© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Decreased Susceptibility to Diet-Induced Atherosclerosis in Human Apolipoprotein A-II Transgenic Mice
From Département d’athérosclérose et INSERM U. 325 (A.T., M.B., G.L., G.C., N.H., P.P., J.-C.F., C.F.), Institut Pasteur, Lille, France, and Rhône-Poulenc Rorer-Gencell Division (J.-M.C., N.D.), Atherosclerosis Department, Centre de Recherche de Vitry-Alfortville, Vitry sur Seine, France.
Correspondence to Anne Tailleux, PhD, Département d’athérosclérose et INSERM U. 325, Institut Pasteur, 1, rue du Professeur Calmette, 59019 Lille Cedex, France. E-mail Anne.Tailleux{at}pasteur-lille.fr
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—Studies performed in vivo have been controversial regarding the implication of human apolipoprotein (apo)A-II in the atherogenic process. Expression of human apoA-II in transgenic mice fed a chow diet leads to (1) a bimodal distribution of high density lipoprotein (HDL) size as in humans, (2) a reduction in total cholesterol concentration that is mainly due to a reduction in non–HDL cholesterol level, and (3) a dramatic reduction in mouse endogenous apoA-I and apoA-II. After 20 weeks on an atherogenic diet, transgenic mice had reduced total cholesterol concentrations because of a reduction in cholesterol associated with all lipoprotein classes. Endogenous apoA-I and apoA-II were also dramatically decreased in transgenic mice. The mean area of atherosclerotic lesions was drastically decreased in transgenic mice (-44%, P=0.0027) compared with control mice. The amount of aortic surface covered by lesions was positively correlated with very low density lipoprotein cholesterol (P<0.01) and intermediate density lipoprotein cholesterol levels (P<0.05). Transgenic mice were protected against the development of atherosclerosis despite a marked decrease in HDL cholesterol and apoA-I concentrations. This protection may be related to the marked reduction in circulating low density lipoprotein (very low density and intermediate density lipoprotein) levels in transgenic mice.
Key Words: atherosclerosis • transgenic mice • lipoproteins
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In most populations, plasma HDL levels correlate inversely with the incidence of atherosclerotic cardiovascular disease.1 Of the 2 major HDL-associated apolipoproteins, apoA-I and apoA-II, the protective effect of apoA-I is established, whereas relatively little is known about the role of apoA-II in HDL metabolism and how this might relate to the antiatherogenic properties of HDL. In humans, apoA-II levels do not correlate with HDL cholesterol (HDL-C) levels.2 However, in some epidemiological studies, apoA-II levels are inversely correlated with coronary heart disease susceptibility, as are HDL-C and apoA-I.1 One patient with total apoA-II deficiency did not show any lipoprotein alteration.3 In contrast, clinical observations and tissue culture studies suggest that increased levels of apoA-II may be proatherogenic by increasing the concentration of HDL containing both apoA-I and apoA-II, a particle with properties thought to be less favorable than HDL containing only apoA-I.4
The availability of genetically engineered mice and the assessment of their susceptibility to atherogenesis provide new substrates to study the effect of gene expression on lipoprotein profile and atherosclerosis development. Transgenic mice expressing mouse apoA-II5 support a role for murine apoA-II in determining HDL structure and levels. These mice have a marked increase in HDL-C and non–HDL-C levels, and they develop severe atherosclerosis even on a chow diet. HDLs from murine apoA-II transgenic mice are unable to prevent LDL oxidation and exhibit proinflammatory properties.6 Some studies performed in apoA-II–deficient mice showed that murine apoA-II displays some antiatherogenic properties, such as the maintenance of the plasma HDL pool, whereas others showed proatherogenic properties, such as decreasing the clearance of lipoprotein remnants and promotion of insulin resistance.7 Mice overexpressing human apoA-II8 do not have elevated HDL-C levels or marked differences in lipid and apolipoprotein profiles, but they do have a modified HDL structure. These mice show a tendency to be protected against atherogenesis.8 In contrast, human apoA-II coexpression with human apoA-I in mice moderates the antiatherogenic effect of apoA-I.8 Expression of human apoA-II in mice, described by Marzal-Casacuberta et al,9 leads to a reduction in HDL-C levels in addition to reduced activity of endogenous lecithin-cholesterol acyltransferase (LCAT). In these mice, human apoA-II is a proatherogenic molecule when it is expressed in mice at a level similar to that in humans but only when the animals are fed a high-fat high-cholesterol diet.10 Finally, it has been reported that mice expressing human apoA-II present the potentially proatherogenic association of postprandial hypertriglyceridemia and low plasma HDL.11 Taken together, these results indicate that the role of human apoA-II in atherosclerosis remains poorly defined and controversial.
