in HDL-stimulated translocation of intracellular cholesterol to the plasma membrane.7 9 Decreased translocation of cholesterol to the plasma membrane, where it can be readily removed by desorption and diffusion onto HDL, has been proposed to lead to the reduced cholesterol efflux and, consequently, to the deposition of excess cholesterol in Tangier cells.7 9
In addition to intact HDL, the apolipoprotein fraction of HDL may also play a direct role in reverse cholesterol transport.13 14 15 16 17 18 Relatively lipid-poor or lipid-free apoA-I has been detected in plasma and lymph and extracellular fluid19 20 21 and has been estimated to represent between 3 and 8% of total apoA-I in serum.19 Lipid-free apoA-I, as well as most of the other amphipathic helix-containing apolipoproteins, have been shown in vitro to be relatively efficient in promoting the efflux of cholesterol from cells.13 14 15 16 17 18 Two models have been proposed for cholesterol efflux by apolipoproteins. In the one-step model, an apolipoprotein binds to the cell membrane and simultaneously removes both cholesterol and phospholipid when the apolipoprotein dissociates from the cell.16 In the two-step model, an apolipoprotein after binding to the cell membrane preferentially removes phospholipid to form an apolipoprotein-phospholipid complex, which can then accept cholesterol that has desorbed from the cell membrane.16 22 Recently, a defect in apoA-I-mediated cholesterol and phospholipid efflux has been described in Tangier disease fibroblasts.11 Compared with normal fibroblasts, apoA-I was shown to be almost completely defective in the efflux of cholesterol and phospholipid from Tangier cells. In the present study, the apolipoprotein acceptor specificity for cholesterol and phospholipid efflux from normal and Tangier disease cells was examined, as well as the biochemical mechanism for lipid efflux by apolipoproteins. In addition to apoA-I, all of the apolipoproteins commonly present on HDL were found to be defective in mediating both cholesterol and phospholipid efflux from Tangier cells. Furthermore, two pathways for cholesterol efflux by HDL and apoA-I were functionally described based on sensitivity to brefeldin, and Tangier cells were found to be defective in a brefeldin-sensitive pathway of lipid efflux.
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Methods |
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Cell Culture
Primary human skin fibroblasts were obtained by explant cultures of skin biopsies taken from the upper arm. Patients from whom Tangier cell lines T1,1 23 T2,1 23 and T324 were obtained were previously described. Tangier cell line T4 was from a 27-year-old female, who at the age of 7 years presented with enlarged orange tonsils, low total cholesterol, and a markedly reduced level of HDL-cholesterol. Normal human skin fibroblasts cell lines (N1–N4) were from the American Type Culture Collection (Rockville, Md). Fibroblasts were routinely grown in Eagle-modified minimum essential medium (GIBCO BRL, Rockville, Md) supplemented with 10% fetal calf serum, 2 mM glutamine, 100 IU/mL penicillin, and 100 µg/mL streptomycin (EMEM10). Fibroblasts were loaded with cholesterol by a 24-hour incubation with 50 µg/ml nonlipoprotein cholesterol in EMEM, containing 2 mg/ml bovine serum albumin (fraction V; EMEM/BSA), as previously described.25
Cholesterol Efflux Assays
The cholesterol efflux assay was essentially
performed as previously described.25 26 Confluent
cholesterol-loaded fibroblasts grown on 24-well plates were
incubated with EMEM10 containing 1 µCi/ml
1,2-[3H]cholesterol (50 Ci/mmol; Dupont;
Wilmington, DE) for 48 hours. Typically, this labeling protocol
resulted in approximately 100 000 counts per minute per well or 1000
counts per minute per µg of protein. Cells were washed three times
with EMEM/BSA and incubated with EMEM/BSA for 24 hours, before
initiating efflux with the indicated cholesterol acceptors
prepared in EMEM/BSA. After the efflux period, media were collected,
centrifuged (10 000xg for 5 minutes), and counted
for radioactivity by liquid scintillation counting. The residual
radioactivity in the cell fraction was determined after an overnight
extraction with isopropanol. The percent efflux was calculated by
dividing the radioactive counts in the efflux media by the sum of the
radioactive counts in the media plus the cell fraction. Unless
indicated, EMEM/BSA media were used as a blank, and the results from
the blank were subtracted from the radioactive counts obtained in the
presence of a cholesterol acceptor. Experiments involving
quantitation of the cellular content of radiolabeled
cholesterol and cholesteryl esters were performed on cells
grown on 6-well plates and fractionated by thin-layer
chromatography, as previously described.26
Cholesteryl ester formation after efflux was determined by the
incorporation of 1-[14C]oleate (50 mCi/mmol;
Dupont) into cholesteryl esters, as previously
described.26
Phospholipid Efflux Assay
The phospholipid efflux assay was essentially performed as
previously described.27 Choline-containing phospholipids
were labeled by incubating confluent cholesterol-loaded
fibroblasts grown on 24-well plates with EMEM10 medium, containing 5
µCi/ml of methyl-[3H]choline chloride (84 Ci/mmol;
Amersham; Arlington Heights, Ill) for 24 hours. Cells were washed three
times with EMEM/BSA, followed by a 1-hour preincubation in EMEM/BSA
before the addition of the indicated phospholipid acceptors prepared in
EMEM/BSA. Typically, this labeling protocol resulted in approximately
500 000 counts per minute per well or 5000 counts per minute per µg
of protein. After the efflux period, media were collected,
centrifuged (10 000xg; 5 minutes), extracted with
chloroform:methanol (2:1), and counted by liquid scintillation. The
remaining radioactivity in the cell fraction was determined after an
overnight extraction with isopropanol, followed by a 1-hour extraction
with hexane:isopropanol (3:2). The percent efflux is calculated by
dividing the radioactive counts in the efflux media by the sum of the
radioactive counts in the efflux media plus the cell fraction. Unless
indicated, EMEM/BSA media was used as a blank, and the results from the
blank were subtracted from the radioactive counts obtained in the
presence of a phospholipid acceptor.
