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© 1997 American Heart Association, Inc.
Articles |
Dietary Fat Clearance in Normal Subjects Is Modulated by Genetic Variation at the Apolipoprotein B Gene Locus
From the Unidad de Lipidos y Arteriosclerosis, Hospital Universitario Reina Sofia, Cordoba, Spain (J.L.-M., M.A.O., C.M., S.J., J.S., A.B.-M., J.A.J.-P., F.L.-S., F.P.-J.), and the Lipid Metabolism Laboratory, USDA Human Nutrition Research Center on Aging, Tufts University, Boston (J.M.O.).
Correspondence and reprint request to Prof. Francisco Perez Jimenez, Unidad de Lipidos y Arteriosclerosis, Hospital Universitario Reina Sofia, Avda. Menendez Pidal, s/n. 14004 Cordoba, Spain.
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Abstract |
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Abstract Apolipoprotein B (apo B) plays a dominant role in cholesterol homeostasis. Several polymorphic sites within or adjacent to the gene locus for apo B have been detected. The X+ allele (XbaI restriction site present) of the XbaI restriction fragment polymorphism on the apo B gene has been found in some studies to be associated with higher serum cholesterol and/or triglyceride levels and with greater dietary response. The present study was designed to evaluate whether the apo B XbaI polymorphism was associated with the interindividual variability observed during postprandial lipemia. Fifty-one healthy young male volunteers [20 X-/X- (X-), and 31 X+/X- or X+/X+ (X+)], homozygotes for the apo E3 allele, were subjected to a vitamin A-fat load test. Subjects with the X- genotype had significantly greater retinyl palmitate (RP) and apo B-48 postprandial responses on both the large and the small TRL lipoprotein fractions compared with X+ subjects. In summary, subjects with the X-/X- genotype at the apo B locus have a greater postprandial response than X+ subjects. These differences observed in postprandial lipoprotein metabolism could explain some of the reported associations of this polymorphism to coronary heart disease risk.
Key Words: postprandial lipemia • apolipoprotein B • XbaI polymorphism • triglycerides • retinyl palmitate
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Introduction |
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Elevated fasting levels of LDL cholesterol and reduced levels of HDL cholesterol (HDL-C) are risk factors for coronary artery disease (CAD), the major cause of death and disability in most industrialized countries.1 2 Subjects in these societies, by eating regular fat-rich meals, are predominantly in a postprandial state throughout the day. In these subjects, the fed state and its effects on lipoprotein metabolism, may be more representative of their physiological status than the fasting state. Since 1979 when Zilversmit proposed the important role of triglyceride-rich lipoproteins (TRL) in the development of atherosclerosis,3 a considerable amount of knowledge on postprandial lipemia has been accumulated and some fasting dyslipidemic conditions, as well as myocardial infarction, have been associated with abnormal postprandial lipoprotein patterns.4 5 6 7 8 9 10 11 12 13 The basic mechanisms involved during alimentary lipemia are relatively well known and the effects of different nutrients on the variability of the postprandial response are under active investigation.14 15 16 17 18 19 20 21 22 23 24 25 26 Less is known, however, regarding the dramatic interindividual variability observed during the postprandial lipemia. Some evidence suggests that genetic variability at the apo E gene locus might affect cholesterol absorption and the postprandial lipemic response.27 28 29 30 31 32 Recent studies indicate that several other gene loci may also be involved in determining this variability.