In the present study, using transgenic mice expressing human apoA-II, we have provided in vivo evidence of the protective role of apoA-II in the development of atherosclerotic lesions. This protective process seems to be independent of HDL pathway.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animals and Diets
Female mice expressing the human apoA-II gene controlled by the antithrombin III gene promoter in the C57BL/6J genetic background were compared with their littermates. Mice were housed in stainless-steel cages in groups of 5 on a 12-hour light-dark cycle and maintained on water and food ad libitum.
Control and transgenic mice were assigned for 10 weeks to a regular chow diet and then were switched for 20 weeks to the atherogenic diet. Mouse chow diet contained (wt/wt) <0.03% cholesterol and 4.5% animal fat but no casein or sodium cholate. The high-fat high-cholesterol diet contained 1.25% cholesterol, 15% fat, 7.5% casein, and 0.5% sodium cholate.
Blood was taken from the retro-orbital plexus after the animals had been fasted overnight and were placed under chloroform anesthesia. Serum was separated by low-speed centrifugation and kept at 4°C until analysis (<1 week).
Lipid, Lipoprotein, and Apolipoprotein Analyses
Total cholesterol (TC), free cholesterol
(FC), triglycerides (TGs), and phospholipids were measured
by using commercially available kits (Boehringer-Mannheim).
Cholesteryl esters (CEs) were calculated as 1.68x(TC-FC).
Human apoA-II was quantified by rocket immunodiffusion with the use of ready-to-use plates (Sebia). Serum levels of mouse apoA-I and apoA-II were measured by immunonephelometric assays with the use of specific polyclonal antibodies.
Lipoprotein cholesterol profiles were obtained by fast protein liquid chromatography (FPLC) as described.12 This system allows for separation of the main lipoprotein classes: VLDL, IDL (when present at a sufficient level), LDL, and HDL. Cholesterol was dosed continuously and directly at the column exit, whereas human apoA-II concentrations were determined in the pooled eluted fractions. Accumulated cholesterol data were analyzed by the Millenium 20/0 program (Waters). Non–HDL-C was calculated as the sum of VLDL-C+IDL-C+LDL-C, where VLDL-C, IDL-C, and LDL-C are VLDL, IDL, and LDL cholesterol, respectively.
VLDL-IDL (density [d]<1.019 g/mL), LDL (1.019<d<1.063 g/mL), and HDL (1.063<d<1.21 g/mL) lipoprotein fractions were isolated by sequential preparative ultracentrifugation13 and assayed for protein14 and lipid (TC, TG, and phospholipid) content.
HDL size was determined as previously described.12 HDL apolipoprotein composition was analyzed by SDS-PAGE (4% to 20% polyacrylamide gradient gel). Gels were stained with Coomassie brilliant blue R-250 or immunorevealed with species-specific antibodies.15
Cholesterol Efflux
Cellular cholesterol efflux studies with the Fu5AH
rat hepatoma cell line incubated with all sera were performed by the
use of the system established by de la Llera Moya et
al.16
LCAT Activity
LCAT activity was determined after the exogenous substrate as
previously described.17
Kinetic Studies
Animals were fasted throughout the 24-hour study period but had
free access to water. Twenty micrograms of murine
125I-labeled apoA-I and 7 µg of murine
131I-labeled apoA-II were injected into the mice
via the tail vein. Blood (50 µL) was obtained at 3, 10, and 90
minutes and then at 4, 7, and 24 hours after injection by retro-orbital
bleeding with animals under slight ether anesthesia, and
plasma samples were directly radioassayed. The radioactivity decay
curve required 2 exponentials for adequate fitting with the use of SAAM
II (SAAM Institute). The fractional catabolic rate was calculated from
the area under the decay curves. The production rates were
calculated as apoA-I or apoA-II concentrationxfractional catabolic
ratex3.33x24.
