© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Role of Serum Amyloid A During Metabolism of Acute-Phase HDL by Macrophages
From Karl-Franzens University Graz (A.A., G.M., W.S., E.M.), Institute of Medical Biochemistry, Graz, Austria, and Unité INSERM 325 (S.L.), Institut Pasteur, Lille, France.
Correspondence to Dr Ernst Malle, Karl-Franzens University Graz, Institute of Medical Biochemistry, Harrachgasse 21, A-8010 Graz, Austria. E-mail ernst.malle{at}kfunigraz.ac.at
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Abstract |
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Abstract—The serum amyloid A (SAA) family of proteins is encoded by multiple genes that display allelic variation and a high degree of homology in mammals. Triggered by inflammation after stimulation of hepatocytes by lymphokine-mediated processes, the concentrations of SAA may increase during the acute-phase reaction to levels 1000-fold greater than those found in the noninflammatory state. In addition to its role as an acute-phase reactant, SAA (104 amino acids, 12 kDa) is considered to be the precursor protein of secondary reactive amyloidosis, in which the N-terminal portion is incorporated into the bulk of amyloid fibrils. However, the association with lipoproteins of the high-density range and subsequent modulation of the metabolic properties of its physiological carrier appear to be the principal role of SAA. Because SAA may displace apolipoprotein A-I, the major protein component of native high density lipoprotein (HDL), during the acute-phase reaction, the present study was aimed at (1) investigating binding properties of native and acute-phase (SAA-enriched) HDL by J774 macrophages, (2) elucidating whether the presence of SAA on HDL particles affects selective uptake of HDL-associated cholesteryl esters, and (3) comparing cellular cholesterol efflux mediated by native and acute-phase HDL. Both the total and the specific binding at 4°C of rabbit acute-phase HDL were
2-fold higher than for native HDL. Nonlinear regression
analysis revealed Kd values of
7.0x10-7 mol/L (native HDL) and 3.1x10-7
mol/L (acute-phase HDL), respectively. The corresponding
Bmax values were 203 ng of total lipoprotein per milligram
of cell protein (native HDL) and 250 ng of total lipoprotein per
milligram of cell protein (acute-phase HDL). At 37°C, holoparticle
turnover was slightly enhanced for acute-phase HDL, a fact reflected by
2-fold higher degradation rates. In contrast, the presence of SAA on
HDL specifically increased (1.7-fold) the selective uptake of HDL
cholesteryl esters from acute-phase HDL by J774 macrophages, a
widely used in vitro model to study foam cell formation and
cholesterol efflux properties. Although ligand blotting
experiments with solubilized J774 membrane proteins failed to identify
the scavenger receptor-BI as a binding protein for both native and
acute-phase HDL, 2 binding proteins with molecular masses of 100 and 72
kDa, the latter comigrating with CD55 (also termed decay-accelerating
factor), were identified. During cholesterol efflux
studies, it became apparent that the ability of acute-phase HDL with
regard to cellular cholesterol removal was considerably
lower than that for native HDL. This was reflected by a 1.7-fold
increase in 
/2 values (22 versus 36 hours; native versus acute-phase
HDL). Our observations of increased HDL cholesteryl ester uptake and
reduced cellular cholesterol efflux (acute-phase versus
native HDL) suggest that displacement of apolipoprotein A-I by SAA
results in considerable altered metabolic properties of its
main physiological carrier. These changes in the
apolipoprotein moieties appear (at least in the in vitro system tested)
to transform an originally antiatherogenic into a proatherogenic
lipoprotein particle.
Key Words: inflammation • cholesterol metabolism • HDL
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Introduction |
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Serum amyloid A (SAA) is a generic term for a family of apolipoproteins coded for by different genes with high allelic variation and a high degree of homology between species.1 2 The SAA proteins in mammals (12 kDa protein, 104 amino acids) are very well conserved throughout evolution, and thus a panel of different activities and biological properties has been suggested. SAA may suppress lymphocytic response to antigens,3 impair platelet aggregability,4 and contribute to the regulation of tissue collagenase expression.5 SAA induces mast cell adhesion to the extracellular matrix,6 7 migration and adhesion of T cells,8 and migration, adhesion, and tissue infiltration of monocytes and polymorphonuclear leukocytes.9 SAA also induces calcium mobilization and chemotaxis in monocytes10 and enhances eicosanoid synthesis in human monocytes.11 However, 3 major functions of SAA must be considered.
First, SAA is predominantly produced by the liver. The synthesis is
largely regulated by inflammation-associated cytokines, peptide
hormone signals produced by endothelial cells,
lymphocytes, and in particular, activated monocytes and
macrophages.12 Different cytokines,
including interferon-
, transforming growth factor-ß, tumor
necrosis factor-
, and interleukins, either alone or in combination,
have been shown to affect SAA synthesis at the transcriptional level.