Lipoprotein, Apolipoprotein, and ApoA-I Vesicle
Preparation
HDL (d=1.063-1.21 g/mL) was isolated from
human plasma by density gradient ultracentrifugation as
previously described.28 Apolipoproteins were purified from
human plasma by column chromatography29
and were determined to be greater than 99% pure as assessed by
SDS-polyacrylamide gel electrophoresis and amino terminal
sequence analysis. Phosphatidylcholine vesicles were prepared
by sonication.30
ApoA-I Binding Assay
ApoA-I was iodinated with [125I]iodide
by the iodide monochloride method31 to a specific activity
of 2x106 counts per minute per µg. Confluent fibroblasts
grown on 24-well plates were incubated in EMEM/BSA with the indicated
concentration of iodinated apoA-I for 3 hours at 37°C in
the presence and absence of a 50-fold excess of the apolipoprotein
fraction isolated from HDL. Cells were then washed rapidly three times
with EMEM/BSA at 4°C. Bound counts were determined by gamma counting,
after dissolving the cell fraction with 0.1 M NaOH and 0.1% SDS.
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Results |
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The ability of HDL and apoA-I to stimulate cholesterol efflux from three normal and four Tangier disease skin fibroblasts was determined and summarized in Fig 1
. HDL
readily promoted cholesterol efflux from both normal and
Tangier cells; however, Tangier cells consistently exhibited
less cholesterol efflux to HDL than did normal cells (Fig 1, panel A). The percent decrease in HDL-mediated
cholesterol efflux was variable among the four Tangier
cell lines tested but ranged between 35 and 60%. In contrast to the
partial reduction in HDL-mediated cholesterol efflux, there
was a virtual absence of cholesterol efflux to apoA-I from
all four Tangier cell lines (Fig 1, panel B).
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Efflux of phospholipid by HDL and apoA-I from normal and Tangier cells
is summarized in Fig 2. Both HDL and
apoA-I were able to mediate phospholipid efflux from normal cells (Fig 2). In contrast, apoA-I was ineffective in promoting phospholipid
efflux from Tangier cells (Fig 2, panel B). Despite the ability of HDL
to partially mediate cholesterol efflux from Tangier cells
(Fig 1
, panel A), HDL also did not stimulate significant phospholipid
efflux from Tangier cells (Fig 2, panel A). In Fig 3, cholesterol and
phospholipid efflux to apoA-I from normal cells were determined before
and after cholesterol loading. Both cholesterol
and phospholipid efflux to apoA-I were significantly enhanced after
cholesterol loading.
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Cholesterol efflux was determined in the presence of
increasing concentrations of HDL and apoA-I (Fig 4) to determine if the decreased efflux
of cholesterol by HDL and apoA-I from Tangier cells was
related to a shift in a dose-response relationship between the
concentration of the acceptor and efflux. HDL stimulated less
cholesterol efflux from Tangier cells relative to normal
cells at all concentrations tested, but both normal and Tangier cells
had a similar curvilinear dose-response curve (Fig 4, panel A). In case
of apoA-I, maximum efflux occurred at 5 µg/mL for normal
cells, but virtually no cholesterol efflux occurred from
Tangier cells, even with 20 µg/mL of apoA-I (Fig 4, panel B).
These results suggest that a change in the dose-response relationship
for cholesterol efflux does not account for the decreased
removal of cholesterol from Tangier cells.
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) and Tangier cells (T1, 
) were labeled with
[3H]cholesterol, followed by
cholesterol loading. Efflux after 20 hours was measured in
the presence of increasing concentrations of HDL (panel A) or apoA-I
(panel B). Results from the blank were not subtracted. The results
represent the mean of triplicates±1 SD. CPM=counts per
minute.
Defective binding of apoA-I has been proposed as a possible mechanism
for the reduced cholesterol efflux from Tangier
cells.11 In panel A of Fig 5, the binding of apoA-I to normal and
Tangier cells before and after cholesterol loading was
examined. Overall, a similar binding curve was found for normal and
Tangier cells at all concentrations of apoA-I. Both normal and Tangier
cells also showed a similar increase in apoA-I binding after
cholesterol loading, which has recently been described to
also occur for HepG2 cells.32 When the binding data were
analyzed by a Scatchard plot, a curvilinear plot was obtained,
indicating multiple binding sites with various affinities.
