© 1997 American Heart Association, Inc.
Articles |
Impact of Gender on the Metabolism of Apolipoprotein A-I in HDL Subclasses LpAI and LpAI:AII in Older Subjects
From the Lipid Metabolism Laboratory (A.H.L., W.V.C., J.M.O., E.J.S.); the Mass Spectrometry Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston (G.D.); the Helsinki University Central Hospital, Helsinki, Finland (M.T.K.); the Hospital Universitari Sant Joan, Reus, Spain (J.J., E.V.); and the Northwest Lipid Research Laboratories, Seattle, Wash (M.C.C.).
Correspondence to Ernst J. Schaefer, MD, Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington St, Boston, MA 02111.
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Abstract The behavior of apolipoprotein (apo) A-I in lipoprotein (Lp) AI and LpAI:AII was studied in 11 postmenopausal females and 11 males matched for plasma triglyceride and total cholesterol levels. Subjects consumed a baseline diet [35% fat (14% saturated, 15% monounsaturated, and 7% polyunsaturated), 15% protein, 49% carbohydrate, and 147 mg cholesterol/1000 kcal] for 6 weeks before the start of the kinetic study. At the end of the diet period, using a primed-constant infusion of [5,5,5-2H3]leucine, residence times (RT) and secretion rates (SR) of apoA-I were determined in 2 subpopulations of high-density lipoprotein (HDL) particles, LpAI and LpAI:AII. Plasma total cholesterol, low-density lipoprotein cholesterol, and triglyceride concentrations were similar in males and females. The mean plasma HDL cholesterol concentration in males (1.14± 0.23 mmol/L; mean±SD) was lower than in females (1.42±0.18 mmol/L; P=.0034). Similarly, the mean plasma concentration of apoA-I in males (130±21 mg/dL) was lower than that in females (150±19 mg/dL; P=.0421). The RT of apoA-I in either LpAI or LpAI:AII was similar between men and women. Despite the higher plasma apo A-I levels in female compared with male subjects, total apoA-I and apoA-I in LpAI and LpAI:AII pool sizes were similar between the two groups, attributable to the lower body weight of the female subjects. The mean SR of total apoA-I in males (8.5±2.7 mg · kg-1 · d-1) was 22% lower than in females (10.9±2.3 mg · kg-1 · d-1; P=.0389). The SR of both apoA-I in LpAI and LpAI:AII was lower in males than females, although the differences did not reach statistical significance. These data suggest that the difference observed in HDL cholesterol concentration between males and females is attributable to SR of apoA-I and not the catabolic rate.
Key Words: kinetics • LpAI • LpAI:AII • sex • lipoproteins
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Introduction |
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Increased plasma HDL cholesterol concentration has been associated with a reduced risk of developing premature coronary heart disease (CHD).1 The major protein of HDL is apoA-I and is found in two distinct HDL subpopulations, LpAI, which contains apoA-I only, and LpAI:AII, which contains apoA-I and apo A-II.2 3 4 Puchois et al5 have reported lower plasma concentrations of LpAI but not LpAI:AII in normotriglyceridemic patients with CHD. In contrast, others have reported that patients with CHD and reduced HDL cholesterol concentrations have lower levels of both LpAI and LpAI:AII.6 7 8
HDL cholesterol levels in men and women diverge at puberty, and thereafter, women have significantly higher levels of HDL cholesterol and apoA-I than men. Additionally, there is a shift in lipoprotein concentrations and risk of developing CHD in women as they age. Premenopausal women have lower levels of LDL and triglyceride-rich lipoprotein than postmenopausal women, whereas the levels of HDL cholesterol and apoA-I are similar between the two groups.9 10 11 12 13 This shift in lipoprotein patterns in women after menopause is associated with increased rates of developing CHD.14
Premenopausal women have been reported to have higher levels of LpAI, yet similar levels of LpAI:AII, than men.9 15 16 Additionally, premenopausal women have been reported to have higher levels of large LpAI particles relative to men.16 No significant differences in the concentrations of LpAI and LpAI:AII have been reported between premenopausal and postmenopausal women.11 However, a shift toward smaller, lipid-poor and protein-rich HDL particles has been observed in postmenopausal, as compared with premenopausal, women.10 11
The primary factors controlling plasma apoA-I levels are somewhat uncertain. Both the FCR17 18 19 and SR20 21 of HDL apoA-I have been reported to be important factors. Rader et al22 have reported that the turnover rate of apoA-I in LpAI is faster than that of apoA-I in LpAI:AII particles in young, normolipidemic adult subjects. Recently, Ikewaki et al15 have suggested that the rate of catabolism of apoA-I is an important factor in determining LpAI levels and that the rate of apoA-II production is a major determinant of the distribution of apoA-I between LpAI and LpAI:AII.
