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1,
* Institute of Clinical Chemistry and Laboratory Medicine, Central Laboratory, Westphalian Wilhelms University, D-48129 Münster, Germany;
Institute of Arteriosclerosis Research, D-48149 Münster, Germany;
Institute of Pharmacological Sciences, University of Milan, I-20133 Milano, Italy; and
Institute of Physiology, Westphalian Wilhelms University, D-48129 Münster, Germany
1Correspondence: Institut für Klinische Chemie und Laboratoriumsmedizin, Zentrallaboratorium, Westfälische Wilhelms-Universität, Albert-Schweitzer-Strasse 33, D-48129 Münster, Germany. E-mail: vonecka{at}uni-muenster.de
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: ABCA1 • Tangier disease • apoE
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 2)
. It mediates the clearance of
these lipoproteins and their remnants from the circulation (1
, 2)
. The hypolipidemic and antiatherogenic effect of apoE is
illustrated by the accumulation of lipoprotein remnants in plasma and
the early onset of atherosclerosis in both humans and mice lacking apoE
(3
4
5)
.
Macrophages also produce apoE, although to a much lesser extent than
hepatocytes (2
, 6)
. Without producing gross changes in
plasma lipid levels, expression of a human apoE transgene in
macrophages of apoE-deficient mice prevented atherosclerosis
(7)
whereas transplantation of apoE-deficient macrophage
stem cells into wild-type mice (8)
promoted
atherosclerosis. Possible explanations for the anti-atherogenicity of
macrophage-derived apoE include the ability of macrophage-derived apoE
to promote cholesterol efflux from these and other cells (2
, 6
, 9
, 10)
, to inhibit the proliferation and migration of smooth
muscle cells (11)
and to interfere with the expression of
cellular adhesion molecules by endothelial cells (12)
.
The mechanism and regulation of apoE secretion from macrophages are
little understood. Enrichment of cells with cholesterol and activation
of protein kinase A with the cyclic adenosine monophosphate analog
8-Br-cAMP stimulate the secretion of apoE (13
, 14)
. ApoE
secretion is also stimulated in the presence of exogenous HDL and
apoA-I (15
, 16)
. Finally, apoE secretion from macrophages
is inhibited by brefeldin A, which disrupts structure and function of
the Golgi apparatus, the trans-Golgi network (TGN),
endosomes (17)
, as well as interferon-
(18)
.
Regulation of apoE secretion from macrophages shares several properties
with the regulation of cholesterol efflux from these cells. Cholesterol
efflux is stimulated by the presence of apoA-I, HDL, and 8-Br-cAMP
(19
, 20)
and is inhibited by brefeldin A (21)
and interferon- (22)
. An important regulator of
cholesterol efflux is the adenosine trisphosphate (ATP) binding
cassette transporter 1 (ABCA1) (23)
. ABCA1 has been
suggested to serve either as a regulator of vesicular transport between
the TGN and the plasma membrane (24)
or as a channel
protein or so-called floppase within the plasma membrane
(24
25
26)
. ABCA1 deficiency in Tangier disease disrupts
apoA-I-mediated cholesterol efflux from cells and leads to HDL
deficiency and foam cell formation (23
, 27)
. Cholesterol
loading and cyclic AMP treatment up-regulate ABCA1 expression in
macrophages (20
, 28
29
30)
.
Because of the similarities in the regulation of apoE secretion,
cholesterol efflux, and ABCA1 activity, we investigated whether ABCA1
controls apoE secretion from macrophages. We also investigated the role
of human ABC8, which shows homologies to the white gene in
Drosophila and that, like ABCA1, was shown to be regulated
by cholesterol and to mediate cholesterol efflux (29)
.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and acetylated as described by Brown and colleagues
(32)
.