Apolipoprotein (apo) B plays a dominant role in cholesterol
homeostasis. It is required for the assembly and secretion of
chylomicrons in intestine and VLDL in liver, and it also acts as the
ligand for the recognition of LDL by the LDL receptor. The apo B gene
extends over 43 Kb and resides in chromosome 2.33 34 35 36 37
Several polymorphic sites within or adjacent to the gene loci for
apo B have been detected, and numerous reports have associated some of
these polymorphisms with abnormal lipid levels and/or increased CAD
risk.38 39 40 41 42 43 44 Specifically, the X+ allele of the XbaI
restriction fragment polymorphism of the apo B gene has been found
associated with elevated serum cholesterol and/or
triglyceride (TG) levels in several adult
populations.39 40 41 45 46 This polymorphism involves the
third base of the threonine codon 2488 (ACC
ACT) and, although no
amino acid change results from the DNA change creating the XbaI
restriction site,47 this polymorphism is strongly
associated with the presence of certain Ag epitopes on the LDL
particle.48 49 Turnover studies have demonstrated that the
presence of the X+ allele is associated with a slower clearance of
LDL compared with the presence of the X- allele, suggesting that
an alteration in apo B could reduce its binding to the LDL receptor in
these subjects50 51 ; however, in a recent study this
effect was not found significant.52 The previous
hypothesis receives support from an in vitro study showing that LDL
from X-/X- subjects was degraded more rapidly by cultured human
fibroblasts than LDL from X+/X+ subjects.52 Furthermore,
Tikkanen et al53 showed that subjects bearing the X+
allele had a significantly greater LDL-C increase following a
high-fat diet than those subjects homozygous for the X- allele.
The present study was therefore designed to evaluate whether the
apo B XbaI polymorphism could explain some of the interindividual
variability observed in postprandial lipoprotein metabolism
in subjects homozygous for the apo E3 allele.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human Subjects
Sixty subjects volunteered to participate in this study. Fifty-one healthy male subjects, 20 X-/X- (X-) and 31 X-X+ or X+X+ (X+), were selected after excluding those who were not homozygotes for the apo E3 allele. They ranged in age from 18 to 49 years. None had diabetes or liver, renal, or thyroid disease. They were not taking medication or vitamins known to affect plasma lipids. Their fasting plasma lipids, lipoproteins, apolipoproteins, age, and body mass index (BMI) are shown in Table 1
. All studies
were carried out in the Research Unit of the Reina Sofia University
Hospital. The experimental protocol was approved by the Human
Investigation Review Committee of the Reina Sofia University Hospital.
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Vitamin A Fat-Loading Test
After a 12-hour fast, subjects were given a fatty meal enriched
with 60 000 U/m2 of body surface area of vitamin A. The
fatty meal consisted of 2 cups of whole milk, eggs, bread, bacon,
cream, walnuts, and butter. The amounts given were 1 g of fat and
7 mg of cholesterol per kilogram of body weight. The meal
contained 65% of calories as fat, 15% as protein, and 25% as
carbohydrates and was eaten in 20 minutes. After the meal the subjects
ate no calories for 11 hours but were allowed to drink water. Blood
samples were drawn before the meal, every hour until the sixth hour,
and every 2 hours and 30 minutes until the 11th hour.
Lipoprotein Separations
Blood was collected in tubes containing EDTA to give a final
concentration of 0.1% EDTA. Plasma was separated from red cells by
centrifugation at 1500g for 15 minutes at
4°C. The chylomicron fraction of TRL (large TRL) was isolated from 4
mL of plasma overlayered with 0.15 mol/L NaCl, 1
mmol/L EDTA (pH 7.4, d 1.006 g/mL) by a single
ultracentrifugal spin (20 000 rpm, 30 minutes, 4°C) in a 50-type
rotor (Beckman Instruments). Chylomicrons contained in the top layer
were removed by aspiration after cutting the tubes and the infranatant
was centrifuged at a density of 1.019 g/mL for 24 hours
at 45 000 rpm in the same rotor. The nonchylomicron fraction of TRL
(also referred as small TRL) was removed from the top of the tube. All
operations were done in subdued light. Large and small TRL fractions
were stored at -70°C until assayed for retinyl palmitate (RP).