Lipolytic Activity
The activities of lipoprotein lipase and hepatic lipase (HL)
were measured in postheparin plasma incubated with a gum
arabic–stabilized TG emulsion containing glycerol
tri[1-14C] as previously described.18
Quantitative Atherosclerosis Measurement
One hundred sections (10 µm thick) were prepared from the
top of the left ventricle, where the aortic valves were first visible,
up to a position in the aorta at which the valves were just
disappearing from the field. The sections were stained with oil red O.
Ten of the 100 sections, each separated by 90 µm, were used for
morphometric evaluation with a computerized Biocom morphometric system.
Data are expressed as the mean lesion size of these 10 sections.
Statistical Analysis
Values were reported as mean±SEM. Statistical differences were
determined by the Mann-Whitney U test. Spearman correlation
coefficients were used to determine the significance of linear
relationships between sets of measurements. A value of
P<0.05 was accepted as statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Characterization of the Human ApoA-II Transgenic Mouse Model Fed a Chow Diet
Lipid Concentration
Table 1
shows lipid and
apolipoprotein concentrations. A reduction in TC was observed in the
transgenic group compared with the control group because of a reduction
in non–HDL-C, whereas HDL-C only exhibited a tendency to decrease.
However, it is noteworthy that the HDL-C/TC and non–HDL-C/TC ratios
were significantly increased and reduced, respectively. The FC level
was significantly decreased in the transgenic mouse group compared with
control group, whereas CE concentrations were not different, thus
leading to an FC/CE ratio significantly lower in transgenic animals. TG
concentrations were significantly higher in the transgenic group.
|
Apolipoprotein Analysis
The mean level of human apoA-II expression in the transgenic mice
was 43±7 mg/dL, a concentration spanning the range in humans. The
expression of human apoA-II was associated with a dramatic reduction
(
40%) in murine apoA-I and apoA-II (Table 1
). No human
apoA-II was detectable in the VLDL and LDL fractions separated by FPLC,
whereas the totality of this apolipoprotein was associated with the HDL
peak fraction (data not shown).
To understand the metabolic mechanism underlying the
decreased endogenous apolipoprotein levels, turnover
studies were performed in control and transgenic mice with murine
apoA-I and apoA-II. Results in Table 2
showed a decreased production rate in the transgenic group for
murine apoA-I and apoA-II (-27% and -28%, respectively). Moreover,
the catabolism of both apolipoproteins was reduced in transgenic mice
(-22% for apoA-I and -16% for apoA-II).
|
HDL Composition and Size
HDL from transgenic mice was shown to contain dimeric human
apoA-II in addition to murine apoA-I and monomeric apoA-II (data not
shown) as previously described.19 HDL isolated from
control mice consists of 1 population with a mean Stokes
diameter of 9 nm and contained apoA-I and apoA-II. In the transgenic
mice, the HDL population displayed a bimodal size distribution. A first
HDL population with a mean diameter of 9 nm was shown to contain human
apoA-II in addition to murine apoA-I and apoA-II, showing the existence
of chimeric particles containing human and murine apolipoproteins.
Conversely, a second HDL population with a mean Stokes diameter of 8 nm
was free of murine apolipoproteins and contained exclusively human
apoA-II. The lipid and protein composition of ultracentrifugally
isolated total HDL showed no differences between the 2 groups of
chow-fed animals (Table 3).
|
Cholesterol Efflux
To examine the properties of serum-promoting
cholesterol efflux in vitro, we measured the efflux of
labeled cholesterol from the Fu5AH hepatoma cells after a
4-hour incubation (Figure 1). All
serum samples promoted cholesterol efflux. However, mean
cholesterol efflux promoted by the incubation of samples
from the transgenic group was slightly but significantly lower than
that from the control group (-23% of control value,
P<0.05).
|
Enzymatic Activities
The LCAT activity showed a tendency to increase in serum from
transgenic animals compared with serum from control animals
(15.96±1.41 versus 13.92±0.87 nmol/mL per hour, mean±SEM), but the
difference was not significant.