Cells
Human monocytes were obtained from healthy volunteers and from
two Tangier patients by leukapheresis and elutriation
(13)
. The Tangier patients have been described and were
homozygous for the N890S mutation (formerly denominated N875S mutation)
and for a frameshift mutation in the ABCA1 gene, respectively
(33
, 34)
. Since the apoE genotype affects apoE secretion
from macrophages (13)
, we took care that all donors had
the apoE3/3 phenotype. Purity of the monocytes was controlled by FACS
analysis and amounted to >95%. 106 monocytes
per 35 mm dish or 107 monocytes per 75
cm2 flask were differentiated into macrophages by
12 days cultivation in RPMI 1640 (BioWhittaker, Verviers, Belgium)
containing 10% autologous human serum (Biochrom, Berlin, Germany) and
penicillin (100 units/ml)/streptomycin (0.1 mg/ml) (Sigma, Deisenhofen,
Germany) as antibiotics. THP1 monocytes were purchased from American
Type Culture Collection (Manassas, VA) and cultivated with RPMI 1640
containing 20% fetal calf serum (Biochrom, Berlin, Germany) and
penicillin (100 units/ml)/streptomycin (0.1 mg/ml) (Sigma) as
antibiotics. 106 THP1 monocytes were seeded into
35 mm dishes and differentiated into macrophages by 96 h
incubation with the phorbol ester phorbol 12-myristate 13-acetate (100
nM PMA, Sigma) and 50 nM ß-mercaptoethanol. For some experiments,
human monocyte-derived macrophages (HMDM) and THP1 macrophages were
converted into foam cells by loading with 100 µg/ml acetylated LDL
(acLDL) for 48 h (32)
.
Antisense oligonucleotides
Phosphothionate antisense oligonucleotides were used for the
inhibition of ABCA1 and ABC8. The antisense oligonucleotide directed
against the ABCA1 mRNA was purchased from Biognostik (Göttingen,
Germany) and had the sequence 5'-CATGTTGTTCATAGGGTGGGTAGCTC-3'
(35)
; the antisense oligonucleotide directed against the
ABC8 mRNA was purchased from Metabion (Martinsried, Germany) and had
the sequence 5'-TGCCGACCGAGAAAG-3' (29)
. As control
oligonucleotides, we used the reverse complements of the target
sequences. No cross homologies were found in the GenBank database. The
efficient cellular uptake of these oligonucleotides was controlled by
fluorescence microscopy of macrophages that were incubated with the
FITC-labeled homologues of the antisense oligonucleotides. The two
nucleotides were used at a concentration of 4.4 nmol/l at which they
were previously shown to inhibit cholesterol efflux from cells by
50% (29
, 35)
.
Quantification of apoE in media and cells
HMDM or THP1 macrophages were cultivated for varying intervals
of time in serum-free RPMI 1640 that was supplemented with potential
modulators of ABCA1 or ABC8. As a potential stimulator, we used 0.3
µmol/l 8-Br-cAMP (Calbiochem, Bad Soden, Germany). As potential
inhibitors, we used different concentrations of glyburide (Calbiochem,
Bad Soden, Germany), 4,4-diisothiocyanostilbene-2,2' disulfonic
acid, or bromosulfthalein (both from Sigma). If dimethyl sulfoxide
(DMSO) was needed as the solvent, we used RPMI 1640 with DMSO as
controls. Antisense oligonucleotides and control oligonucleotides were
added to the medium at a final concentration of 4.4 nmol/l. After
incubation, media were collected for the quantification of apoE by
ELISA (13
, 36)
. Cells were harvested with a rubber
policeman for the quantification of cellular protein by the Lowry
method or for the measurement of cellular apoE by ELISA. The apoE ELISA
was performed using a monoclonal anti-apoE antibody (DUNN,
Asbach, Germany) as the capturing antibody and IgG from a lab-made
rabbit anti-human apoE antiserum as the second antibody. The
immunoreaction was visualized by serial incubation with biotinylated
anti-rabbit IgG (DAKO, Hamburg, Germany), streptavidin horseradish
peroxidase as the conjugate, and ortho-phenylenediamine as the
substrate (Sigma).
Detection of apoE mRNA by Northern blotting
Total RNA was purified from macrophages by using the RNeasy mini
kit (Qiagen GmbH, Hilden, Germany) according to the manufacturer’s
protocol and treated with DNase (MessageClean kit, GenHunter,
Nashville, TN) to remove residual contaminations with DNA.
Single–stranded cDNA was prepared from 5 µg RNA using the
SuperScriptTM RT-PCR kit (Life Technologies, Eggenstein, Germany),
yielding 20 µl. PCR was performed in a 50 µl reaction containing 1
µl of cDNA, 2.5 units of HotStarTaq (Qiagen), the supplied reaction
buffer (Qiagen), 200 µM of each dNTP, and 0.5 µM of each primer.