This effect is mediated via cis-acting promoter elements
that are binding sites for cytokine-activated nuclear
factors, acute-phase protein factor, and the glucocorticoid receptor
and liver specific transcription factors.13 In the
circulation, SAA levels may increase by 1000-fold in response to
injury, infection, and inflammation, and thus SAA has properties
resembling a classic positive acute-phase reactant. Because
concentrations of acute-phase reactants may be correlated with the
amount of damaged tissue, measurements of SAA are of value in the
assessment of activity and response to therapy during several
inflammatory diseases.14
Second, chronically elevated concentrations of acute-phase SAA are a prerequisite for the pathogenesis of secondary amyloidosis, a progressive and fatal disease characterized by the deposition in major organs of insoluble plaque composed principally of proteolytically cleaved acute-phase SAA, and may also contribute to processes that lead to atherosclerosis. SAA is deposited in the spleen, kidney, and liver, where it is processed, leaving the amino half to two thirds of its sequence behind in the fibril.15 16 How SAA becomes deposited as an amyloid A protein (the 76–amino acid N-terminal portion of SAA) is largely unknown; however, it is possible that its physiological carrier (see below) could contribute to this process.
Finally, as shown first in mice17 but later also in other mammals,18 19 20 SAA associates rapidly during the acute phase with HDL, on which it becomes the predominant apolipoprotein (apo SAA), exceeding apo A-I (the major apolipoprotein of native HDL) in quantity.2 14 Although significant amounts of apo SAA were also found to be associated with other lipoproteins,18 it seems that HDL subfraction 3 (HDL3) is the preferential acceptor particle.19 21 SAA-enriched HDL3 was found to be larger than normal HDL3 (d=1.12 to 1.21 g/mL), having a radius of 4.5 to 5.3 nm that extended into the size range observed for normal HDL2 (d=1.063 to 1.125 g/mL).19 SAA may account for 17% to 87% of the total apolipoproteins present in acute-phase HDL,18 and as a consequence, the percentage of lipid-free apo A-I may increase in parallel.21 While it remodels the lipoprotein particle by displacing primarily apo A-I, apo SAA may also significantly alter the protective function of its physiological carrier. Impaired activities of HDL-associated enzymes, ie, paraoxonase and the platelet-activating factor acetylhydrolase, are probably responsible for the impaired antioxidative properties of HDL during the acute phase.20 Subsequently, impaired activity of lecithin:cholesterol acyltransferase, an enzyme activated by apo A-I, might be responsible for altered cholesterol hemostasis of acute-phase HDL compared with native HDL. Acton et al22 have shown that scavenger receptor-BI (SR-BI), a CD36-related class B type 1 scavenger receptor, is involved in selective uptake of HDL lipids and that apo A-I may mediate SR-BI–dependent hepatic selective uptake of HDL-associated cholesteryl esters (HDL-CEs).23 24 25 During this process, HDL-CEs are taken up in vivo or in vitro without concomitant lipoprotein particle uptake.26 27 On the basis of these findings, altered binding properties of acute-phase HDL (as a result of apo A-I displacement) to hepatocytes compared with native HDL could be anticipated. Finally, the participation of native HDL in "reverse cholesterol transport" from peripheral cells to the liver is critical for the antiatherogenic properties of this lipoprotein. Because the efflux of cholesterol from peripheral tissues is mediated by HDL and (at least in part) via SR-BI,28 29 30 changes in the apolipoprotein moiety during the acute-phase reaction are tightly coupled with altered cholesterol homeostasis. It may be assumed that acute-phase HDL could mediate phospholipid and cholesterol/CE delivery to regenerating tissue at sites of inflammation, where neutrophils, monocytes, and macrophages are present.31 32 This concept has been supported by the observation that acute-phase HDL binds strongly to peritoneal macrophages.33 Alternatively, it was hypothesized that acute-phase SAA targets the HDL particle to activated macrophages, where it enhances clearance of excess cholesterol from these cells.31 34
The purpose of the present study was 2-fold: first, to determine binding properties, including association, internalization, and degradation, of native and acute-phase (SAA-enriched) HDL to macrophages; and second, to elucidate whether selective uptake of HDL-CEs is increased by the presence of SAA on acute-phase HDL particles and whether reverse cholesterol transport from these cells is altered in parallel. Because a number of studies have indicated that cholesterol and lipoprotein changes (including changes in HDL-associated apolipoproteins) during the acute-phase reaction in rabbits closely resemble those seen in humans,19 21 35 36 we used rabbit lipoproteins during our experiments. In addition, enrichment of rabbit HDL by SAA under inflammatory conditions in vivo is similar to that in humans, and finally, owing to the high homology of rabbit and human SAA isoforms,2 identical surface-located SAA epitopes present on acute-phase HDL particles in rabbits and humans can be anticipated.37 38
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Methods |
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Rabbit Lipoproteins
Rabbit plasma was obtained from New Zealand White rabbits (weight, 3 to 4 kg each), which were obtained from Charles River Germany (Sulzfeld). The acute phase was induced by injection of a 1% croton oil (vol/vol) emulsion in saline (1 mL/kg) into 5 sites in the larger lower-back muscle.35 Each rabbit served as its own control. Blood samples were drawn from the central ear artery into tubes containing 0.1% EDTA, pH 7.4, before and 48 hours after the injection of croton oil. HDL (d=1.063 to 1.21 g/mL) was prepared by discontinuous density ultracentrifugation of plasma. HDL was recovered from the tubes, dialyzed against PBS (10 mmol/L, pH 7.4, 0.15 mol/L NaCl), and stored at 4°C in the presence of EDTA and NaN3. Protein concentrations of the lipoprotein particles were determined by the Lowry procedure39 with BSA used as the standard. Individual apolipoprotein content was established by pyridine extraction of Coomassie blue–stained bands from SDS–polyacrylamide gel electrophoresis (PAGE) on 10% to 20% gels and subsequent densitometric evaluation.40 Concentrations of phospholipids (bioMerieux), total cholesterol (Greiner), free cholesterol (Merck), and triglycerides (bioMerieux) were assayed with commercially available enzymatic kits.