Lipoprotein lipase activity was comparable in the transgenic and control groups (194±26 versus 206±30 nmol/mL per minute, mean±SEM). HL activity was significantly higher in the transgenic group compared with the control group (135±7 versus 67±3 nmol/mL per minute, mean±SEM; P<0.001).
Lipoprotein Profile of Transgenic Mice Fed a High-Fat
High-Cholesterol Diet
Administration of an atherogenic diet for 20 weeks did not change
body mass (20.6±1.5 versus 20.4±1.5 g) or liver weight (2.5±0.3
versus 2.3±0.4 g) in the transgenic and control groups,
respectively.
Lipid Concentration
As expected, animals fed the atherogenic diet developed high
levels of cholesterol, especially IDL fractions, which
became highly detectable by FPLC (Table 4). A marked lower level of TC
concentration was observed in the transgenic group compared with the
control group because of the lower cholesterol
concentration associated with all lipoprotein fractions (VLDL, IDL,
LDL, and HDL). It is important to note that the HDL-C/TC and
non–HDL-C/TC ratios were comparable in the 2 mouse groups. The FC/CE
ratio showed no difference between the transgenic and the control mice.
As on the chow diet, murine apoA-I and apoA-II concentrations
associated with the atherogenic diet were lower in the transgenic
group, but the decrease was lesser than in mice fed the chow diet. Mass
composition of HDL showed no major differences between control and
transgenic mice, except for a slight increase in protein content (Table 3).
|
Cholesterol Efflux
Figure 1 shows that the mean cholesterol efflux
promoted by the incubation of samples from the transgenic group was
slightly but significantly lower than that from the control group
(-22% of control value, P<0.05).
Enzymatic Activities
Significantly higher LCAT activity was observed in transgenic mice
compared with control mice (36.62±1.97 versus 29.78±2.37 nmol/mL per
minute, mean±SEM; P<0.05).
For lipoprotein lipase activity, a decreasing trend was observed in the transgenic group compared with the control group (976±78 versus 1177±188 nmol/mL per minute, respectively; mean±SEM). By contrast, HL activity appears slightly higher in the transgenic group compared with the control group (293±24 versus 213±27 nmol/mL per minute, respectively; mean±SEM). The extent of the changes was not statistically significant.
Atherosclerotic Lesions
After 20 weeks of the cholesterol-rich diet, animals
were euthanized, and the extent of aortic lesions was measured. The
control group had 10 053±3979 mm2 of aorta
covered by atherosclerotic lesions, whereas this surface was only
4496±635 mm2 (mean±SEM,
P<0.01) in the transgenic group (Figure 2). When the data from all mice (control
and transgenic) were considered, marked significant correlations were
apparent between the extent of aortic lesions and VLDL-C
(r=0.60, P<0.01) or IDL-C (r=0.58,
P<0.05) concentrations in sera. Conversely, the surface of
lesions was independent of HDL-C, apoA-I, or LDL-C concentrations.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
We undertook the present study to establish a better in vivo delineation of the role of human apoA-II in lipoprotein metabolism and the atherogenic process with the use of transgenic mice expressing human apoA-II in the liver.
Some of the results obtained in the present study differ from those of previous studies of human apoA-II transgenic mice in terms of plasma lipid levels, enzymatic activities, or even atheroprotection. However, comparisons are rendered difficult because of the different nutritional status of mice (fed or fasted), the level of protein expression, the genomic construct of the transgene and the kind of promoter, the genetic background of the mice used for microinjection, the length of atherogenic diet needed to induce atherogenesis, and the sex and age of animals at the time of the study.
The expression of human apoA-II in mice on a chow diet leads to the appearance of HDL free of murine apolipoprotein and containing human apoA-II exclusively. Such particles have been previously described in patients with a structural mutation in the apoA-I gene (apoA-I Seattle)20 and in plasma from subjects with Tangier disease.21 The observation that apoA-II–HDL particles have a similar size in humans and in mice suggests a dominant role of the human apoA-II primary sequence in determining the size of these particles. In human plasma, apoA-II is usually found with apoA-I in HDL particles. Schultz et al19 suggested that stable apoA-II–HDL particles could form in situations in which the apoA-II concentration becomes elevated relative to the concentration of apoA-I. Although the function of these particles remains unknown, it has been reported that apoA-II–HDLs (in the absence of apoA-I or apoA-I/apoA-II–HDL) become efficient acceptors and/or donors of apoC peptides and apoE22 and may serve as surrogate acceptors of FC from peripheral cells.