Sequences of the primers are listed in Table 1
. Amplification was performed with a DNA thermal cycler (Applied
Biosystems, GeneAmp, PCR system 9700, Branchburg, NJ) under the
following conditions: hot start at 94°C for 15 min, followed by 40
cycles (94°C for 45 s, 59°C for 90 s, 72°C for 1 min),
and a final incubation at 72°C for 7 min. PCR products of the human
apoE gene (bp 14–321 of GenBank Acc NM 000041) and GAPDH gene (bp
81–306 of GenBank Acc. NM 002046) were gel purified using a 2%
agarose TAE gel and a gel extraction kit (Qiagen). Digoxigenin (DIG)
-labeled probes were generated using the DIG DNA labeling and Detection
Kit (Roche Molecular Biochemicals, Mannheim, Germany). Sensitivity of
the probe was determined by dot blot analysis.
|
For Northern blot analysis, 5 µg of total RNA was separated on a denaturing formaldehyde 1% agarose gel. The RNA was transferred onto a positively charged nylon filter (Roche Molecular Biochemicals) by capillary transfer and hybridized with the above-described DIG-labeled DNA probes directed against human apoE and GAPDH gene according to the manufacturer’s protocol (DIG DNA Labeling and Detection Kit, Roche Molecular Biochemicals). The hybridization signal was detected with an anti-digoxigenin alkaline phosphatase conjugate and CDP-Star by chemoluminescence using Hyperfilm ECL detection (Amersham Pharmacia Biotech, Buckinghamshire, UK). Autoradiographs were scanned and processed with the AIDA program (Raytest, Straubenhardt, Germany.
Immunofluorescence microscopy of apoE
Monocytes were seeded into 24-well cell culture dishes that
contained coverslips with 12 mm diameter. After 14 days of cultivation
and lipid loading as required, the cells were fixed in 4%
paraformaldehyde in phosphate-buffered saline (PBS) and permeabilized
by incubation with 0.1% Triton X-100 in PBS. To suppress unspecific
binding of antibodies, the cells were blocked with 20%
heat-inactivated goat serum in PBS (Sigma). Thereafter, the cells were
blocked and incubated with in-house rabbit anti-apoE antiserum and
subsequently with Cy3-labeled goat anti-rabbit IgG (Dianova, Hamburg,
Germany). Confocal immunofluorescence microscopy was performed
with an Olympus Fluoview IX 70.
Statistics
The paired t test was used to calculate levels of
statistical significance.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) or 3 h (non-loaded cells; not shown). Longer
incubations with 8-Br-cAMP led to a significant decrease of apoE
secretion (Fig. 1A
). Likewise, 8-Br-cAMP increased apoE
secretion from HMDM during incubations up to 6 h but decreased
apoE secretion during incubations for 24 h (Fig. 1B
).
|
Glyburide inhibited apoE secretion at concentrations >100 µmol/l.
Maximal inhibition was reached at a glyburide concentration of 250
µmol/l and amounted to >90% and 80% in nonloaded and loaded THP1
macrophages, respectively (Fig. 2
) and to 35% and 55% in unloaded and loaded HMDM, respectively
(Table 2
).
|
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ApoE secretion is decreased by antisense oligonucleotides directed
against ABCA1 mRNA and in ABCA1-deficient cells
Compared with control oligonucleotides, antisense oligonucleotides
directed against either ABCA1 or ABC8 mRNA reduced apoE secretion from
nonloaded THP1 macrophages by 45% to 50% (P<0.01, Fig. 2A
) and from acLDL-loaded cells by 65% to 70%
(P<0.01, Fig. 2B
). The combination of the two
antisense oligonucleotides did not enhance the inhibitory effect of the
single antisense oligonucleotides. It is noteworthy that the antisense
oligonucleotides were less efficient in inhibiting apoE secretion from
THP1 cells as compared to glyburide.
The antisense oligonucleotide directed against ABCA1 mRNA significantly
decreased the secretion of apoE from nonloaded and acLDL-loaded HMDM by
80% and 45%, respectively (P<0.01; Table 2
). The
antisense oligonucleotide was as effective as glyburide in inhibiting
apoE secretion from HMDM. The antisense oligonucleotide directed
against ABC8 mRNA inhibited apoE secretion from unloaded HMDM by only
20% (P<0.05) and was ineffective at inhibiting apoE
secretion from acLDL-loaded HMDM. The combination of anti-ABCA1 and
anti-ABC8 antisense oligonucleotide did not increase the inhibitory
effect of the anti-ABCA1-antisense oligonucleotides alone.