The aim of the present study was to explore the kinetic mechanism accounting for the sex difference in plasma HDL cholesterol levels. We investigated the in vivo metabolism of apoA-I in two HDL subpopulations, LpAI and LpAI:AII, in postmenopausal women and older men with similar plasma triglyceride and total cholesterol levels.
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Study Subjects
Eleven postmenopausal females and 11 males over the age of 50 years were recruited for the study. Subjects were matched for plasma triglyceride and total cholesterol levels. All subjects underwent a complete physical examination, and blood samples were collected for laboratory analysis. Renal or hepatic disorders were excluded on the basis of laboratory tests and medical history. The subjects neither had signs or symptoms of CHD or of thyroid or other endocrine diseases nor were receiving medication known to influence plasma lipid levels. All female subjects were postmenopausal, and none were receiving hormone replacement therapy. The mean age of the female subjects was about 10 years higher than the mean age of the male subjects, although the minimum age criterion for study participation was the same for both genders. This difference in age reflects the demographics of the eligible pool of subjects for participation in the study. The age difference observed would not be expected to have a physiologically significant impact on the study outcome. Conversely, menopausal status of the females would be expected to have an impact on study outcome.
For 6 weeks before the kinetic studies, the subjects were provided with an isocaloric natural-food diet consisting of 35% fat (14% saturated, 15% monounsaturated, and 7% polyunsaturated), 15% protein, 49% carbohydrate, and 147 mg cholesterol/1000 kcal. Subjects reported to our metabolic research unit a minimum of 4-times per week, were weighed at each visit, and were provided with all food and drink.23 Minor adjustments in the amount of food provided were made, if necessary, in order to avoid weight gain or loss.
Study Protocol
Each study began in the morning following a 12-hour fast. An
intravenous line was inserted into one forearm for the
infusion solution, and another line was placed into the opposite arm
for blood sampling.24 At zero hour a priming dose
of 10 µmol/kg per body weight of
[5,5,5-2H3]leucine was
given intravenously and was followed by a constant infusion
of [5,5,5-2H3]leucine at
a rate of 10 µmol/kg/h for the next 15 hours (0 hours to 15
hours). Blood samples were collected into tubes containing EDTA. For
this study enrichment of apoA-I in LpAI and LpAI:AII was determined at
0 hours, 6 hours, 10 hours, 12 hours, and 15 hours, and enrichment of
apoB-100 in VLDL was determined at 0 hours, 1 hour, 2 hours, 3 hours, 4
hours, 6 hours, 8 hours, 10 hours, 12 hours, and 15 hours.
The kinetic studies were carried out while subjects were in the fed state as previously described.24 The subjects received 20 identical small meals, the nutrient content of which was comparable to the prestudy diet, given as small meals every hour starting 5 hours (-5 hours) before the stable isotope infusion. Each small meal contained 1/20 of their daily caloric intake. The studies were conducted in the metabolic research unit of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University. The study protocol was approved by the Human Investigation Review Committee of the New England Medical Center and Tufts University.
Isolation of Plasma Lipoproteins and LpAI and LpAI:AII
Plasma lipoprotein fractions were isolated by sequential
ultracentrifugation in a Beckman L8 to 70
ultracentrifuge (Beckman Instruments) using a Beckman 50.3-Ti
rotor as previously described.25 VLDL, IDL, LDL,
and HDL were isolated at densities 1.006, 1.019, 1.063, and 1.21 g/mL,
respectively.