Lipoprotein Labeling
Labeling of the Protein Moiety
Iodination of rabbit HDL particles was performed as described by
Sinn et al41 with N-Br-succinimide as the
coupling agent. Routinely, 1 mCi of [125I]NaI
(DuPont NEN) was used to label 5 mg of lipoprotein. This procedure
resulted in specific activities between 300 and 500 counts per minute
per nanogram protein. Nonspecific lipid-associated activity was always
<3% of total activity.
Labeling of the Lipid Moiety
Native and acute-phase rabbit HDLs were labeled with
[1,2,6,7-3H-cholesteryl]palmitate (DuPont NEN)
by CE transfer protein–catalyzed transfer from donor liposomes as
described previously.42 In brief, 200 µCi of the
corresponding label and 100 µg of egg yolk lecithin (Sigma) were
dried under argon, followed by the addition of 1 mL of PBS. The mixture
was shaken for 2 minutes at 37°C and sonicated. Lipoproteins (1 mL,
containing 3 to 6 mg of protein), 1 mL of rabbit lipoprotein-deficient
serum (LPDS, as a source of CE transfer protein), and 1 mL of PBS were
added. The mixture was incubated under argon at 37°C in a shaking
water bath overnight. Subsequently, the labeled HDL fractions were
reisolated in a TLX120 bench-top ultracentrifuge in a TLA100.4
rotor (Beckman) as described previously.43 The HDL band
was aspirated and dialyzed against 10 mmol/L PBS, pH 7.4. This
labeling procedure resulted in specific activities of 8 to 15 counts
per minute per nanogram protein.
Cell Culture Studies
Permanent mouse J774 macrophages were plated on 6- or
12-well plates (Costar) in RPMI-1640 medium (Bio Whitaker, containing
10% [vol/vol] fetal calf serum [FCS] and L-glutamine)
under standard conditions (37°C, 5% CO2, 95%
humidity). Twelve hours before the experiments, cells were incubated in
RPMI-1640 containing 10% (vol/vol) LPDS as indicated (concentrations
of free apo A-I were 3.5 µg/mL medium containing 10% LPDS).
Binding Studies
Binding studies of native and SAA-enriched (acute-phase) rabbit
HDLs to J774 macrophages were performed at 4°C with
increasing amounts of 125I-labeled lipoproteins
in the absence (total binding) or presence of a 20-fold excess
(nonspecific binding) of unlabeled autologous lipoprotein species.
Iodinated HDL particles were added to a final concentration
of 50 µg protein/well, and cells were incubated in RPMI-1640
containing 10% (vol/vol) LPDS at 4°C for 5 hours. After this
incubation, the medium was aspirated, and the cells were washed twice
in Tris-buffered saline (TBS) containing 5% (vol/wt) BSA followed by 2
washes in TBS. Cells were lysed with 0.3N NaOH (1 mL, 1 hour at 4°C)
to determine bound radioactivity and cell protein in the lysate.
Protein measurement was performed as described
previously.39 Specific binding (4°C) was calculated as
the difference between total and nonspecific binding.
To determine bound, internalized, and degraded lipoproteins, cells were incubated at 37°C for 5 hours as described above with the same amounts of labeled and unlabeled lipoproteins. Subsequently, the medium was aspirated, and the cells were washed as described above. To release cell membrane–bound HDL particles, the cells were incubated at 4°C for 1 hour in the presence of trypsin (0.05%, Cytosystems). The trypsin-releasable fraction is referred to as "bound" fraction. Cells were then lysed in 0.3N NaOH to determine both the non–trypsin-releasable fraction ("internalized" fraction) and the cell protein in the lysate. We estimated degradation of native and acute-phase iodinated HDL particles by J774 macrophages by measuring the non–trichloroacetic acid (TCA)–precipitable radioactivity in the medium after precipitation of free iodine with AgNO3.44 In brief, 0.5 mL of medium was removed, mixed with 100 µL of BSA (30 mg/mL) and 1 mL of TCA (3 mol/L, 4°C), and left at 4°C for 30 minutes. Subsequently, 250 µL of AgNO3 (0.7 mol/L) was added and mixed, and the samples were centrifuged at 3000 rpm at 4°C for 15 minutes. One milliliter of the supernatant was counted on a gamma counter.
To determine holoparticle and selective uptake of HDL-associated CEs during the same experiment, the cells were incubated with [3H]cholesterol (16:0)–labeled native and acute-phase HDL at 37°C for 5 hours. After removing the medium and washing the cells, we estimated cell association by measuring the radioactivity and protein content of the cell lysates, respectively. Specific binding/internalization/degradation/cell association was calculated as the difference between total and nonspecific binding/internalization/degradation/cell association.