As already described,23 a dramatic decrease in murine apoA-I and apoA-II was observed in the transgenic mice. Steady-state apolipoprotein levels are dependent on 2 pathways, endogenous synthesis and degradation or tissue clearance, which are quantifiable as the mean of the production rate and the fractional catabolic rate, respectively. In the present study, the dramatic reduction in endogenous murine apolipoproteins in the transgenic group was the result of a decrease in production and catabolism. The decrease in the production rates of both apolipoproteins was predominant, leading to a reduction in circulating murine apoA-I and apoA-II.
Cholesterol efflux from peripheral cells is the first step of reverse cholesterol transport, the series of metabolic steps by which excess of cholesterol is returned from peripheral cells to the liver either for excretion from the body or for recycling. In this way, cholesterol efflux may participate in preventing atherosclerosis. Transgenic mouse serum showed a slightly decreased capacity compared with that of control mice. This could be related to the significant decrease in apoA-I concentration reported in transgenic mice.
Because of its unique function as the key enzyme involved in the esterification of intravascular FC, LCAT may not only modulate HDL concentrations in plasma but may also have an important role in the processes of reverse cholesterol transport and atherosclerosis. In the present study, the transgenic group exhibits a tendency toward an increase in LCAT activity. In addition, hepatic lipase plays an important role in the metabolism of HDL by contributing in the exchanges of lipids and apolipoproteins between IDL and HDL and, consequently, in the remodeling of HDL2 to HDL3. HL activity was significantly higher in transgenic than in control mice. Finally, the dramatic decrease in apoA-I concentrations and the slight decrease in cellular cholesterol efflux in transgenic mice fed a chow diet may suggest an atherogenic role for apoA-II. Conversely, when some data are taken into consideration (decrease in non–HDL-C level, the tendency of LCAT activity to increase, and higher HL activity), the animals’ phenotypes tended toward protection against atherosclerosis.
After 20 weeks on an atherogenic diet, human apoA-II transgenic mice
developed less extensive aortic atherosclerosis than
did control mice. The mechanism by which transgenic mice are protected
may be activated by different parameters, including
atherogenic or antiatherogenic lipoprotein levels and/or composition,
LCAT activity, lipase activities, or else interaction between several
of these. First of all, it was determined that both groups of mice had
the same mean body weight at the time of euthanasia to demonstrate that
protection against atherosclerosis development was
independent of their feeding. A higher LCAT activity along with a
tendency to increased HL in the transgenic group could have a role in
the antiatherogenic process by activating reverse
cholesterol transport. Most striking was the
consistent decrease in the TC level in the transgenic group,
which was due to a drop in cholesterol in each lipoprotein
class. This affected equally the atherogenic lipoproteins (VLDL, IDL,
and LDL) and the nonatherogenic ones (HDL), inasmuch as the HDL-C/TC
and non–HDL-C/TC ratios were no different between the 2
genotypes. The same can be said of the mass composition of
ultracentrifugally isolated HDL particles (Table 2), VLDL, IDL,
and LDL particles (data not shown). This suggests that the reduction in
cholesterol was due to a decrease in the number of
circulating lipoproteins in each class.
Inasmuch as previous studies have clearly demonstrated the protective effect of HDL and apoA-I against atherosclerosis,24 the drop in HDL-C and apoA-I levels in our transgenic animals came as a contradiction and may appear as a paradoxical result because the transgenic mice developed fewer lesions than did the control mice. This is reinforced by the slight decrease in cholesterol efflux measured in vitro. However, because no correlation was observed between the extent of atherosclerotic lesions and HDL-C or apoA-I concentrations, it could be supposed that neither absolute apoA-I nor HDL-C levels have a significant role in determining antiatherogenicity in these animals. It has been generally accepted for some years that lipids and lipoproteins are not exclusive parameters implicated in the atherogenic process. Oxidation, inflammation, and even vascular wall remodeling are actors in atherosclerotic lesion development.