Nevertheless, no difference was found in the shape of the binding curve
between normal and Tangier cell lines, thus suggesting that there is no
significant difference in the binding of apoA-I to normal and Tangier
cells. It was previously reported that Tangier cells exhibit decreased
apoA-I binding relative to normal cells at only submicrogram per
milliliter quantities of apoA-I11 ; however, in panel B of
Fig 5, no consistent difference was observed in the binding of
apoA-I at 0.5 µg/mL between the four normal and four Tangier
cell lines tested.
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) and without (
) cholesterol loading.
Only nonspecific binding for cholesterol-loaded Tangier
cells is shown (
), which is representative of the
results obtained for the nonspecific binding for all other conditions
and cell lines. The results represent the mean of duplicates.
Panel B, The specific binding of radioiodinated apoA-1 for
3 hours at 37°C to normal (N1–N4; solid bars) and Tangier cells
(T1-T4; open bars) was examined at 0.5 µg/mL apoA-I. The results
represent the mean of quadruplicates±1 SD.
To determine the apolipoprotein acceptor specificity for the
cholesterol efflux defect in Tangier cells, the ability of
different apolipoproteins to stimulate lipid efflux from normal and
Tangier cells was examined. All of the apolipoproteins tested
stimulated cholesterol efflux from normal but not Tangier
cells (Fig 6, panel A). Similarly, all of
the apolipoproteins promoted more phospholipid efflux from normal cells
than from Tangier cells (Fig 6, panel B). Interestingly, in contrast to
HDL, free apolipoproteins were relatively more efficient at effluxing
phospholipid than cholesterol. Overall, these results
indicate that the decreased cholesterol and phospholipid
efflux to apoA-I from Tangier cells are not unique to apoA-I but also
occur for other amphipathic helix-containing apolipoproteins.
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In Fig 7, the specificity of the efflux
defect in Tangier cells was further examined by comparing
cholesterol efflux from normal and Tangier cells with
phospholipid vesicles and cyclodextrin
(2-hydroxypropyl-ß-cyclodextrin), which removes
cholesterol by aqueous diffusion,33 34 a
process whereby cholesterol desorbs from the cell membrane
and diffuses onto an acceptor.22 In addition to
cholesterol that effluxed from the cell, radioactive
cholesterol and cholesteryl ester counts remaining in the
cell fraction after the efflux period were also quantitated. As was
previously observed (Fig 1), apoA-I was ineffective in effluxing
cholesterol from Tangier cells (Fig 7, panel A), and as
would be predicted, there was no significant change after efflux in
either the free cholesterol or cholesteryl ester fraction
from Tangier disease cells (Fig 7, panel B and C). In contrast, the
addition of apoA-I to the normal cells resulted in decreased cellular
levels of cholesteryl ester. Although HDL facilitated
cholesterol efflux into the media for both Tangier and
normal cells, albeit at a reduced level for Tangier cells, HDL caused
significant depletion of cholesteryl ester from only normal cells and
not Tangier cells (Fig 7, panel C). Phospholipid vesicles and
cyclodextrin were nearly equally effective in promoting
cholesterol efflux from normal and Tangier cells (Fig 7, panel A). Both acceptors also resulted in a significant depletion of
cellular cholesteryl ester from both normal and Tangier cells (Fig 7, panel C). These results suggests that depending on the type of
acceptor, namely phospholipid vesicles and cyclodextrin,
cholesterol efflux from Tangier cells can potentially be
relatively normal.
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To further examine the mechanism of apoA-I-mediated efflux, the effect
of brefeldin was determined on lipid efflux from normal and Tangier
cells (Fig 8). Brefeldin blocks vesicular
movement between the endoplasmic reticulum and the Golgi
apparatus35 and has recently been shown to
partially inhibit cholesterol efflux by HDL.36
Brefeldin inhibited, by approximately 40%, cholesterol
efflux from normal cells to HDL (Fig 8, panel A) but did not cause
significant inhibition of HDL-mediated cholesterol efflux
from Tangier cells. Interestingly, the level of cholesterol
efflux by HDL from Tangier cells was approximately equivalent to the
level of HDL efflux from normal cells after treatment with brefeldin.
Similar results were obtained for all of the normal and Tangier cell
lines. In contrast to the partial inhibition of HDL efflux, brefeldin
almost completely blocked apoA-I-mediated cholesterol
efflux from normal cells (Fig 8, panel B). In addition, brefeldin also
inhibited, with a similar dose-response relationship, phospholipid
efflux by apoA-I from normal cells. In Fig 9, the effect of brefeldin treatment on
cholesteryl ester formation by normal cells after efflux with HDL and
apoA-I was also examined. Both HDL and apoA-I decreased cholesteryl
ester formation because of their ability to promote net efflux of
cholesterol from cells and to decrease the pool of
cholesterol that is available for
esterification.25 After treatment with brefeldin, however,
no decrease in cholesteryl ester formation was observed, because of the
apparent block by brefeldin of cholesterol efflux from
cells by apoA-I and HDL, even though brefeldin only partially blocked
HDL-mediated cholesterol efflux (Fig. 8). Normal cells
after brefeldin treatment, therefore, acted similar to Tangier cells in
cholesterol efflux based on their similar level of
HDL-mediated cholesterol efflux (Fig 8, panel A), their
inability to efflux cholesterol to apoA-I (Fig 8, panel B),
and the lack of cholesteryl ester depletion from cells after efflux
with either HDL or apoA-I (Figs 7 and 9).
