© 1995 American Heart Association, Inc.
Articles |
Apolipoprotein A-II Production Rate Is a Major Factor Regulating the Distribution of Apolipoprotein A-I Among HDL Subclasses LpA-I and LpA-I:A-II in Normolipidemic Humans
From the Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
Correspondence to Daniel Rader, MD, University of Pennsylvania Medical Center, BRB-1 Rm 409, 422 Curie Blvd, Philadelphia, PA 19104-6069.
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Abstract |
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Abstract HDLs are heterogeneous in their apolipoprotein composition. Apolipoprotein (apo) A-I and apoA-II are the major proteins found in HDL and form the two major HDL subclasses: those that contain only apoA-I (LpA-I) and those that contain both apoA-I and apoA-II (LpA-I:A-II). Substantial evidence indicates that these two subclasses differ in their in vivo metabolism and effect on atherosclerosis, with LpA-I the more specifically protective subfraction against atherosclerosis. The purpose of this study was to investigate the effect of apoA-I and apoA-II production and catabolism on plasma LpA-I and LpA-I:A-II levels. Fifty normolipidemic subjects (those with HDL cholesterol levels in the top and bottom tenth percentiles were excluded) underwent kinetic studies with radiolabeled apoA-I and apoA-II, and the kinetic parameters of apoA-I and apoA-II were correlated with LpA-I and LpA-I:A-II levels. ApoA-I levels were strongly correlated with apoA-I residence times and less strongly correlated with apoA-I production rates. In contrast, apoA-II levels were correlated only with apoA-II production rates and not with apoA-II residence times. Levels of apoA-I in LpA-I were correlated with apoA-I residence times, whereas levels of apoA-I in LpA-I:A-II were correlated primarily with apoA-II production rates. The fraction of apoA-I in LpA-I was highly inversely correlated with apoA-II production rate (r=-.67, P<.001). In multiple regression analysis, apoA-II production rate was the most significant independent variable determining percent apoA-I in LpA-I among all the kinetic parameters. These results indicate that in normolipidemic individuals (1) apoA-I levels are regulated primarily by apoA-I catabolism and apoA-II levels by apoA-II production; (2) the rate of catabolism of apoA-I is an important factor determining LpA-I levels, while the rate of apoA-II production is the major determinant of the amount of apoA-I in LpA-I:A-II; and (3) the rate of apoA-II production is a major factor determining the distribution of apoA-I between LpA-I and LpA-I:A-II, thereby possibly modulating susceptibility to atherosclerosis in humans.
Key Words: apoA-I • apoA-II • kinetics • radiotracer • HDLs
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Plasma concentrations of HDL cholesterol (HDL-C) are inversely correlated with the risk of coronary artery disease.1 Apolipoprotein (apo) A-I and apoA-II are the two major proteins in HDL. Epidemiological studies have also demonstrated a strong inverse correlation of plasma apoA-I levels with the risk of coronary artery disease.2 3 Some evidence suggests that apoA-I is directly protective against atherosclerosis. Increased production of apoA-I has been associated with possible longevity in one kindred.4 Furthermore, transgenic mice overexpressing human apoA-I are relatively resistant to diet-induced atherosclerosis.5 In contrast to apoA-I, apoA-II levels are not clearly inversely associated with coronary artery disease.2 3 In fact, animal studies have suggested that apoA-II may promote atherosclerosis. Naturally selected mouse strains with elevated apoA-II levels are prone to the development of atherosclerosis on an atherogenic diet.6 Furthermore, transgenic mice overexpressing mouse apoA-II develop early atherosclerosis.7 Finally, coexpression of human apoA-II in transgenic mice also expressing human apoA-I counteracts the beneficial effect of the apoA-I on atherosclerosis development.8
HDL is heterogeneous in apolipoprotein composition. The major HDL subclasses are those containing only apoA-I (LpA-I) and those containing both apoA-I and apoA-II (LpA-I:A-II).9 Substantial evidence indicates that these subclasses differ in their metabolism and effect on atherosclerosis. LpA-I and LpA-I:A-II have different rates of catabolism in normolipidemic subjects10 and in patients with genetic lecithin:cholesterol acyltransferase defects,11 indicating distinct metabolic pathways for these two HDL subclasses. Cholesteryl ester transfer protein interacts preferentially with LpA-I,12 whereas hepatic lipase interacts preferentially with LpA-I:A-II.13 Some but not all clinical studies support the concept that LpA-I may be a more specific "antiatherogenic" lipoprotein particle than LpA-I:A-II.14 15 16
A number of kinetic studies have been conducted to investigate factors regulating plasma apoA-I and apoA-II steady-state levels. Several studies have concluded that apoA-I levels are regulated primarily by the rate of apoA-I catabolism17 18 19 ; others found that apoA-I production rates also affect apoA-I levels.20 21 In contrast, apoA-II levels appear to be regulated solely by apoA-II production rates.17 18 19 However, the metabolic regulation of LpA-I and LpA-I:A-II levels is not understood. In the present study, we investigated apoA-I and apoA-II kinetics in normolipidemic subjects to determine the major kinetic factors regulating LpA-I and LpA-I:A-II levels.