LpAI and LpAI:AII particles were separated from plasma using immunoaffinity chromatography columns, as previously described.4 In brief, monoclonal antibodies against human apoA-I and apoA-II were separately conjugated to CNBr-Sepharose 4B and were cross-linked using glutaraldehyde according to the method described by Kowal and Parsons26 and McConathy.27 Plasma (1 mL) was applied first to the anti-apoA-I column. The bound lipoproteins were eluted with 0.01 mol/L Tris, 3 mol/L NaSCN, pH 8.0, and dialyzed overnight against 0.01 mol/L Tris, 0.01 mol/L NaCl, pH 8.0, at 4°C. ApoA-I containing lipoproteins isolated with the first column were applied to an anti-apoA-II column. The unretained fraction containing LpAI and other lipoproteins with apoA-I was collected and dialyzed against 0.01 mol/L Tris, 0.01 mol/L NaCl, pH 8.0, at 4°C overnight. The retained fraction containing LpAI:AII was eluted with 3 mol/L NaSCN and dialyzed against 0.01 mol/L ammonium bicarbonate solution at 4°C. The capacity of apoA-I and apoA-II columns to bind apoA-I and apoA-II, respectively, was in excess based on the undetectable amount of apoA-I or apoA-II among unbound proteins. Finally, the fraction containing LpAI and apoB containing lipoproteins was applied to an anti-apoB column. The unretained fraction containing LpAI was dialyzed against 0.01 mol/L ammonium bicarbonate solution at 4°C overnight. The LpAI and LpAI:AII fractions were lyophilized and apoA-I was isolated from LpAI and LpAI:AII using a nonreducing SDS-polyacrylamide gradient gel (7%–20%) electrophoresis and the Tris-glycine buffer system.28 The SDS-polyacrylamide gradient gels were loaded by protein content. Apolipoproteins were identified by comparing migration distances with those of known molecular weight standards.
Determination of Deuterium Enrichment
ApoA-I protein bands were excised from the gels and
hydrolyzed in 12N HCl at 110°C for 24 hours and dried under nitrogen.
The hydrolyzates were converted to n-propyl ester,
N-heptafluorobutyramide derivatives and dried under
nitrogen, as previously described.24 After
resolubilization in ethyl acetate, the supernatant was placed in
autosampler vials. The samples were analyzed with a 5985B gas
chromatograph-mass spectrometer (Hewlett-Packard Co) using
methane as the reagent gas.
Analyses of Kinetic Data
FSR of apoA-I were calculated by dividing the rate of appearance
of deuterated leucine in apoA-I within HDL subspecies by the VLDL
apoB-100 plateau enrichment. The VLDL apoB-100 plateau enrichment was
assumed to represent the precursor pool
enrichment29 30 31 and in each individual was
calculated from a minimum of 3 time points representing the
highest isotopic enrichment of VLDL apoB-100 and a deviation from the
linear increase in enrichment observed for the earlier time
points.32 The rate of appearance of deuterated
leucine in apoA-I in LpAI and LpAI:AII particles was calculated by
linear regression, which can be used for estimating kinetic
parameters of slowly turning over proteins in primed
constant infusion studies.31 A 0.5-hour lag
period representing the mean of the data from the study
subjects on the appearance of total apoA-I was factored into the
calculations. Since subjects were in the steady state with respect to
plasma lipoprotein levels24 the FSR was assumed
to be equal to the FCR. The RT of apoA-I was calculated as the
reciprocal of the FCR. SR of the apoA-I was calculated by multiplying
the FCR by the pool size of the individual apolipoproteins and
normalizing to body weight. Apolipoprotein pool sizes were estimated by
multiplying the plasma apolipoprotein concentrations by the estimated
plasma volumes (body weightx0.045).
Analytical Methods
Cholesterol and triglyceride levels in
plasma and lipoprotein fractions were analyzed with
standardized enzymatic methods.28 Plasma was
ultracentrifuged (Beckman Instruments Inc, Palo Alto, CA) using
a Beckman 50.3-Ti rotor at 39 000 rpm for 18 hours at 4°C, at a
density of 1.006 g/mL to separate VLDL according to the method of
Havel et al.25 HDL cholesterol
concentration was measured in plasma using the dextran
sulfate/MgCl2 precipitation
method.33 LDL cholesterol was
calculated as the 1.006 g/mL infranatant cholesterol minus
the HDL cholesterol. Plasma apoA-I and apoB concentrations
were assayed with a noncompetitive, enzyme-linked immunosorbent assay
(ELISA) using immunopurified polyclonal
antibodies.34 The concentration of LpAI in the
HDL subfraction was measured using
immunoelectrophoresis35 with commercially
available kits consisting of hydrated agarose gels and monospecific
antisera to apoA-I and apoA-II (Sebia, Issyles-Moulineaux, France). The
concentration of apoA-I in LpAI was determined using standards provided
by the manufacturer. The concentration of apoA-I in LpAI:AII particles
was calculated by subtracting the LpAI concentration from the total
apoA-I plasma concentration as analyzed by ELISA. The between
and within run coefficients of variation for the lipid assays were
<5% and for the other assays were <10%.