To facilitate the comparison of results obtained with 125I-labeled and [3H]cholesterol (16:0)–labeled lipoproteins, selective HDL and acute-phase HDL uptakes are expressed as apparent HDL particle uptake, as suggested by Pittman et al.45 Apparent HDL particle uptake is expressed in terms of HDL protein (calculated on the basis of the specific activity of the corresponding labeled HDL preparation used) that would be necessary to deliver the observed amount of tracer. These calculations were performed to compare uptake of 125I- and 3H-tracers on the same basis.
Efflux Experiments
Efflux of labeled cholesterol from J774
macrophages was measured by appearance of
[3H]cholesterol in the cellular
supernatant and remaining radioactivity in cell lysates. The cells were
incubated in the presence of RPMI-1640 containing 10% (vol/vol) LPDS
and [3H]cholesterol (0.05 µCi/mL)
for 24 hours.46 47 Before the cholesterol
efflux experiments were performed, the
[3H]cholesterol-containing medium
was aspirated, and the cells were washed twice with TBS (containing 5%
[wt/vol] BSA) and twice with TBS. Efflux experiments were initiated
by the addition of native or acute-phase HDL (0.5 mg protein/mL) in
RPMI-1640 containing 10% (vol/vol) LPDS. At the indicated time points
(up to 24 hours), the medium was collected, and the cells were washed
as described above. Then, the cells were lysed in 0.3N NaOH to estimate
both the remaining radioactivity and the cellular protein content.
Efflux of radioactive label to the medium was calculated as the
percentage of radioactivity present in the cells before the
addition of native or acute-phase HDL-containing medium.
SDS-PAGE, Immunoblot, and Ligand-Blot Analyses
SDS-PAGE of native and acute-phase rabbit HDL apolipoproteins
was performed with 10% to 20% polyacrylamide gradient gels
with electrophoresis at 150 V for 90 minutes in a Bio-Rad mini protean
chamber 48 and buffers as described
previously.49 Samples for SDS-PAGE (2.5 to 50 µg
protein) were treated with sample buffer (0.1 mol/L Tris/HCl, pH 6.8,
4% SDS, 15% glycerol, and l % mercaptoethanol) at a ratio of 1:1
(vol/vol) and incubated at 95°C for 5 minutes before application to
gels.
J774 macrophages were cultured in RPMI-1640 (containing 10% FCS or LPDS), and cell membrane proteins were prepared according to Schneider et al.50 SDS-PAGE of membrane proteins (40 µg/lane) was performed with 8% polyacrylamide gels. For Western blotting experiments, proteins were electrophoretically transferred to nitrocellulose membranes (150 mA, 4°C, 90 minutes).
Immunochemical detection of proteins from solubilized membrane protein fractions was performed with the following primary antibodies: for identification of SR-BI, a polyclonal, sequence-specific rabbit anti-rat SR-BI peptide (496-509) antibody (dilution 1:100) was used; for identification of CD55, mouse anti-human CD55 antibody (dilution 1:200) was purchased from Serotec. Peroxidase-conjugated goat anti-rabbit IgG (diluted 1:2000) or rabbit anti-mouse IgG (diluted 1:2000) was used as a secondary antibody. To visualize immunoreactive bands, enhanced chemiluminescence (ECL)-Western blotting detection reagents and Cronex medical x-ray films (Sterling Diagnostic Imaging USA) were used according to the manufacturer’s suggestions.
For ligand blotting experiments, the nitrocellulose membranes were incubated with blocking buffer containing 50 µg of either native or acute-phase HDL per milliliter, and the blots were incubated at 4°C or 25°C on a rotating platform. After washing, the membranes were incubated with rabbit anti-apo A-I antisera (1:1000) or anti-human SAA antiserum overnight, and visualization of bound lipoprotein was performed with peroxidase-conjugated goat anti-rabbit IgG (diluted 1:2000) as a secondary antibody after ECL development.
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Results |
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Characterization of Native and Acute-Phase Rabbit HDL Particles
Before we studied the binding properties of native and acute-phase HDLs to J774 cells, the particles were characterized with respect to changes in the protein (Figure 1
) and the
lipid moiety (Table) due to the
inflammatory response. Electrophoretic characterization of rabbit HDL
particles revealed that after a 48-hour inflammation period, levels of
apo A-I were decreased, whereas at the same time, levels of SAA were
increased (Figure 1, lanes A and B). SAA levels ranged between
22% and 42% of total apolipoprotein content. A comparison of the
lipid composition of HDL particles from the same rabbits before and 48
hours after induction of the acute phase revealed that the phospholipid
content was also slightly increased during the acute phase, but a
marked increase in triglyceride concentration was observed
(Table 1); these data are in line with those of other
reports.35 36 Similar changes in phospholipid and
triglyceride concentrations became apparent in sera
obtained from rabbits during the acute-phase reaction
(Table 1).