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Methods |
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Study Subjects
Fifty healthy normolipidemic volunteers (22 men and 28 women) were admitted to the Clinical Center of the National Institutes of Health for these studies. None of the study subjects had total cholesterol, triglyceride, or LDL cholesterol levels exceeding the 90th percentile or HDL-C levels in the top or bottom 10th percentile for age and sex.22 None of the study subjects had abnormal fasting glucose levels or evidence of thyroid, liver, or renal dysfunction and none were taking medications at the time of the study. Subjects gave informed written consent to the study protocol, which was approved by the Clinical Research Subpanel of the National Heart, Lung, and Blood Institute.
Isolation and Iodination of Apolipoproteins
ApoA-I and apoA-II were isolated from normal HDL by
gel-permeation chromatography and ion-exchange
chromatography23 and stored at -20°C. Purified
apolipoproteins were redissolved in a buffer of 6 mol/L guanidine-HCl
and 1 mol/L glycine, pH 8.5, and iodinated with 125I and
131I by a modification of the iodine monochloride
method.10 Iodinated apoA-I and apoA-II were reassociated
with separate aliquots of autologous plasma and extensively dialyzed
against phosphate-buffered saline containing 0.01% EDTA at 4°C
overnight.10 The samples were sterile-filtered through a
0.22-µm Millipore filter and tested for pyrogens and sterility prior
to injection.
Study Protocol
Three days prior to the study, subjects were placed on an
isoweight diet containing 47% carbohydrate, 37% fat, 16% protein,
200 mg cholesterol/1000 kcal, and a polyunsaturated/saturated fat ratio
of 0.3. Meals were given three times per day, and the diet was
continued during the metabolic study. One day prior to the study, the
subjects were started on potassium iodide (900 mg) in divided doses;
this regimen was continued throughout the study period. After a 12-hour
fast, the subjects were injected with 125I-apoA-I (50
µCi) and 131I-apoA-II (25 µCi). All 50 subjects
received the radiolabeled apoA-I, and 35 of the subjects also received
radiolabeled apoA-II. Blood samples were obtained 10 minutes after the
injection and then at 1, 3, 6, 12, 18, 24, and 36 hours; daily through
day 5; and on days 7, 9, 11, and 14. Urine was collected continuously
throughout the study.
Blood samples (20 mL) were drawn into tubes containing EDTA (final concentration, 0.1%). The blood was kept on ice, and the plasma was immediately separated by centrifugation at 2300 rpm for 30 minutes at 4°C. Sodium azide and aprotinin were added to the plasma at final concentrations of 0.05% and 200 KIU/mL, respectively. Radioactivity in plasma and urine was quantified in a Packard Cobra gamma counter (Packard Instrument Co).
Analytical Methods
Plasma decay curves were constructed as the fraction of injected
dose by dividing the plasma radioactivity at each time point by the
radioactivity in the 10-minute plasma sample. Multiexponential
functions were fit to the plasma decay curves using SAAM
31.24 Residence times (RT) were obtained from the areas
under the curves. Production rates (PR) were calculated from the
formula
PR=(Plasma Apolipoprotein Concentration)x (Plasma Volume)/(RT)/(Body Weight)
Plasma volume was determined by the radioactivity in the 10-minute plasma sample.