Lipid Analysis
Cholesterol and triglycerides in plasma
and lipoprotein fractions were assayed by enzymatic
procedures.54 55 Apo A-I and apo B were determined by
turbidimetry.56 HDL cholesterol (HDL-C) was
measured by analyzing the supernatant obtained following precipitation
of a plasma aliquot with dextran sulphate-Mg2+, as
described by Warnick et al.57 LDL cholesterol
(LDL-C) was obtained as the difference between the HDL-C and the
cholesterol from the bottom part of the tube after
ultracentrifugation at 1.019 g/mL.
Retinyl Palmitate Assay
The retinyl palmitate (RP) content of large and small TRL
fractions was assayed using a method previously
described.58 Briefly, different volumes of the various
fractions (100 µL for chylomicrons and 100-500 µL for remnant) were
placed in 13x100-mm glass tubes. The total volume in each tube was
adjusted, as necessary, to 500 µL using normal saline. Retinyl
acetate (40 ng in 200 µL of mobile phase buffer) was added to each
tube as internal standard. Methanol (500 µL) was added, followed by
the addition of 500 µL of the mobile phase buffer for a total volume
of 1.7 mL. The mobile phase buffer was prepared fresh on a daily basis
by combining 90 mL of hexane, 15 mL of n-butyl chloride, 5
mL of acetonitrile, and 0.01 mL of acetic acid (82:13:5 by volume
with 0.01 mL of acetic acid). The tubes were thoroughly mixed after
each step. The final mixture was centrifuged at 350g
for 15 minutes (at room temperature) and the upper layer was carefully
removed by aspiration and placed into individual autosampler vials. The
autoinjector was programmed to deliver 100 µL per injection and a new
sample every 10 minutes in a custom prepacked silica column SupelcoSil
LC-SI (5 µm, 25 cmxmm intradermal) provided by Supelco, Inc.
The flow was maintained at a constant rate of 2 mL/min and the peaks
were detected at 330 nm. The peak of RP and retinyl acetate was
identified by comparing its retention time with a purified standard
(Sigma) and the RP concentration in each sample was expressed as the
ratio of the area under the RP peak to the area under the RA
peak.59 Here, too, all operations were performed in
subdued light.
Determination Of Apo B-48 and Apo B-100
Apo B-48 and apo B-100 were determined by
SDS-Polyacrylamide gel electrophoresis as described by Karpe
and Hamsten.60 In summary, samples containing isolated
lipoprotein fractions were delipidated in a methanol/diethyl
ether solvent system and the protein pellet was dissolved in 100 to 500
µL of 0.15 mol/L of sodium phosphate, 12.5% glycerol, 2%
sodium dodecyl sulfate (SDS), 5% mercaptoethanol, and 0.001%
bromophenol blue, pH 6.8, at room temperature for 30 minutes followed
by denaturation at 80°C for 10 minutes. Electrophoresis was performed
with a vertical Hoefer Mighty Small II electrophoresis
apparatus connected to an EPS 400/500 (Pharmacia) power
supply on 3 to 20% gradient polyacrylamide gels. The upper and
lower electrophoresis buffers contained 25 mmol/L Tris,
192 mmol/L glycine, and 0.2% SDS adjusted to pH 8.5. Apo
B-100 derived from LDL was used as a reference protein and for standard
curve dilutions. A dilution curve ranging from 0.10 to 2 µg of apo
B-100 was applied to four of the gel lanes. Electrophoresis was run at
60 V for the first 20 minutes and then at 100 V for 2 hours. Gels were
fixed in 12% trichloroacetic acid for at least 30 minutes and stained
in 02% Coomassie G-250-40% methanol-10% acetic acid for at least 4
hours. Destaining was done in 12% methanol-7% acetic acid with four
changes of destaining solution for 24 hours. Gels were scanned with a
videodensitometer scanner (TDI, Madrid, Spain) connected to a personal
computer for integration of the signals. Background intensity was
calculated after scanning an empty lane. The coefficient of variation
for the SDS-PAGE was 7.3% for apo B-48 and 5.1% for apo B-100.
DNA Amplification and Genotyping
DNA was extracted from 10 mL of EDTA-containing blood.