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Binding of Native and SAA-Containing HDL Particles to
Macrophages
To investigate binding properties of native and SAA-containing HDL
particles to J774 macrophages at 4°C, the protein moiety was
labeled with [125I]NaI. Binding of
125I-labeled native and acute-phase rabbit HDLs
in the presence or absence of a 20-fold excess of unlabeled lipoprotein
is presented in Figure 2 (A and
B). Both the total (119.1 versus 51.5 ng lipoprotein/mg cell protein)
and the specific binding of rabbit acute-phase HDL (73.6 versus 37.5 ng
lipoprotein/mg cell protein) were higher than for native HDL at the
highest lipoprotein concentrations used. Binding experiments with 3
different preparations and subsequent calculation by nonlinear
regression analysis (with the GraphPad program) yielded mean
Kd values of
7.0x10-7 mol/L (native HDL) and
3.1x10-7 mol/L (acute-phase HDL), respectively.
The corresponding Bmax values were 203 ng total
lipoprotein/mg cell protein (native HDL) and 250 ng total
lipoprotein/mg cell protein (acute-phase HDL), assuming a molecular
mass of 3x102 kDa and a protein content of
50% (wt/wt). Similar binding properties were observed when rabbit
HDL was isolated by discontinuous density
ultracentrifugation at d=1.125 to 1.21
g/mL.
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),
nonspecific (
), and total binding (•), the cells were incubated
under the same conditions but in the absence (total binding) or
presence of a 20-fold excess (nonspecific binding) of unlabeled
lipoproteins. After 5 hours, the cells were washed and lysed in 0.3N
NaOH to determine the amount of bound label and the cellular protein
content. The amount of SAA in corresponding HDL preparations ranged
between 22% and 35% of total apolipoprotein content. Results shown
represent mean values from triplicate dishes.
The next series of experiments was designed to study binding
properties of 125I-labeled native and acute-phase
rabbit HDL particles at 37°C in the presence or absence of a 20-fold
excess of unlabeled lipoproteins. Bound lipoproteins were released with
trypsin from the cells, and the trypsin-releasable fraction was
referred to as bound fraction. Binding of native HDL to J774
macrophages was saturable and specific (Figure 3A). For acute-phase HDL, no plateau
value was obtained under the same experimental conditions (Figure 3B). Specific binding was 41.5 ng/mg cell protein (native HDL)
and 27.2 ng/mg cell protein (acute-phase HDL) at the highest protein
concentrations used. Next, the radioactivity was measured in the
non–trypsin-releasable fraction, which is referred to as the
internalized fraction. Compared with the trypsin-releasable
radioactivity, the internalized radioactivity was much higher for both
lipoprotein particles (Figures 3C and 3D). Specific
internalization revealed similar values for native (234.1 ng
lipoprotein/mg cell protein) and acute-phase (242.5 ng lipoprotein/mg
cell protein) HDL particles at the highest lipoprotein concentrations
used. In a parallel series of experiments, the degradation of
125I-labeled native and acute-phase HDL particles
by J774 macrophages was estimated by measurement of the
non–TCA-precipitable radioactivity in the medium after precipitation
of free iodine with AgNO3. From Figures 3E and 3F, it is evident that specific degradation of acute-phase
HDL particles was 1.5-fold higher than for native HDL (104±27
versus 72±38 ng lipoprotein/mg cell protein) at the highest HDL
concentrations used.
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Selective HDL-CE Uptake of Native and Acute-Phase HDL Particles
by Macrophages
To determine the ability for selective uptake of HDL-associated
CEs, J774 macrophages were incubated in the presence of
125I-labeled and
[3H]cholesterol (16:0)–labeled
native and acute-phase HDLs. In the case of
125I-labeled HDL, the cell-associated and
non–TCA-precipitable radioactivity in the medium was counted (sum of
cell-associated and degraded HDL reflects holoparticle uptake). For the
[3H]cholesterol (16:0)–labeled HDL
preparations, only cell-associated radioactivity was counted and
calculated as apparent particle uptake. The difference between apparent
particle uptake and holoparticle uptake reflects selective HDL-CE
uptake.
As shown for iodinated HDL, specific cell association of
[3H]cholesterol (16:0)–labeled
native HDL was also lower than
[3H]cholesterol (16:0)–labeled
acute-phase HDL (868 versus 1337 ng lipoprotein/mg cell protein;
Figures 4A and 4B). In line
with reports for mouse peritoneal macrophages51
and permanent J774 macrophages,52 we have observed
pronounced capacity for lipid tracer uptake in excess of particle
association, exceeding holoparticle association by 2.6-fold for native
HDL (868 versus 330 ng lipoprotein/mg cell protein) (Figure 5). Selective uptake of HDL-CE from
native HDL particles exceeded holoparticle uptake by 1.6-fold (538
versus 330 ng lipoprotein/mg cell protein) at the highest HDL
concentrations used (Figure 5A). Selective uptake of HDL-CE from
acute-phase HDL exceeded holoparticle uptake by 2.1-fold (901 versus
435 ng lipoprotein/mg cell protein) at the highest HDL concentrations
used (Figure 5B). However, total CE delivery (selective and
holoparticle uptake) was significantly higher for acute-phase HDL than
for native HDL (1337 versus 868 ng lipoprotein/mg cell protein).