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Discussion |
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As illustrated in Fig 1
, Tangier cells are partially defective in
HDL-mediated cholesterol efflux and are almost completely
defective in apoA-I-mediated cholesterol efflux. Because
the four Tangier cell lines in this study plus the two Tangier cell
lines that were previously described11 have markedly
decreased apoA-I-mediated cholesterol and phospholipid
efflux, it suggests that the observed lipid efflux defect may be
generally applicable to the majority of subjects with Tangier
disease.
The defect in apolipoprotein-mediated cholesterol and
phospholipid efflux from Tangier cells is not specific for apoA-I,
because other apolipoproteins, including apoA-II, apoA-IV, apoC-I,
apoC-II, and apoC-III (Fig. 6), showed decreased lipid efflux from
Tangier cells. This is consistent with previous studies that
have shown that several other apolipoproteins besides apoA-I can
mediate lipid efflux.13 14 15 17 37 The ability of an
apolipoprotein to mediate lipid efflux has been proposed to be
dependent on the presence of type A amphipathic
helices.17 27 38 39 The lack of acceptor specificity in
the apolipoprotein-mediated lipid efflux defect in Tangier cells makes
it less likely that a defect in the binding of apoA-I to Tangier
cells11 is the mechanism for the decreased lipid efflux.
All of the apolipoproteins tested (Fig 6) have different primary amino
acid sequences, which makes it less likely that a single receptor would
bind all of these proteins, although some receptors such as LRP and the
scavenger receptors can bind a multitude of different
ligands.40 The results presented in Fig 4, which
show that cholesterol efflux does not begin to saturate
until after 5 µg/mL of apoA-I, are also inconsistent
with a defect in binding at only submicrogram per milliliter
concentrations of apoA-I11 as the mechanism for the
decreased cholesterol efflux. Furthermore, when directly
assessed, no significant difference in the binding of apoA-I between
normal and Tangier disease cells was detected (Fig 5).
Heterogeneity in the biochemical basis for Tangier
disease or methodologic differences in the binding assay could
potentially be the cause for the difference between this study and the
previous report of decreased apoA-I binding in Tangier
cells.11
In addition to the defect in apolipoprotein-mediated
cholesterol efflux, Tangier cells also showed reduced
cholesterol efflux into the media with HDL (Fig 1) and no
reduction in cellular cholesteryl ester levels after efflux with HDL
(Fig 7), as has been described previously.11 Because the
level of cholesteryl ester is tightly coupled to the total
cholesterol mass of a cell,22 25 the lack of
depletion of cholesteryl ester from Tangier cells by HDL suggests that
there was no net efflux of cholesterol by HDL from Tangier
cells and that the radioactive cholesterol counts appearing
in the HDL-containing media are only the result of bidirectional
exchange of cholesterol between the plasma membrane and HDL
and not net movement of cholesterol from the cell.
Interestingly, phospholipid vesicles and cyclodextrin, both of which
remove cholesterol by aqueous diffusion, 33 34
were equally effective in facilitating cholesterol efflux
from normal and Tangier cells (Fig 7). Because both of these acceptors
do not initially contain cholesterol, any
cholesterol efflux into the media must represent
net cholesterol movement away from the cell. Efflux with
both phospholipid vesicles and cyclodextrin also led to a similar
reduction in cholesteryl ester levels from normal and Tangier cells
(Fig 7). Overall, these results suggests that the hydrolysis of
cholesteryl ester and the efflux of cholesterol is
potentially normal in Tangier cells, depending on the type of acceptor.
Tangier cells effluxed cholesterol normally to phospholipid
vesicles and cyclodextrin but were defective in apolipoprotein-mediated
efflux and in that part of HDL-mediated efflux that leads to net
cholesterol efflux and subsequent cholesteryl ester
depletion. Interestingly, Fu5AH cells, J744 cells, and
macrophages from atherosclerosis-susceptible
pigeons have all been shown to respond as Tangier cells in
cholesterol efflux to HDL.41 42 These cells
can undergo bidirectional exchange of cholesterol with HDL,
but it does not lead to depletion of cholesteryl ester from the cells
because for unknown reasons there is no net movement of
cholesterol from these cells to HDL.