ApoE secretion from macrophages of two patients with Tangier disease
was compared with apoE secretion from macrophages of two control donors
that were cultivated in parallel with the Tangier cells and with apoE
secretion from macrophages obtained from eight separate donations
(Fig. 3
). All healthy donors and Tangier patients exhibited the apoE3/3
phenotype. The apoE level in the media of Tangier macrophages was the
lowest of all 12 macrophage cell isolates and amounted to 50% of
the mean apoE level in the media of control macrophages
(P<0.05).
|
Effect of ABCA1 and ABC8 on apoE mRNA and cellular apoE
The influence of ABCA1 inhibition or deficiency on apoE production
was assessed by the measurement of apoE mRNA and cellular apoE in HMDM.
Neither glyburide, 8-Br-cAMP, nor antisense oligonucleotides directed
against ABCA1 or ABC8 mRNA affected the abundance of apoE mRNA relative
to that of the housekeeping gene GAPDH (Fig. 4
). ApoE gene expression in Tangier macrophages was also not different
from that in normal macrophages (not shown).
|
The cellular content of apoE was measured by ELISA of cell lysates and
did not change upon incubation of HMDM or THP1 macrophages with either
glyburide or antisense oligonucleotides directed either against ABCA1
or ABC8. However, inhibition of ABCA1 with antisense oligonucleotides
affected the distribution of apoE in HMDM (Fig. 5
). In nonloaded and loaded HMDM, which were either incubated with medium
alone or with control oligonucleotides (Figs. 5A
, B
),
anti-apoE immunoreactive material was localized in perinuclear
compartments, representing the endoplasmic reticulum and/or the Golgi
apparatus. The granular staining in the cell periphery resembles plasma
membrane and strong vesicular localization (Figs. 5A
, B
).
Incubation of cells with anti-ABCA1-antisense oligonucleotides (Fig. 5C
) led to the disappearance of this fine granular material
in the periphery.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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First, in agreement with the results of a previous study of apoE
secretion from the murine macrophage cell line RAW264.7
(14)
, we found that apoE secretion increased from human
macrophages in the presence of 8-Br-cAMP (Fig. 1)
. This activator of
protein kinase A was previously shown to increase ABCA1 gene expression
and ABCA1-mediated cholesterol efflux from macrophages (26
, 30)
. However, in our study 8-Br-cAMP exerted stimulatory effects
on apoE secretion during incubations up to 6 h, but had even more
pronounced inhibitory effects during 24 h of incubation with
macrophages. Since cyclic AMP is a very common second messenger that
regulates a broad variety of metabolic processes (37)
,
8-Br-cAMP exerts contrasting effects on the cellular processing and
secretion of apoE depending on the experimental conditions used. The
stimulatory effect on apoE secretion possibly via ABCA1 activation
(26
, 30)
appears to be rate-limiting only during short
time incubation.
Second, apoE secretion was decreased by the sulfonylurea derivative
glyburide (Fig. 2
, Table 2
), previously shown to inhibit ABCA1-mediated
secretion of lipids, anions, and interleukin 1beta (IL-1ß) as well as
ABCA1-mediated engulfment of apoptotic cells by macrophages (35
, 38
39
40)
. Glyburide was less efficient in inhibiting apoE
secretion from HMDM than from THP1 cells.
Third, an antisense oligonucleotide directed against ABCA1 mRNA,
previously shown to inhibit cholesterol efflux from fibroblasts by 50%
(35)
, inhibited apoE secretion from both primary HMDM and
transformed THP1 macrophages by at least 50% (Fig. 2
, Table 2
). An
antisense oligonucleotide directed against ABC8 mRNA that had been
shown to inhibit efflux of cholesterol and phospholipids from HMDM by
20 to 30% (30)
inhibited apoE secretion, also by 50%,
from THP1 cells and by 20% (Fig. 2)
from unloaded HMDM. However, this
antisense oligonucleotide was ineffective at inhibiting apoE secretion
from acLDL-loaded HMDM (Table 2)
. The combination of the two antisense
oligonucleotides did not increase the inhibitory effect of the
anti-ABCA1 antisense oligonucleotide alone. These observations are
similar to those made on the role of ABC8 in cholesterol efflux.