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) was calculated
as the difference between [3H]cholesterol
(16:0) (
Identification of Possible Binding Proteins for Native and
Acute-Phase HDL Particles by Ligand Blotting Experiments
Because different binding proteins for HDL have been identified on
various cell types,25 we also tried to identify a possible
receptor for native and acute-phase HDLs. Ligand blotting experiments
with J774 membrane protein fractions revealed 2 major binding proteins
for native and acute-phase HDLs, with molecular masses of 100 and 72
kDa, respectively (Figure 6).
Nitrocellulose blots were stripped and further incubated with
antibodies raised against possible binding proteins. Recently, a
100-kDa protein, HB2, has been identified as a
macrophage HDL receptor.53 In line with this
observation, we found pronounced binding of native and acute-phase HDLs
to a 100-kDa J774 membrane protein (Figure 6, lanes 1 and 2).
Nion et al54 recently suggested CD55, also termed
decay-accelerating factor (DAF), as a possible binding protein for
native HDL. The 72-kDa HDL-binding protein identified in our ligand
blots aligned with the 72-kDa protein recognized by anti-CD55 (Figure 6, lane 3), whereas the 110 kDa demonstrated an unspecific
immunological cross-reactivity. Although a sequence-specific polyclonal
antiserum (prepared against the 15 C-terminal amino acids of
rat SR-BI) detected 2 proteins of 82 and 78 kDa (Figure 6, lane 4), in line with other reports,28 55 56 we could
not detect HDL binding to J774 proteins compared with these proteins
recognized by polyclonal anti–SR-BI peptide antiserum.
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Effect of Native and Acute-Phase HDLs on Cellular Cholesterol
Efflux
We have been interested in whether the in vivo exchange of apo A-I
by apo SAA may alter the efficiency of HDL to promote
cholesterol efflux from J774 macrophages, a widely
used in vitro model to study foam cell formation and
cholesterol efflux properties.46 Results of a
representative experiment are shown in Figure 7. During incubation with the radioactive
tracer, cells acquired 44.746±4.43 dpm/mg of cell protein (n=3; 33%
of the initial radioactivity added). After a 24-hour incubation of
macrophages in the presence of native HDL, the cellular
cholesterol content decreased to 43.8±3.0%. However,
58.9±2.9% of the cholesterol remained cell-associated
when the efflux experiment was performed in the presence of acute-phase
(SAA-enriched) HDL. Accordingly, the radioactivity present in the
medium (after a 24-hour incubation) was 50.8±1.6% and 38.0±1.9% of
the initial radioactivity when cells were cultivated in the presence of
native and acute-phase HDLs, respectively. The lower ability of
acute-phase HDL to promote cellular cholesterol efflux was
also reflected by a significant, 1.6-fold increase in /2 (time
necessary to remove 50% of cholesterol; 22 versus 36
hours, native versus acute-phase HDL). Similar results were obtained
when SAA enrichment of acute-phase rabbit HDL particles was 22% only
or increased to 37% (graph not shown).
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Discussion |
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There is ample evidence that acute inflammation interferes with the metabolism of lipids and lipoproteins and affects the concentration and composition of different lipoproteins and/or associated enzymes involved. In mammals, plasma concentrations of apolipoproteins, in particular apo A-I, decrease significantly, but levels of triglyceride-, phospholipid-, and cholesterol-rich particles are also changed in parallel.19 21 35 36 57 To study acute inflammation in animals, 2 types of injury are generally used58 : localized inflammation induced by the formation of a sterile abscess after subcutaneous injection of oils35 36 59 and systemic inflammation induced by intravenous injection of lipopolysaccharide.58 Although slight interspecies differences in the inflammatory response may occur between both types of inflammation,59 rabbits have been proven as a suitable animal model to study inflammation-related changes in lipoprotein and apolipoprotein metabolism35 36 ; therefore, we decided to use rabbit acute-phase HDL as a source of SAA-containing particles. The enrichment of rabbit HDL with SAA during the acute-phase reaction occurs in a similar manner as described for humans, and the acute-phase SAA isoforms of the 2 species are highly homologous. The overall percentage identity between human and rabbit SAA is 83.3% (for SAA1, the main SAA isoform, which constitutes >90% of total SAA expressed during the acute-phase reaction) and 80.4% (for SAA2).2 Surface-located epitopes of HDL-associated SAA (which are most likely responsible for acute-phase HDL-cell interactions) revealed identities of 87.5% (amino acids 31 to 39), 89% (amino acids 64 to 78), and 80% (amino acids 95 to 104) for human and rabbit SAA1, respectively.37 38 Finally, epitopes of human apo A-I assumed to be responsible for binding and cholesterol efflux properties from cells60 61 62 have an overall identity and similarity with rabbit apo A-I of 81% and 89.5%, respectively. Therefore, rabbit acute-phase HDL serves a suitable model to mimic inflammation-related lipoprotein changes occurring in humans and represents an experimentally easily accessible source of SAA-containing lipoproteins and corresponding autologous controls.