On the basis of the effect of brefeldin on lipid efflux (Fig 8), two
components of cholesterol efflux by HDL can be functionally
defined, a brefeldin-sensitive and a brefeldin-resistant
component. Normal cells, as has been previously
described,36 are only partially inhibited in
cholesterol efflux by brefeldin and exhibit both a
brefeldin-sensitive and a brefeldin-resistant component of
HDL-mediated efflux (Fig 8, panel A). In contrast, brefeldin had a
minimal effect on HDL-mediated cholesterol efflux from
Tangier cells (Fig 8). Interestingly, the level of HDL-mediated efflux
from normal cells after treatment with brefeldin is similar to what was
observed from Tangier cells, which suggests that Tangier cells are
missing a brefeldin-sensitive component of cholesterol
efflux but have a near normal level of the brefeldin-resistant
component of cholesterol efflux (Fig 8, panel A). The fact
that cholesterol efflux by apoA-I is completely
brefeldin-sensitive in normal cells and is absent in Tangier cells
further supports the idea that Tangier cells have a general defect in a
brefeldin-sensitive pathway for lipid efflux. Because it is likely that
there are multiple steps involved in the efflux of
cholesterol by apoA-I, the cholesterol efflux
defect in Tangier cells is not necessarily at a brefeldin-sensitive
step but in a pathway for lipid efflux that can be inhibited by
brefeldin.
The mechanism for the brefeldin-resistant component of
efflux, which was the largest component of cholesterol
efflux from fibroblasts (Fig 8), is likely to occur by aqueous
diffusion from the plasma membrane, which has been well described to be
quantitatively the most important pathway for cholesterol
efflux.22 Because the plasma membrane already contains the
majority of cellular cholesterol,43 44
blocking intracellular translocation of additional
cholesterol to the plasma membrane by
brefeldin35 36 45 would not be predicted to have a major
affect on cholesterol efflux to HDL by aqueous diffusion.
Because the brefeldin-resistant component of
cholesterol efflux by HDL is relatively normal in Tangier
cells (Fig. 8), this suggests that cholesterol efflux by
aqueous diffusion may be normal in Tangier cells. This is supported by
the nearly equal cholesterol efflux observed between normal
and Tangier cells by phospholipid vesicles and cyclodextrin (Fig 7),
which remove cholesterol by aqueous
diffusion.33 34 It has been shown for cyclodextrin that
brefeldin does not affect its ability to efflux cholesterol
from the plasma membrane.46 In addition, it has recently
been shown that trypsin treatment of HDL, which prevents the binding of
HDL to cells but does not affect efflux by aqueous diffusion, results
in the same level of efflux from normal and Tangier
cells.11 Overall, these results are consistent
with a model by which Tangier cells can readily efflux
cholesterol by aqueous diffusion but are instead defective
in another pathway of lipid efflux, which is sensitive to
brefeldin.
The mechanism for the brefeldin-sensitive component of efflux is
not known but is likely to involve the intracellular translocation of
vesicles between the endoplasmic reticulum and the Golgi
apparatus, which brefeldin is known to
inhibit.35 47 The fact that lipid efflux by apoA-I was
more sensitive to brefeldin than HDL (Fig 8) suggests that apoA-I uses
the brefeldin-sensitive pathway for lipid efflux more than does HDL. It
has been proposed previously that the intracellular translocation of
cholesterol to the plasma membrane and its eventual efflux
is stimulated by the binding of HDL and apoA-I to cells.48
This translocation also appears to be dependent on protein kinase C
activation.49 Decreased translocation of newly synthesized
cholesterol to the plasma membrane and efflux to HDL has
recently been described in Tangier cells7 9 and is
corrected by activation of protein kinase C.7 Brefeldin,
by interfering with vesicular trafficking, may block intracellular
translocation of cholesterol to the plasma membrane, where
a direct interaction of lipid-free apolipoproteins with the plasma
membrane eventually results in cholesterol efflux.
Alternatively, brefeldin may interfere with cholesterol
efflux, not by blocking intracellular cholesterol
translocation45 but by inhibiting the translocation of
other lipids or proteins to the plasma membrane, where they may
facilitate cholesterol efflux by interacting with
lipid-free apolipoprotein acceptors. The fact that brefeldin completely
blocked cholesteryl ester depletion by HDL and apoA-I from normal cells
(Fig 9) suggests that it is the brefeldin-sensitive pathway of efflux
that leads to the net cholesterol efflux from
fibroblasts.
In Fig 10, a two-step model for lipid
efflux by apolipoproteins is presented.16 In this
model, apoA-I first removes phospholipid38 after a direct
interaction with the plasma membrane (Fig. 10, step 1) and then in a
second step the apoA-I phospholipid complex or nascent-like HDL
particle is then competent to accept cholesterol by aqueous
diffusion (Fig. 10, step 2). Based on this model, the observed decrease
in phospholipid efflux in Tangier cells (Fig 2) during step 1 would
subsequently lead to a decreased concentration of apoA-I lipidated with
phospholipid in the extracellular media. Although the potential for
cholesterol efflux by aqueous diffusion in Tangier cells
appears to be relatively normal, based on the efflux data with
phospholipid vesicles and cyclodextrin (Fig 7), there would be a
decrease in cholesterol efflux by aqueous diffusion (Fig 10, step 2) simply because of the lack of available apoA-I-phospholipid
complexes in the media.