In humans, considerable evidence from clinical and epidemiological studies suggests that TG-rich lipoprotein remnants play a role in the pathogenesis of atherosclerosis.25 26 In the present study, VLDL-C and IDL-C levels were both positively correlated (P<0.01 and P<0.05, respectively) with the area of atherosclerotic lesions, whereas HDL-C levels were not. Therefore, we can question whether the protection against atherosclerosis in human apoA-II transgenic mice reported in the present study is related to the decrease in remnant lipoproteins rather than to changes occurring in the HDL fraction. However, further studies are needed to elucidate the mechanism underlying the role of apoA-II in the remnant metabolism.
|
Acknowledgments |
|---|
This work was supported by grants from Institut Pasteur de Lille, INSERM, Rhône-Poulenc Rorer, and the Région Nord-Pas de Calais. We thank J. Frémaux, B. Delfly, and C. Lasselin for excellent technical assistance.
Received February 28, 2000; accepted July 10, 2000.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Miller NE. Associations of high-density lipoprotein subclasses and apolipoproteins with ischemic heart disease and coronary atherosclerosis. Am Heart J. 1987;113:589–597.[Medline] [Order article via Infotrieve]
2.
Brinton EA, Eisenberg S, Breslow JL. Human HDL
cholesterol levels are determined by apoA-I fractional
catabolic rate, which correlates inversely with estimates of HDL
particle size: effects of gender, hepatic and lipoprotein lipases,
triglyceride and insulin levels, and body fat distribution.
Arterioscler Thromb. 1994;14:707–720.
3. Deeb SS, Takata K, Peng RL, Kajiyama G, Albers JJ. A splice-junction mutation responsible for familial apolipoprotein A-II deficiency. Am J Hum Genet. 1990;46:822–827.[Medline] [Order article via Infotrieve]
4.
Huang Y, von Eckardstein A, Wu S, Assmann G.
Cholesterol efflux, cholesterol esterification,
and cholesteryl ester transfer by LpA-I and LpA-I/A-II in native
plasma. Arterioscler Thromb Vasc Biol. 1995;15:1412–1418.
5.
Warden CH, Hedrick CC, Qiao JH, Castellani LW, Lusis
AJ. Atherosclerosis in transgenic mice overexpressing
apolipoprotein A-II [published erratum appears in Science.. 1993;262:164]. Science. 1993;261:469–472.
6. Castellani LW, Navab M, Lenten BJV, Hedrick CC, Hama SY, Goto AM, Fogelman AM, Lusis AJ. Overexpression of apolipoprotein AII in transgenic mice converts high density lipoproteins to proinflammatory particles. J Clin Invest. 1997;100:464–474.[Medline] [Order article via Infotrieve]
7.
Weng W, Breslow JL. Dramatically decreased high
density lipoprotein cholesterol, increased remnant
clearance, and insulin hypersensitivity in apolipoprotein A-II knockout
mice suggest a complex role for apolipoprotein A-II in
atherosclerosis susceptibility. Proc Natl Acad
Sci U S A. 1996;93:14788–14794.
8. Schultz JR, Rubin EM. The properties of HDL in genetically engineered mice. Curr Opin Lipidol. 1994;5:126–137.[Medline] [Order article via Infotrieve]
9.
Marzal-Casacuberta A, Blanco-Vaca F, Ishida BY,
Julve-Gil J, Shen J, Calvet-Marquez S, Gonzalez-Sastre F, Chan L.
Functional lecithin:cholesterol acyltransferase deficiency
and high density lipoprotein deficiency in transgenic mice
overexpressing human apolipoprotein A-II. J Biol Chem. 1996;271:6720–6728.
10.
Escola-Gil JC, Marzal-Casacuberta A, Julve-Gil J,
Ishida BY, Ordonez-Llanos J, Chan L, Gonzalez-Sastre F, Blanco-Vaca F.
Human apolipoprotein A-II is a pro-atherogenic molecule when it is
expressed in transgenic mice at a level similar to that in humans:
evidence of a potentially relevant species-specific interaction with
diet. J Lipid Res. 1998;39:457–462.
11.
Boisfer E, Lambert G, Atger V, Tran NQ, Pastier D,
Benetollo C, Trottier JF, Beaucamps I, Antonucci M, Laplaud M, et al.