The major findings of the present study can be summarized as
follows: (1) increased binding of acute-phase HDL at 4°C; (2)
slightly higher holoparticle turnover at 37°C, reflected by higher
degradation rates of acute-phase HDL; (3) acute-phase and native HDLs
bind to the same J774 proteins on nitrocellulose; and (4) compared with
native HDL, acute-phase HDL has a lower capacity to promote cellular
cholesterol efflux. Our observations concerning the
increased binding affinity of SAA-containing HDL particles are in line
with a previous report performed with mouse peritoneal
macrophages.33 During the present study, we
observed differences in binding properties between native and
acute-phase HDL particles, suggesting that alterations in the protein
moiety and lipid composition are the cause of the altered binding
capacity of SAA-containing particles at 4°C. Also, at 37°C,
holoparticle turnover was slightly higher for acute-phase HDL than for
the native lipoprotein. Under the conditions used during the
present study, this was best reflected by increased degradation
rates of acute-phase HDL (2-fold higher than for native HDL). As a
consequence, total and selective CE uptake by J774 macrophages
was higher for SAA-containing HDL. There is also clear evidence from in
vitro and in vivo studies that scavenger receptors of the B class are
responsible for selective uptake of HDL-associated CE, mediating
reverse cholesterol transport and fuelling steroidogenesis.
In line with other reports28 63 we could detect SR-BI in
detergent-solubilized membrane protein fractions obtained from J774
cells; we were, however, unable to detect SR-BI–mediated HDL binding
during ligand blotting experiments. The reason for this negative
finding is presently not clear but might be a result of SR-BI
inactivation due to conformational changes during SDS-PAGE and/or
transfer to nitrocellulose. Although we could not detect binding to a
band comigrating with those recognized by anti–SR-BI peptide
antiserum, we detected 2 proteins with molecular masses of 72 and 100
kDa that have bound native and acute-phase HDL on ligand blots. The
72-kDa protein colocalized with 1 protein recognized by anti-CD55
(anti-DAF). DAF is a GPI-anchored protein that protects cells from
damage by autologous complement activation. Although our findings do
not necessarily prove a role for DAF as an HDL binding protein on
macrophages, reports of CD55 binding by LDL64 and
HDL,65 localization of CD55 in caveolae,66
and expression on the surface of circulating blood cells, including
monocytes,67 makes this hypothesis attractive. In
addition, Nion et al54 recently suggested that DAF could
act as a binding protein for native HDL on caveolae-rich SKMES cells.
Whether the 100-kDa band is identical to
HB2,53 an HDL binding protein
present on macrophages, remains to be established. Whether
and to what extent endogenously expressed lipoprotein
lipase could contribute to increased selective uptake of HDL-associated
CEs51 68 is also unclear presently.
Recently, recombinant apo SAAp, a hybrid of human apo SAA1 and apo SAA2 isoforms, was shown to bind cholesterol with high affinity69 and to modulate uptake of free cholesterol by HepG2 cells. In human monocytic THP-1 cells, apo A-I is the principal mediator of cholesterol efflux,70 and therefore the presence of SAA on HDL had little impact on cellular cholesterol efflux except when apo SAA represented >50% of total HDL apoproteins.71 Our studies were performed with J774 mouse macrophages and have clearly demonstrated diminished capacity for cholesterol efflux by acute-phase HDL even at an SAA enrichment of only 22%. In particular, these SAA concentrations occur in a broad range of various physiologically occurring inflammatory events related to altered lipoprotein profiles.
SR-BI plays a key role during hepatic HDL metabolism in determining plasma HDL cholesterol levels and possibly by mediating cellular cholesterol efflux from peripheral cells. In line with a role of SR-BI during reverse cholesterol transport, a linear relationship between expression levels of SR-BI on different cell lines, including J774 cells, and the degree of HDL-mediated cellular cholesterol efflux was determined.28 63 Our findings of increased binding of acute-phase HDL and significantly reduced cellular cholesterol efflux from the cells do not exclude a possible role of SR-BI; as reported by de la Llera-Moya and colleagues.30 SR-BI–dependent stimulation of cholesterol efflux is not simply due to SR-BI–mediated HDL binding to the cell surface. These authors30 suggested that SR-BI expression could involve a generalized redistribution of membrane cholesterol to caveolae, thus facilitating cholesterol exchange to HDL. Phospholipid subspecies are an important determinant (in addition to others) in mediating cellular cholesterol efflux to a given acceptor particle. This, in conjunction with reports that HDL undergoes severe redistribution of phospholipid subspecies during the acute phase,19 35 36 57 could provide another plausible explanation for our findings relating to the reduced capacity of SAA-containing HDL for cellular cholesterol removal.
Although the association of SAA with HDL has been confirmed for a number of years, the physiological significance of this change remains controversial.31 Kisilevsky et al34 postulated that the principal role for SAA in acute inflammation is to enhance cholesterol removal from sites of tissue destruction, whereas Gonnermann et al32 proposed that SAA may commandeer HDL during the acute-phase response to deliver phospholipids and cholesterol to cells involved in tissue repair at sites of inflammation. Our present in vitro data, in particular a 2-fold higher selective SAA-enriched HDL-CE uptake by macrophages, provide support for the latter hypothesis. Increased selective uptake of acute-phase HDL CEs and subsequent hydrolysis could transform monocyte-derived macrophages into cholesterol-enriched foam cells, which are the hallmark of fatty streaks and the earliest recognizable lesion of atherosclerosis. The possibility that SAA could direct lipids to and modulate lipid flow in atherosclerotic lesions is further strengthened by the fact that SAA has been found to be expressed in human arterial walls that shows signs of atherosclerotic lesions.72 Members of the acute-phase SAA family are among the inflammatory genes that have also been found to be abundantly expressed in high-fat diet–enriched, atherosclerosis-susceptible C57BL/6 mice, whereas atherosclerosis-resistant C3H/HeJ mice did not express SAA at all.73 A similar phenomenon was observed in MRL/lpr mice fed an atherogenic diet.74 The presence of acute-phase SAA in atherosclerotic lesions,69 74 75 the induction of acute-phase SAA genes in human monocyte/macrophage cells mediated by minimally modified LDL,76 and the proinflammatory role of acute-phase HDL,20 in addition to enhanced selective uptake of HDL-associated CE as shown in the present study, hold implications for the involvement of SAA during atherogenesis.