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Based on this model HDL, which is already complexed phospholipid,
should readily efflux cholesterol by aqueous diffusion from
Tangier cells (Fig. 10, step 2). Compared with normal cells, however,
HDL was not as effective in removing cholesterol from
Tangier cells (Fig 1). This suggests that the partial reduction in
HDL-mediated cholesterol efflux from Tangier cells may
occur because part of HDL efflux is mediated by the same mechanism as
for apoA-I efflux, which may be the brefeldin-sensitive component of
HDL efflux (Fig 8) that appears to lead to net cholesterol
efflux (Fig 9). One possibility is that a portion of total
cholesterol efflux that occurs by HDL is mediated by apoA-I
that has dissociated from HDL (Fig 10, see upward arrow step 1). This
is supported by the recent observation that probucol, which prevents
the binding of apoA-I to cells and subsequent cholesterol
efflux, also partially reduces cholesterol efflux by
HDL.50 Overall, these results suggest that Tangier cells
are defective in the initial interaction of apolipoproteins with the
plasma membrane (Fig. 10, step 1) as seen by the reduced phospholipid
efflux to apoA-I and HDL (Figs 1 and 2). This abnormal interaction may
be a consequence of differences in how normal and Tangier cells respond
to cholesterol loading, which enhances apoA-I-mediated
efflux in normal but not Tangier cells (Fig 3). A potential defect in a
brefeldin-sensitive pathway for intracellular lipid transfer may result
in a modification of the plasma membrane of
cholesterol-loaded Tangier cells in such a way that it
interferes with lipid efflux by apolipoproteins.
In summary, the acceptor specificity and the mechanism of apolipoprotein-mediated cholesterol efflux was examined from normal and Tangier cells. Tangier cells were confirmed, as previously described,11 to be defective in cholesterol efflux to HDL and apoA-I, and the defect in apolipoprotein-mediated lipid efflux was not specific for apoA-I but also occurred for other apolipoproteins. Furthermore, brefeldin had a differential effect on lipid efflux from normal and Tangier cells, and a model is proposed whereby a defect in a brefeldin-sensitive pathway leads to decreased lipid efflux from Tangier cells. Future studies aimed at defining further the mechanism of apoA-I-mediated cholesterol efflux and the effect of brefeldin on lipid efflux should provide further insight into the molecular basis of the defect in Tangier disease.
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Acknowledgments |
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We thank J.M. Hoeg for helpful discussions and critical reading of the manuscript.
Received July 12, 1996; accepted February 14, 1997.
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R. H. See, R. A. Caday-Malcolm, R. R. Singaraja, S. Zhou, A. Silverston, M. T. Huber, J. Moran, E. R. James, R. Janoo, J. M. Savill, et al. Protein Kinase A Site-specific Phosphorylation Regulates ATP-binding Cassette A1 (ABCA1)-mediated Phospholipid Efflux J. Biol. Chem., October 25, 2002; 277(44): 41835 - 41842. [Abstract] [Full Text] [PDF]
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W. T. Doerrler and C. R. H. Raetz ATPase Activity of the MsbA Lipid Flippase of Escherichia coli J. Biol. Chem., September 20, 2002; 277(39): 36697 - 36705. [Abstract] [Full Text] [PDF]
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M. L. Fitzgerald, A. L. Morris, J. S. Rhee, L. P. Andersson, A. J. Mendez, and M. W. Freeman Naturally Occurring Mutations in the Largest Extracellular Loops of ABCA1 Can Disrupt Its Direct Interaction with Apolipoprotein A-I J. Biol. Chem., August 30, 2002; 277(36): 33178 - 33187. [Abstract] [Full Text] [PDF]
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R. Arakawa and S. Yokoyama Helical Apolipoproteins Stabilize ATP-binding Cassette Transporter A1 by Protecting It from Thiol Protease-mediated Degradation J. Biol. Chem., June 14, 2002; 277(25): 22426 - 22429. [Abstract] [Full Text] [PDF]
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N. Fournier, A. Cogny, V. Atger, D. Pastier, D. Goudouneche, A. Nicoletti, N. Moatti, J. Chambaz, J.-L. Paul, and A.-D. Kalopissis Opposite Effects of Plasma From Human Apolipoprotein A-II Transgenic Mice on Cholesterol Efflux From J774 Macrophages and Fu5AH Hepatoma Cells Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 638 - 643. [Abstract] [Full Text] [PDF]
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K. Gillotte-Taylor, M. Nickel, W. J. Johnson, O. L. Francone, P. Holvoet, S. Lund-Katz, G. H. Rothblat, and M. C. Phillips Effects of Enrichment of Fibroblasts with Unesterified Cholesterol on the Efflux of Cellular Lipids to Apolipoprotein A-I J. Biol. Chem., March 29, 2002; 277(14): 11811 - 11820. [Abstract] [Full Text] [PDF]