Plasma total cholesterol and triglyceride levels were determined by automated enzymatic techniques on an Abbott VPSS analyzer (Abbott Labs). HDL-C was measured by dextran sulfate precipitation.25 Plasma apoA-I and apoA-II concentrations were quantified using an immunoturbidometric assay (Boehringer-Mannheim). ApoB concentration was measured by a competitive enzyme-linked immunoassay.26 The plasma LpA-I concentration was measured by the method described by Parra et al27 and expressed as the apoA-I mass (in milligrams) in LpA-I per unit of volume (in deciliters). The apoA-I concentration in LpA-I:A-II was obtained by subtracting the LpA-I value from the total plasma apoA-I concentration. The mean values of the male and female groups were compared by using Student's t test. Regression analysis was performed using the SPSS statistical program.
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Results |
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The characteristics of the study subjects are shown in Table 1
. Total cholesterol, LDL cholesterol, apoA-II, and apoB
levels did not differ by gender. HDL-C and apoA-I levels were
significantly higher and triglyceride levels were significantly lower
in the women. LpA-I but not LpA-I:A-II levels were significantly higher
in the women, resulting in their having a significantly higher
percentage of apoA-I in LpA-I. There was a significant correlation
between HDL-C and apoA-I levels (r=.80, P<.001)
but not between HDL and apoA-II levels. Triglyceride levels were
inversely correlated with HDL-C (r=-.36, P<.01)
and LpA-I (r=-.52, P<.001; Fig 1A) but not with LpA-I:A-II (r=.03,
P=.83; Fig 1B).
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indicates men; 
, women.
The kinetic parameters of apoA-I and apoA-II are summarized in Table 2. The mean residence time of apoA-I was 4.47±0.69 days
and of apoA-II, 5.10±0.62 days. Mean residence times of apoA-I and
apoA-II were not significantly different by gender; however, the women
tended toward longer apoA-I residence times (P=.08).
Production rates of apoA-I and apoA-II were not different between the
two groups.
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The correlations between plasma apoA-I levels and apoA-I kinetic
parameters are shown in Fig 2. ApoA-I levels were
strongly correlated with apoA-I residence time (r=.54,
P<.001) and with apoA-I production rate to a relatively
weaker degree (r=.30, P<.05). In contrast,
apoA-II levels were strongly correlated with apoA-II production rate
(r=.82, P<.001) but not with apoA-II residence
time (r=-.14, P=.43; Fig 3).
LpA-I levels were highly positively correlated with both apoA-I and
apoA-II residence times (r=.59, P<.001 and
r=.47, P<.01, respectively) and negatively
correlated with apoA-II production rate (r=-.41,
P<.05; Fig 4). However, LpA-I:A-II levels
did not correlate with apoA-II residence time and were only weakly
correlated with apoA-I residence time (Fig 5). In
contrast, LpA-I:A-II levels were strongly correlated with both apoA-I
(r=.42, P<.01) and apoA-II (r=.49,
P<.01) production rates. Thus, the distribution of apoA-I
in LpA-I was strongly inversely correlated with apoA-II production rate
(r=-.67, P<.001), weakly correlated with apoA-I
production rate and apoA-II residence time, and not correlated with the
apoA-I residence time (Fig 6).
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Multiple regression analysis was performed using the apoA-I and
apoA-II kinetic parameters as the independent variables (Table 3). In whole-group analysis, the apoA-II production
rate was found to be the most significant factor correlated with the
percentage of apoA-I in LpA-I (P=.003). Table 4 presents the lipid, apolipoprotein, and kinetic
parameters between two groups based on their apoA-II production rates.