Overexpression of human apolipoprotein A-II in mice induces
hypertriglyceridemia due to defective very
low density lipoprotein hydrolysis. J Biol Chem. 1999;274:11564–11572.
12.
Peters JM, Hennuyer N, Staels B, Fruchart JC, Fievet C,
Gonzalez FJ, Auwerx J. Alterations in lipoprotein
metabolism in peroxisome proliferator-activated
receptor alpha-deficient mice. J Biol Chem. 1997;272:27307–27312.
13. Havel RJ. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest. 1955;34:1345–1353.
14.
Lowry OH. Protein measurement with the folin phenol
reagent. J Biol Chem. 1951;193:265–275.
15.
Towbin H, Staehelin T, Gordon J. Electrophoretic
transfer of proteins from polyacrylamide gels to nitrocellulose
sheets: procedure and some applications. Proc Natl Acad Sci
U S A. 1979;76:4350–4354.
16.
de la Llera Moya M, Atger V, Paul JL, Fournier N,
Moatti N, Giral P, Friday KE, Rothblat G. A cell culture system for
screening human serum for ability to promote cellular
cholesterol efflux: relations between serum components and
efflux, esterification, and transfer. Arterioscler Thromb. 1994;14:1056–1065.
17. Chen CH, Albers JJ. Characterization of proteoliposomes containing apoprotein A-I: a new substrate for the measurement of lecithin: cholesterol acyltransferase activity. J Lipid Res. 1982;23:680–691.[Abstract]
18. Henderson AD, Richmond W, Elkeles RS. Hepatic and lipoprotein lipases selectively assayed in postheparin plasma. Clin Chem. 1993;39:218–223.[Abstract]
19.
Schultz JR, Gong EL, McCall MR, Nichols AV, Clift SM,
Rubin EM. Expression of human apolipoprotein A-II and its effect on
high density lipoproteins in transgenic mice. J Biol
Chem. 1992;267:21630–21636.
20.
Deeb SS, Cheung MC, Peng RL, Wolf AC, Stern R, Albers
JJ, Knopp RH. A mutation in the human apolipoprotein A-I gene: dominant
effect on the level and characteristics of plasma high density
lipoproteins. J Biol Chem. 1991;266:13654–13660.
21. Assmann G, Herbert PN, Fredrickson DS, Forte T. Isolation and characterization of an abnormal high density lipoprotein in Tangier disease. J Clin Invest. 1977;60:242–252.
22. Bekaert ED, Alaupovic P, Knight-Gibson C, Norum RA, Laux MJ, Ayrault-Jarrier M. Isolation and partial characterization of lipoprotein A-II (LP-A-II) particles of human plasma [published erratum appears in Biochim Biophys Acta. 1992;1127:103]. Biochim Biophys Acta. 1992;1126:105–113.
23. Breslow JL. Lipoprotein metabolism and atherosclerosis susceptibility in transgenic mice. Curr Opin Lipidol. 1994;5:175–184.[Medline] [Order article via Infotrieve]
24. Tall AR. Plasma high density lipoproteins: metabolism and relationship to atherogenesis. J Clin Invest. 1990;86:379–384.