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X.-P. Yang, L. A. Freeman, C. L. Knapper, M. J. A. Amar, A. Remaley, H. B. Brewer Jr., and S. Santamarina-Fojo The E-box motif in the proximal ABCA1 promoter mediates transcriptional repression of the ABCA1 gene J. Lipid Res., February 1, 2002; 43(2): 297 - 306. [Abstract] [Full Text] [PDF]
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H. Liao, T. Langmann, G. Schmitz, and Y. Zhu Native LDL Upregulation of ATP-Binding Cassette Transporter-1 in Human Vascular Endothelial Cells Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 127 - 132. [Abstract] [Full Text] [PDF]
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W. Chen, Y. Sun, C. Welch, A. Gorelik, A. R. Leventhal, I. Tabas, and A. R. Tall Preferential ATP-binding Cassette Transporter A1-mediated Cholesterol Efflux from Late Endosomes/Lysosomes J. Biol. Chem., November 16, 2001; 276(47): 43564 - 43569. [Abstract] [Full Text] [PDF]
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A. D. Attie, J. P. Kastelein, and M. R. Hayden Pivotal role of ABCA1 in reverse cholesterol transport influencing HDL levels and susceptibility to atherosclerosis J. Lipid Res., November 1, 2001; 42(11): 1717 - 1726. [Abstract] [Full Text] [PDF]
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J. F. Oram, A. M. Vaughan, and R. Stocker ATP-binding Cassette Transporter A1 Mediates Cellular Secretion of alpha -Tocopherol J. Biol. Chem., October 19, 2001; 276(43): 39898 - 39902. [Abstract] [Full Text] [PDF]
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J. F. Oram and R. M. Lawn ABCA1: the gatekeeper for eliminating excess tissue cholesterol J. Lipid Res., August 1, 2001; 42(8): 1173 - 1179. [Abstract] [Full Text] [PDF]
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C. G. Panousis, G. Evans, and S. H. Zuckerman TGF-{beta} increases cholesterol efflux and ABC-1 expression in macrophage-derived foam cells: opposing the effects of IFN-{{gamma}} J. Lipid Res., May 1, 2001; 42(5): 856 - 863. [Abstract] [Full Text]
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S. Tomimoto, M. Tsujita, M. Okazaki, S. Usui, T. Tada, T. Fukutomi, S. Ito, M. Itoh, and S. Yokoyama Effect of Probucol in Lecithin-Cholesterol Acyltransferase-Deficient Mice : Inhibition of 2 Independent Cellular Cholesterol-Releasing Pathways In Vivo Arterioscler Thromb Vasc Biol, March 1, 2001; 21(3): 394 - 400. [Abstract] [Full Text] [PDF]
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B. Haidar, S. Mott, B. Boucher, C. Y. Lee, M. Marcil, and J. Genest , Jr. Cellular cholesterol efflux is modulated by phospholipid-derived signaling molecules in familial HDL deficiency/Tangier disease fibroblasts J. Lipid Res., February 1, 2001; 42(2): 249 - 257. [Abstract] [Full Text]
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A. von Eckardstein, J.-R. Nofer, and G. Assmann High Density Lipoproteins and Arteriosclerosis : Role of Cholesterol Efflux and Reverse Cholesterol Transport Arterioscler Thromb Vasc Biol, January 1, 2001; 21(1): 13 - 27. [Abstract] [Full Text] [PDF]
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R. Arakawa, S. Abe-Dohmae, M. Asai, J.-i. Ito, and S. Yokoyama Involvement of caveolin-1 in cholesterol enrichment of high density lipoprotein during its assembly by apolipoprotein and THP-1 cells J. Lipid Res., December 1, 2000; 41(12): 1952 - 1962. [Abstract] [Full Text]
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M. E. Brousseau, G. P. Eberhart, J. Dupuis, B. F. Asztalos, A. L. Goldkamp, E. J. Schaefer, and M. W. Freeman Cellular cholesterol efflux in heterozygotes for Tangier disease is markedly reduced and correlates with high density lipoprotein cholesterol concentration and particle size J. Lipid Res., July 1, 2000; 41(7): 1125 - 1135. [Abstract] [Full Text]
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M. E. Brousseau, E. J. Schaefer, J. Dupuis, B. Eustace, P. Van Eerdewegh, A. L. Goldkamp, L. M. Thurston, M. G. FitzGerald, D. Yasek-McKenna, G. O'Neill, et al. Novel mutations in the gene encoding ATP-binding cassette 1 in four Tangier disease kindreds J. Lipid Res., March 1, 2000; 41(3): 433 - 441. [Abstract] [Full Text]
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A. T. Remaley, S. Rust, M. Rosier, C. Knapper, L. Naudin, C. Broccardo, K. M. Peterson, C. Koch, I. Arnould, C. Prades, et al. Human ATP-binding cassette transporter 1 (ABC1): Genomic organization and identification of the genetic defect in the original Tangier disease kindred PNAS, October 26, 1999; 96(22): 12685 - 12690. [Abstract] [Full Text] [PDF]
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J. F. Oram, A. J. Mendez, J. Lymp, T. J. Kavanagh, and C. L. Halbert Reduction in apolipoprotein-mediated removal of cellular lipids by immortalization of human fibroblasts and its reversion by cAMP: lack of effect with Tangier disease cells J. Lipid Res., October 1, 1999; 40(10): 1769 - 1781. [Abstract] [Full Text]
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M. W. Freeman Effluxed lipids: Tangier Island's latest export PNAS, September 28, 1999; 96(20): 10950 - 10952. [Full Text] [PDF]