Statistical Analyses
Statistical analyses were done with BMDP statistical
software (University of California Press, 1995). Values are expressed
as means±SD. Comparison of data between groups was performed using the
Mann-Whitney nonparametric test. Spearman correlation
coefficients were calculated to estimate correlations between
variables.
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Results |
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Plasma Lipids and Lipoproteins
Mean clinical characteristics, and plasma lipid and lipoprotein values of the participants are given in Table 1
. Plasma total cholesterol,
LDL cholesterol, and triglyceride
concentrations were similar in males and females. The mean HDL
cholesterol concentration of the males (1.14±0.23
mmol/L) was 80% of the mean HDL cholesterol concentration
of the females (1.42±0.18 mmol/L; P=.0034). The mean
plasma concentration of apoA-I (130±21 mg/dl) in the males was 87% of
the mean value in the females (150±19 mg/dl; P=.0421). The
mean apoA-I concentration in LpAI was similar in males and females
(43±11 mg/dl and 47±10 mg/dl, respectively). In the LpAI:AII
subclass, the mean apoA-I concentration tended to be lower in males
than in females (88±15 mg/dl versus 103±24 mg/dl), but the difference
did not reach statistical significance (P=.1004).
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In male subjects there was a significant relationship between
plasma concentrations of apoA-I and LpAI (r=.667;
P<.05) and LpAI:AII (r=.718; P<. 01)
levels, respectively (Fig 1). In
females subjects, plasma apoA-I concentrations were strongly correlated
with LpAI:AII (r=.852; P<.001), but not with
LpAI (r=.226; P=NS) levels.
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Kinetics of ApoA-I
The data for FCR and RT of apoA-I in LpAI and LpAI:AII are shown
in Table 2. There was no significant
difference in the FCR or RT of apo A-I in either LpAI or LpAI:AII
particles between men and women. Independent of gender, the FCR and RT
of apoA-I in LpAI and LpAI:AII are similar.
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The mean pool sizes of total plasma apoA-I, and apoA-I in LpAI and
LpAI:AII are shown in Table 3. There were
no significant differences in these parameters between
males and females. Although female subjects had a higher concentration
of plasma apoA-I than male subjects, when corrected for body weight,
this difference disappeared.
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The mean SR rate of total apoA-I in males (8.5±2.7
mg · kg-1 · d-1) was significantly
(22%) lower than in females (10.9±2.3
mg · kg-1 · d-1, P=.039;
Table 3
). Following the same trend, the mean SR of apoA-I in LpAI
particles tended to be lower in males (2.7±0.9
mg · kg-1 · d-1) compared with
females (3.3±0.9 mg · kg-1 · d-1);
as was the mean SR of apoA-I in LpAI:AII particles in males (5.9±2.2
mg · kg-1 · d-1) compared with
females (7.6±2.1 mg · kg-1 · d-1).
However, in neither case did the differences reach statistical
significance (P=.1104 and P=.0780, LpAI and
LpAI:AII, respectively). Overall, our data suggest that HDL
cholesterol and apoA-I levels in males are lower than in
females because of decreased secretion of apoA-I.
In males, there was a significant correlation between HDL cholesterol levels and the RT of apoA-I in LpAI particles (r=.664, P<.05) and with apoA-I in LpAI:AII particles (r=.609; P<.05). In females there was a significant relationship between HDL cholesterol and the RT of apoA-I in LpAI:AII (r=.627, P<.05), but not with the RT of apoA-I in LpA-I. In contrast, there was no correlation between plasma HDL cholesterol level and the SR of apoA-I into LpAI or LpAI:AII in either males or females (data not shown).