25. Bradley WA, Gianturco SH. Triglyceride-rich lipoproteins and atherosclerosis: pathophysiological considerations. J Intern Med Suppl. 1994;736:33–39.[Medline] [Order article via Infotrieve]
26. Luc G, Fievet C, Arveiler D, Evans AE, Bard JM, Cambien F, Fruchart JC, Ducimetiere P. Apolipoproteins C-III and E in apoB- and non-apoB-containing lipoproteins in two populations at contrasting risk for myocardial infarction: the ECTIM study: Etude Cas Temoins sur l’Infarctus du Myocarde. J Lipid Res.. 1996;37:508–517.[Abstract]
This article has been cited by other articles:
 |
|
 |
|
  T. Koike, S. Kitajima, Y. Yu, Y. Li, K. Nishijima, E. Liu, H. Sun, A. B. Waqar, N. Shibata, T. Inoue, et al. Expression of Human ApoAII in Transgenic Rabbits Leads to Dyslipidemia: A New Model for Combined Hyperlipidemia Arterioscler Thromb Vasc Biol, December 1, 2009; 29(12): 2047 - 2053. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. E. MacDonald, R. R. Singaraja, N. Bissada, P. Ruddle, R. Watts, J. M. Karasinska, W. T. Gibson, C. Fievet, J. E. Vance, B. Staels, et al. Absence of stearoyl-CoA desaturase-1 ameliorates features of the metabolic syndrome in LDLR-deficient mice J. Lipid Res., January 1, 2008; 49(1): 217 - 229. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Birjmohun, G. M. Dallinga-Thie, J. A. Kuivenhoven, E. S.G. Stroes, J. D. Otvos, N. J. Wareham, R. Luben, J. J.P. Kastelein, K.-T. Khaw, and S. M. Boekholdt Apolipoprotein A-II Is Inversely Associated With Risk of Future Coronary Artery Disease Circulation, October 30, 2007; 116(18): 2029 - 2035. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Corella, D. K. Arnett, M. Y. Tsai, E. K. Kabagambe, J. M. Peacock, J. E. Hixson, R. J. Straka, M. Province, C.-Q. Lai, L. D. Parnell, et al. The -256T>C Polymorphism in the Apolipoprotein A-II Gene Promoter Is Associated with Body Mass Index and Food Intake in the Genetics of Lipid Lowering Drugs and Diet Network Study Clin. Chem., June 1, 2007; 53(6): 1144 - 1152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Nicholls, B. Cutri, S. G. Worthley, P. Kee, K.-A. Rye, S. Bao, and P. J. Barter Impact of Short-Term Administration of High-Density Lipoproteins and Atorvastatin on Atherosclerosis in Rabbits Arterioscler Thromb Vasc Biol, November 1, 2005; 25(11): 2416 - 2421. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. W. Castellani, P. Gargalovic, M. Febbraio, S. Charugundla, M.-L. Jien, and A. J. Lusis Mechanisms mediating insulin resistance in transgenic mice overexpressing mouse apolipoprotein A-II J. Lipid Res., December 1, 2004; 45(12): 2377 - 2387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. de Beer, L. W. Castellani, L. Cai, A. J. Stromberg, F. C. de Beer, and D. R. van der Westhuyzen ApoA-II modulates the association of HDL with class B scavenger receptors SR-BI and CD36 J. Lipid Res., April 1, 2004; 45(4): 706 - 715. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. G. Brown, M. C. Cheung, A. C. Lee, X.-Q. Zhao, and A. Chait Antioxidant Vitamins and Lipid Therapy: End of a Long Romance? Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1535 - 1546. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Boisfer, D. Stengel, D. Pastier, P. M. Laplaud, N. Dousset, E. Ninio, and A.-D. Kalopissis Antioxidant properties of HDL in transgenic mice overexpressing human apolipoprotein A-II J. Lipid Res., May 1, 2002; 43(5): 732 - 741. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Barbier, I. P. Torra, Y. Duguay, C. Blanquart, J.-C. Fruchart, C. Glineur, and B. Staels Pleiotropic Actions of Peroxisome Proliferator-Activated Receptors in Lipid Metabolism and Atherosclerosis Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 717 - 726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
F. Blanco-Vaca, J. C. Escola-Gil, J. M. Martin-Campos, and J. Julve Role of apoA-II in lipid metabolism and atherosclerosis: advances in the study of an enigmatic protein J. Lipid Res., November 1, 2001; 42(11): 1727 - 1739. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. de Beer, D. M. Durbin, L. Cai, N. Mirocha, A. Jonas, N. R. Webb, F. C. de Beer, and D. R. van der Westhuyzen Apolipoprotein A-II Modulates the Binding and Selective Lipid Uptake of Reconstituted High Density Lipoprotein by Scavenger Receptor BI J. Biol. Chem., May 4, 2001; 276(19): 15832 - 15839. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. M. Morton, M. C. Holmes, C. Fievet, B. Staels, A. Tailleux, J. J. Mullins, and J. R. Seckl Improved Lipid and Lipoprotein Profile, Hepatic Insulin Sensitivity, and Glucose Tolerance in 11beta -Hydroxysteroid Dehydrogenase Type 1 Null Mice J. Biol. Chem., October 26, 2001; 276(44): 41293 - 41300. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||