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Y. Takahashi and J. D. Smith Cholesterol efflux to apolipoprotein AI involves endocytosis and resecretion in a calcium-dependent pathway PNAS, September 28, 1999; 96(20): 11358 - 11363. [Abstract] [Full Text] [PDF]
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M. Marcil, L. Yu, L. Krimbou, B. Boucher, J. F. Oram, J. S. Cohn, and J. Genest Jr Cellular Cholesterol Transport and Efflux in Fibroblasts Are Abnormal in Subjects With Familial HDL Deficiency Arterioscler Thromb Vasc Biol, January 1, 1999; 19(1): 159 - 169. [Abstract] [Full Text] [PDF]
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K. L. Gillotte, W. S. Davidson, S. Lund-Katz, G. H. Rothblat, and M. C. Phillips Removal of cellular cholesterol by pre-ß-HDL involves plasma membrane microsolubilization J. Lipid Res., October 1, 1998; 39(10): 1918 - 1928. [Abstract] [Full Text]
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W. Zhang, B. Asztalos, P. S. Roheim, and L. Wong Characterization of phospholipids in pre-{alpha} HDL: selective phospholipid efflux with apolipoprotein A-I J. Lipid Res., August 1, 1998; 39(8): 1601 - 1607. [Abstract] [Full Text]
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A. von Eckardstein, A. Chirazi, S. Schuler-Lüttmann, M. Walter, J. J. P. Kastelein, J. Geisel, J. T. Real, R. Miccoli, G. Noseda, G. Höbbel, et al. Plasma and fibroblasts of Tangier disease patients are disturbed in transferring phospholipids onto apolipoprotein A-I J. Lipid Res., May 1, 1998; 39(5): 987 - 998. [Abstract] [Full Text]
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P. Costet, Y. Luo, N. Wang, and A. R. Tall Sterol-dependent Transactivation of the ABC1 Promoter by the Liver X Receptor/Retinoid X Receptor J. Biol. Chem., September 1, 2000; 275(36): 28240 - 28245. [Abstract] [Full Text] [PDF]
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A. E. Bortnick, G. H. Rothblat, G. Stoudt, K. L. Hoppe, L. J. Royer, J. McNeish, and O. L. Francone The Correlation of ATP-binding Cassette 1 mRNA Levels with Cholesterol Efflux from Various Cell Lines J. Biol. Chem., September 8, 2000; 275(37): 28634 - 28640. [Abstract] [Full Text] [PDF]
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W. Chen, D. L. Silver, J. D. Smith, and A. R. Tall Scavenger Receptor-BI Inhibits ATP-binding Cassette Transporter 1- mediated Cholesterol Efflux in Macrophages J. Biol. Chem., September 29, 2000; 275(40): 30794 - 30800. [Abstract] [Full Text] [PDF]
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N. Wang, D. L. Silver, P. Costet, and A. R. Tall Specific Binding of ApoA-I, Enhanced Cholesterol Efflux, and Altered Plasma Membrane Morphology in Cells Expressing ABC1 J. Biol. Chem., October 13, 2000; 275(42): 33053 - 33058. [Abstract] [Full Text] [PDF]
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A. J. Mendez, G. Lin, D. P. Wade, R. M. Lawn, and J. F. Oram Membrane Lipid Domains Distinct from Cholesterol/Sphingomyelin-Rich Rafts Are Involved in the ABCA1-mediated Lipid Secretory Pathway J. Biol. Chem., January 26, 2001; 276(5): 3158 - 3166. [Abstract] [Full Text] [PDF]
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M. L. Fitzgerald, A. J. Mendez, K. J. Moore, L. P. Andersson, H. A. Panjeton, and M. W. Freeman ATP-binding Cassette Transporter A1 Contains an NH2-terminal Signal Anchor Sequence That Translocates the Protein's First Hydrophilic Domain to the Exoplasmic Space J. Biol. Chem., April 27, 2001; 276(18): 15137 - 15145. [Abstract] [Full Text] [PDF]
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L. B. Cavelier, Y. Qiu, J. K. Bielicki, V. Afzal, J.-F. Cheng, and E. M. Rubin Regulation and Activity of the Human ABCA1 Gene in Transgenic Mice J. Biol. Chem., May 18, 2001; 276(21): 18046 - 18051. [Abstract] [Full Text] [PDF]
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N. Wang, D. L. Silver, C. Thiele, and A. R. Tall ATP-binding Cassette Transporter A1 (ABCA1) Functions as a Cholesterol Efflux Regulatory Protein J. Biol. Chem., June 22, 2001; 276(26): 23742 - 23747. [Abstract] [Full Text] [PDF]
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E. B. Neufeld, A. T. Remaley, S. J. Demosky, J. A. Stonik, A. M. Cooney, M. Comly, N. K. Dwyer, M. Zhang, J. Blanchette-Mackie, S. Santamarina-Fojo, et al. Cellular Localization and Trafficking of the Human ABCA1 Transporter J. Biol. Chem., July 13, 2001; 276(29): 27584 - 27590. [Abstract] [Full Text] [PDF]
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N. Fournier, A. Cogny, V. Atger, D. Pastier, D. Goudouneche, A. Nicoletti, N. Moatti, J. Chambaz, J.-L. Paul, and A.-D. Kalopissis Opposite Effects of Plasma From Human Apolipoprotein A-II Transgenic Mice on Cholesterol Efflux From J774 Macrophages and Fu5AH Hepatoma Cells Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 638 - 643. [Abstract] [Full Text] [PDF]
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