The mean apoA-II production rate of 2.68
mg · kg-1 · d-1 was used for the
grouping. HDL levels did not differ between the two groups. However, in
the group with high apoA-II production rates, LpA-I was significantly
lower (P<.01) and LpA-I:A-II higher (P=.06),
resulting in a decreased fraction of apoA-I in LpA-I.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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ApoA-I levels are inversely associated with risk of coronary artery disease, and apoA-I is probably directly protective against atherosclerosis. However, substantial data suggest that the distribution of apoA-I between LpA-I and LpA-I:A-II may strongly affect the ability of apoA-I to protect against atherosclerosis. The major goal of this study was to determine whether the production or catabolic rates of apoA-I or apoA-II regulate the levels of LpA-I and LpA-I:A-II or the distribution of apoA-I between these two HDL subclasses.
Consistent with previous reports,17 18 19 we confirmed that the rate of apoA-I catabolism is the major metabolic factor regulating apoA-I levels. However, the apoA-I production rate was also correlated (albeit more weakly) with apoA-I concentration. The most likely explanation for these apparent discrepancies is that this study and that of Gylling et al21 excluded individuals with low HDL levels, whereas the other studies17 18 19 included some individuals with HDL levels in the bottom tenth percentile. Although apoA-I catabolism is clearly the major determinant of apoA-I levels across the entire range of HDL levels, apoA-I production rates also appear to have some effect in determining apoA-I levels when the extreme 10th percentiles are excluded. In contrast, we found that apoA-II levels are entirely determined by the rate of apoA-II production.
Levels of apoA-I in LpA-I were most strongly correlated with the catabolic rate of apoA-I, consistent with a major effect of apoA-I turnover on LpA-I levels. However, we also found that LpA-I levels were inversely correlated with apoA-II production rates. Consistent with this was the observation that the levels of apoA-I in LpA-I:A-II were most strongly correlated with apoA-II production rates. The most straightforward interpretation of these findings is that higher rates of apoA-II production result in a shift of apoA-I from LpA-I to LpA-I:A-II. This would be expected to result in lower levels of LpA-I, higher levels of LpA-I:A-II, and a substantially smaller fraction of apoA-I in LpA-I. In fact, on multivariate analysis, the distribution of apoA-I among the two subclasses was most strongly influenced by the apoA-II production rate. This indicates that the apoA-II production rate plays a key role in the distribution of apoA-I between LpA-I and LpA-I:A-II in subjects with normal HDL-C. The concept that variation in apoA-II production could influence HDL composition is supported by the earlier observation that a common apoA-II polymorphism was associated with differences in HDL composition28 as well as a recent linkage analysis linking the apoA-II locus to differences in HDL composition.29
The mechanism for the effect of apoA-II production rate on the distribution of apoA-I likely involves simple mass action of additional apoA-II associating with a limited amount of apoA-I. However, the location of this association is unknown: it could occur within the cell prior to secretion, within the hepatic sinusoids, or within the plasma compartment following secretion from the liver. We have no data to directly support or refute any of these possibilities. However, apoA-II can be secreted without apoA-I in vivo30 31 and in vitro,32 and we therefore favor the concept that the association of apoA-II with apoA-I occurs after secretion from the hepatocyte. Further investigation will be required to address this interesting question.
If LpA-I is a more specific antiatherosclerotic lipoprotein than LpA-I:A-II, then factors that result in redistribution of plasma apoA-I from LpA-I to LpA-I:A-II would be expected to cause increased susceptibility to atherosclerosis. This concept is consistent with the finding that naturally selected mouse strains with elevated apoA-II production rates develop more atherosclerosis.6 In addition, overexpression of mouse apoA-II resulted in increased atherosclerosis.7 Finally, overexpression of human apoA-II in mice also overexpressing apoA-I resulted in a shift of apoA-I to LpA-I:A-II particles and elimination of the protective effect of the apoA-I.8 In light of these reports, our finding here may be interpreted as an indication that the apoA-II production rate may be one metabolic determinant of susceptibility to atherosclerosis in humans.
In summary, our results establish that in normolipidemic humans, the distribution of apoA-I between LpA-I and LpA-I:A-II is strongly influenced by the production rate of apoA-II. This result, together with the proposition that LpA-I but not LpA-I:A-II is antiatherogenic, indicates that the apoA-II production rate modulates HDL composition and may influence human susceptibility to atherosclerosis.
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Acknowledgments |
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We are indebted to Glenda Talley and Rosemary Ronan for excellent technical support, Betty Kuzmik for invaluable assistance with the kinetic studies, and the normal volunteers for participating.