Deficiency of ABCA1 completely abolishes cholesterol efflux from cells
of patients with Tangier disease or ABCA1 knockout mice (23
, 24
, 26
, 35
, 40)
. Nevertheless, inhibition of ABC8 with an antisense
oligonucleotide reduced cholesterol efflux, although less efficiently
than an antisense oligonucleotide against ABCA1 (29
, 35)
.
ABCA1 and ABC8 hence may contribute to one transport mechanism where
ABCA1 is the more active component.
Fourth, cholesterol-loaded macrophages from patients with Tangier
disease have a reduced capacity to secrete apoE (Fig. 3)
. That
functioning of ABCA1 is not a prerequisite for secretion of apoE from
macrophages is illustrated by the fact that macrophages from patients
with Tangier disease secrete about half as much apoE as control
macrophages.
Taken together, the data presented here imply that ABCA1 and ABC8
contribute to the secretion of apoE by macrophages. We have ruled out
that inhibition of ABC transporters A1 and 8 decreases apoE
secretion. ApoE mRNA and cellular apoE levels were normal in
macrophages that were incubated with antisense oligonucleotides and in
macrophages of Tangier disease patients (Fig. 3)
. ABCA1 gene expression
was even increased in the liver of ABCA1 knockout mice
(41)
. It thus appears that inhibition of ABCA1 does not
cause an increase in intracellular apoE levels, probably because excess
intracellular apoE undergoes cellular degradation in either lysosomes
or proteasomes (13
, 17
, 18
, 42
, 43)
.
Our data do not allow any conclusion as to the mechanism by which ABCA1
and ABC8 modulate apoE secretion. Net apoE secretion from macrophages
is regulated in a complex manner (17)
. After production in
the ER, a pool of nonglycosylated apoE is transported to the plasma
membrane, where it is sequestered by binding to proteoglycans and apoE
receptors. A considerable proportion is reinternalized and directed
either to lysosomes for intracellular degradation or to the Golgi
apparatus for glycosylation with sialic acid. This pool of sialo-apoE
is transported to the cell surface for eventual secretion
(17)
. This pathway resembles the retroendocytosis of
apoA-I and HDL (44
45
46
47
48)
previously found to be defective
in ABCA1-deficient macrophages (44)
. ABCA1 may be involved
in this transport at various stages. Since ABCA1 was shown to interact
with lipid-free apolipoproteins on the plasma membrane (25
, 26)
, ABCA1 may operate at the plasma membrane by facilitating
the efflux of asialo- and/or sialo-apoE or the reinternalization of
asialo-apoE. Since ABCA1 is responsible for the vesicular transport of
lipids between intracellular compartments and the plasma membrane
(24
, 45)
, it may regulate the transport of asialo-apoE
from the ER to the plasma membrane and/or from the plasma membrane to
the Golgi and/or the transport of the sialo-apoE from the TGN to the
plasma membrane. In agreement with a role of ABCA1 in the intracellular
trafficking of apoE, we observed that inhibition of ABCA1 leads to the
disappearance of apoE containing granular structures from the plasma
membrane (Fig. 5)
. Likewise, ABCA1 was previously postulated to
regulate the intracellular trafficking of the leaderless protein
IL-1ß from the Golgi apparatus to the plasma membrane for secretion
(40
, 48)
. In contrast to other apolipoproteins, which are
synthesized as preproapolipoproteins, apoE is synthesized as preapoE.
After the removal of the prepeptide in the endoplasmic reticulum, apoE
does not contain a signal peptide (propeptide), so that like IL-1ß,
apoE may be considered a leaderless protein (49)
. ABCA1
hence may support apoE secretion by diverting the leaderless apoE from
a degrading lysosomal or proteasomal pathway (13
, 17
, 18
, 42
, 43)
to a secretory route.
In conclusion, we have demonstrated here that ABCA1 and to a lesser extent ABC8 modulate the net secretion of apoE from macrophages. In view of several anti-atherogenic properties of macrophage-derived apoE, our findings add a novel potentially anti-atherogenic property to ABC transporters A1 and 8.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Received for publication March 28, 2001. Accepted for publication April 2, 2001.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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