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The purpose of this study was to compare the apoA-I kinetics in postmenopausal women and older men in the two HDL subspecies, LpAI and LpAI:AII. The results of the current study demonstrate that the SR of apoA-I is higher in postmenopausal women compared with older men. In contrast, the FCR, or catabolic rate of apoA-I both within LpAI and LpAI:AII were similar among subjects. These findings suggest that the higher plasma HDL cholesterol and apo A-I levels observed in postmenopausal women compared with older men are associated with the higher SR of apoA-I and no difference in FCR.
It is well documented that apoA-I has a metabolic fate separate from apoA-II and that apoA-I, the major apolipoprotein of HDL, is generally catabolized more rapidly than apoA-II.17 18 20 22 36 37 38 It has been also established that the apoA-I FCR is a major determinant of apoA-I levels in normal subjects.17 18 19 Rader et al22 have reported the plasma RT for apoA-I in LpAI to be shorter than that in than in LpAI:AII. Ikewaki et al15 have shown that the FCR of apoA-I is an important factor determining LpAI levels and that the rate of apoA-II production is a major determinant of apoA-I distribution between LpAI and LpAI:AII. They reported that approximately 35% of apoA-I is in LpAI and the majority is in LpAI:AII. Similarly, in our male subjects, 33% of apoA-I was in LpAI and in our female subjects, 31% was in LpAI. It was our intent to also assess the kinetic behavior of apoAII, however, low apparent quantities of this apoprotein in several subjects precluded an accurate interpretation of the data. The conditions used to isolate apoAI may have resulted in a low recovery of apoAII.
In the current study, despite higher levels of HDL cholesterol and apoA-I in the postmenopausal females relative to older males, we observed similar apoA-I FCR. Previously, Shepherd et al,39 Schaefer et al,40 and Ikewaki et al15 reported similar FCR of apoA-I in young males and females. Similarly, Brinton et al19 reported similar apoA-I FCR in men and postmenopausal women.
The results of this investigation suggest that the higher levels of HDL cholesterol and apo A-I in postmenopausal females compared to males was due to higher rates of apo A-I production. The results of the present study are consistent with our previous findings, in which we reported that the higher concentrations of HDL cholesterol in young women compared with young men was due to higher apoA-I production rates.17 As with the present investigation, these kinetic studies were conducted while the subjects consumed an isocaloric diet before the start of the kinetic studies. Both Shepherd et al39 and Ikewaki et al15 reported comparable secretion rates of apoA-I in a group of young men and women as did Brinton et al in men and postmenopausal women.19 However, in the later study the mean HDL cholesterol levels of postmenopausal women were similar to those of the men (50 mg/dl and 50 mg/dl, respectively, males and females) and did not represent the gender difference in HDL cholesterol levels normally seen.
In our male subjects, plasma AI correlated with LpAI and LpAI:AII. In our female subjects, plasma AI correlated with LpAI:AII but not with LpAI. A similar pattern was seen between HDL cholesterol levels and the RT of LpAI and LpAI:AII. HDL cholesterol correlated with the RT of both apoAI containing particles in male subjects but only correlated with LpAI:AII and not with LpAI in female subjects. These differences between women and men may be related to the trend toward smaller HDL particles, and reduced HDL2/HDL3 and LpAI/LpAI:AII ratios in women after menopause, possibly due to the increase in hepatic lipase activity.10 11 Our results are consistent with earlier studies that have revealed that plasma HDL cholesterol concentration correlates with plasma apoA-I concentration,19 with plasma apoA-I RT17 and with the FCR of apoA-I.18 41
The combined data of our study suggest that higher plasma HDL cholesterol and apoA-I levels in postmenopausal women compared with men are due to higher SR of apoA-I, while the RT of apoA-I in both HDL subspecies, LpAI and LpAI:AII, are comparable in males and females. Moreover, we observed that this increase in the SR of apoA-I in women may involve the apo A-I moiety of both LpAI and LpAI:AII.
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Acknowledgments |
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Dr Tilly-Kiesi was supported by the Helsinki University Central Hospital and by a grant from the Meilahti Foundation (Helsinki, Finland). The research in the United States was supported by grant HL-39326 from the National Institute of Health and contract 53-3K06-5-10 from the US Department of Agriculture Research Service. The contents of this publication do not necessarily reflect the views or policies of the USDA, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. We are grateful to Dr Jennifer Jenner, Kari Wojtanik, and Zhiyang Sun for excellent technical assistance.
Received January 14, 1997; accepted June 17, 1997.
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