Received August 28, 1994; accepted December 12, 1994.
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 M. A. Clay, D. H. Pyle, K.-A. Rye, and P. J. Barter Formation of Spherical, Reconstituted High Density Lipoproteins Containing Both Apolipoproteins A-I and A-II Is Mediated by Lecithin:Cholesterol Acyltransferase J. Biol. Chem., March 17, 2000; 275(12): 9019 - 9025. [Abstract] [Full Text] [PDF]
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D. M. Durbin and A. Jonas Lipid-free apolipoproteins A-I and A-II promote remodeling of reconstituted high density lipoproteins and alter their reactivity with lecithin:cholesterol acyltransferase J. Lipid Res., December 1, 1999; 40(12): 2293 - 2302. [Abstract] [Full Text] [PDF]
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S. Braschi, T. A-M. Neville, M.-C. Vohl, and D. L. Sparks Apolipoprotein A-I charge and conformation regulate the clearance of reconstituted high density lipoprotein in vivo J. Lipid Res., March 1, 1999; 40(3): 522 - 532. [Abstract] [Full Text]
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A. Ribeiro, D. Pastier, D. Kardassis, J. Chambaz, and P. Cardot Cooperative Binding of Upstream Stimulatory Factor and Hepatic Nuclear Factor 4 Drives the Transcription of the Human Apolipoprotein A-II Gene J. Biol. Chem., January 15, 1999; 274(3): 1216 - 1225. [Abstract] [Full Text] [PDF]
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J. C. Escolà-Gil, A. Marzal-Casacuberta, J. Julve-Gil, B. Y. Ishida, J. Ordóñez-Llanos, L. Chan, F. González-Sastre, and F. Blanco-Vaca 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., February 1, 1998; 39(2): 457 - 462. [Abstract] [Full Text]
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P. J. Pussinen, M. Jauhiainen, J. Metso, L. E. Pyle, Y. L. Marcel, N. H. Fidge, and C. Ehnholm Binding of phospholipid transfer protein (PLTP) to apolipoproteins A-I and A-II: location of a PLTP binding domain in the amino terminal region of apoA-I J. Lipid Res., January 1, 1998; 39(1): 152 - 161. [Abstract] [Full Text]
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 M. Tilly-Kiesi, A. H. Lichtenstein, J. Joven, E. Vilella, M. C. Cheung, W. V. Carrasco, J. M. Ordovas, G. Dolnikowski, and E. J. Schaefer Impact of Gender on the Metabolism of Apolipoprotein A-I in HDL Subclasses LpAI and LpAI:AII in Older Subjects Arterioscler Thromb Vasc Biol, December 1, 1997; 17(12): 3513 - 3518. [Abstract] [Full Text]
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M. Tilly-Kiesi, A. H. Lichtenstein, J. M. Ordovas, G. Dolnikowski, R. Malmstrom, M.-R. Taskinen, and E. J. Schaefer Subjects With ApoA-I(Lys107->0) Exhibit Enhanced Fractional Catabolic Rate of ApoA-I in Lp(AI) and ApoA-II in Lp(AI With AII) Arterioscler Thromb Vasc Biol, May 1, 1997; 17(5): 873 - 880. [Abstract] [Full Text]
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A. Marzal-Casacuberta, F. Blanco-Vaca, B. Y. Ishida, J. Julve-Gil, J. Shen, S. Calvet-Márquez, F. González-Sastre, and L. Chan Functional Lecithin:Cholesterol Acyltransferase Deficiency and High Density Lipoprotein Deficiency in Transgenic Mice Overexpressing Human Apolipoprotein A-II J. Biol. Chem., March 22, 1996; 271(12): 6720 - 6728. [Abstract] [Full Text] [PDF]
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E. A. Brinton Oral Estrogen Replacement Therapy in Postmenopausal Women Selectively Raises Levels and Production Rates of Lipoprotein A-I and Lowers Hepatic Lipase Activity Without Lowering the Fractional Catabolic Rate Arterioscler Thromb Vasc Biol, March 1, 1996; 16(3): 431 - 440. [Abstract] [Full Text]
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