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Acknowledgments |
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This work was supported by Austrian National Bank (OENB 7434, 8127, and 8234) and Austrian Research Foundation FWF (P 11276 to E.M. and P 14109 to W.S.). The authors thank Birgit Hirschmugl for technical assistance.
Received April 26, 1999; accepted September 17, 1999.
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 A. M. Gotto Jr and E. A. Brinton Assessing low levels of high-density lipoprotein cholesterol as a risk factor in coronary heart disease: A working group report and update J. Am. Coll. Cardiol., March 3, 2004; 43(5): 717 - 724. [Abstract] [Full Text] [PDF]
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 G. A. Kaysen and J. P. Eiserich The Role of Oxidative Stress-Altered Lipoprotein Structure and Function and Microinflammation on Cardiovascular Risk in Patients with Minor Renal Dysfunction J. Am. Soc. Nephrol., March 1, 2004; 15(3): 538 - 548. [Abstract] [Full Text] [PDF]
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B. D. Johnson, K. E. Kip, O. C. Marroquin, P. M Ridker, S. F. Kelsey, L. J. Shaw, C. J. Pepine, B. Sharaf, C. N. Bairey Merz, G. Sopko, et al. Serum Amyloid A as a Predictor of Coronary Artery Disease and Cardiovascular Outcome in Women: The National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Circulation, February 17, 2004; 109(6): 726 - 732. [Abstract] [Full Text] [PDF]
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P. J. Pussinen, M. Jauhiainen, T. Vilkuna-Rautiainen, J. Sundvall, M. Vesanen, K. Mattila, T. Palosuo, G. Alfthan, and S. Asikainen Periodontitis decreases the antiatherogenic potency of high density lipoprotein J. Lipid Res., January 1, 2004; 45(1): 139 - 147. [Abstract] [Full Text] [PDF]
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G. Marsche, R. Zimmermann, S. Horiuchi, N. N. Tandon, W. Sattler, and E. Malle Class B Scavenger Receptors CD36 and SR-BI Are Receptors for Hypochlorite-modified Low Density Lipoprotein J. Biol. Chem., November 28, 2003; 278(48): 47562 - 47570. [Abstract] [Full Text] [PDF]
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W. Khovidhunkit, A. H. Moser, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold Endotoxin down-regulates ABCG5 and ABCG8 in mouse liver and ABCA1 and ABCG1 in J774 murine macrophages: differential role of LXR J. Lipid Res., September 1, 2003; 44(9): 1728 - 1736. [Abstract] [Full Text] [PDF]
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 M. W. Rajala and P. E. Scherer Minireview: The Adipocyte--At the Crossroads of Energy Homeostasis, Inflammation, and Atherosclerosis Endocrinology, September 1, 2003; 144(9): 3765 - 3773. [Abstract] [Full Text] [PDF]
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S. P. Tam, A. Flexman, J. Hulme, and R. Kisilevsky Promoting export of macrophage cholesterol: the physiological role of a major acute-phase protein, serum amyloid A 2.1 J. Lipid Res., September 1, 2002; 43(9): 1410 - 1420. [Abstract] [Full Text] [PDF]
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G. Marsche, A. Hammer, O. Oskolkova, K. F. Kozarsky, W. Sattler, and E. Malle Hypochlorite-modified High Density Lipoprotein, a High Affinity Ligand to Scavenger Receptor Class B, Type I, Impairs High Density Lipoprotein-dependent Selective Lipid Uptake and Reverse Cholesterol Transport J. Biol. Chem., August 23, 2002; 277(35): 32172 - 32179. [Abstract] [Full Text] [PDF]
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P. C. TUCKER and G. H. SACK JR Expression of serum amyloid A genes in mouse brain: unprecedented response to inflammatory mediators FASEB J, October 1, 2001; 15(12): 2241 - 2246. [Abstract] [Full Text] [PDF]
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G. A. KAYSEN The Microinflammatory State in Uremia: Causes and Potential Consequences J. Am. Soc. Nephrol., July 1, 2001; 12(7): 1549 - 1557. [Abstract] [Full Text] [PDF]
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W. Khovidhunkit, J. K. Shigenaga, A. H. Moser, K. R. Feingold, and C. Grunfeld Cholesterol efflux by acute-phase high density lipoprotein: role of lecithin:cholesterol acyltransferase J. Lipid Res., June 1, 2001; 42(6): 967 - 975. [Abstract] [Full Text]
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