Amplification of a region of exon 26 of the apo B was done by
polymerase chain reaction (PCR) with 250 ng of genomic DNA and 0.2
µmol of each oligonucleotide primer (P1,
5'-GGAGACTATTCAGAAGCTAA-3', and P2, 5'-GAAGAGCCTGAAGACTGACT-3') in
50 µL. DNA was denatured at 95°C for 5 minutes followed by 30
cycles of denaturation at 95°C for 1 minute, annealing at 56°C for
1.5 minutes and extension at 70°C for 2 minutes. Twenty microliters
of the PCR product were digested with 10 U of restriction enzyme
XbaI (BRL) in a total volume of 35 µL. Digested DNA was separated by
electrophoresis on an 8% nondenaturing polyacrylamide gel at
150 V for 2 hours. Bands were visualized by silver staining. Samples
containing the X- allele characterized by the absence of the
polymorphic XbaI cutting site were amplified a second time to
verify the genotype.
Amplification of a region of 266-bp of the apo E gene was done by PCR with 250 ng of genomic DNA and 0.2 µmol of each oligonucleotide primer (E1, 5'-GAACAACTGACCCCGGTGGCGGAG-3', and E2, 5'-TCGCGGGCCCCGGCCTGGTACACTGCCA-3') and 10% dimethyl sulfoxide in 50 µL. DNA was denatured at 95°C for 5 minutes followed by 30 cycles of denaturation at 95°C for 1 minute, annealing at 63°C for 1.5 minutes and extension at 72°C for 2 minutes. Twenty microliters of the PCR product were digested with 10 U of restriction enzyme CfoI (BRL) in a total volume of 35 µL. Digested DNA was separated by electrophoresis on an 8% nondenaturing polyacrylamide gel at 150 V for 2 hours. Bands were visualized by silver staining.
Statistical Analysis
The following variables were calculated to characterize the
postprandial responses of plasma triglycerides, large TRL,
and small TRL to the test meal: Area under the curve (AUC) was the area
between the plasma concentration versus time curve and a baseline drawn
parallel to the horizontal axis through the 0 hour concentration. We
calculated this area with a computer program using the trapezoidal
rule. Other variables were the normalized peak concentration, which
was the average of the peak and the second highest concentration above
the baseline; and the peak time, which was the average of the time to
peak concentration and the time to the second highest concentration.
Data were tested for statistical significance between genotypes
by ANOVA and the Kruskal-Wallis test, and between genotypes and
time by ANOVA for repeated measures. BMI and age were introduced as
covariates in all analyses. When statistical significance was
found, the Tukeys post hoc comparison test was used to identify group
differences. A probability value less than .05 was considered
significant. Stepwise multiple regression analyses were carried
out using small and large TRL-triglycerides, and small and
large TRL-RP, and apo B-48 AUC as dependent variables, and age,
BMI, apo B genotypes, basal cholesterol, and
triglyceride values as independent variables. Discrete
variables were divided into classes for analysis. All data
presented in text and tables are mean±SD.
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Results |
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The baseline characteristics of the study subjects are shown in Table 1
. No significant differences for any of the variables
analyzed were detected between subjects with the X+ allele
(n=31) and those homozygous for the X- allele (n=20).
Plasma cholesterol and triglyceride responses
following the fat load test are presented in Fig 1. Significant time effects were seen for
both total cholesterol (P=.022) and
triglycerides (P<.0001), showing that the
cholesterol levels decreased during the postprandial
period, whereas the opposite effect was seen for
triglycerides. Plasma triglyceride levels
remained significantly elevated over the baseline for all time points
except the last determination (11 hours). There were no differences in
total cholesterol and triglyceride response
between X- and X+ subjects (P=.760 and P=.831,
respectively). The distribution of plasma triglyceride
within the different lipoprotein fractions examined is
presented in Fig 2.
Triglyceride levels in large TRL particles (Fig 2A)
remained significantly elevated over the baseline in X- subjects
during the entire period; however, these values were not significantly
different at the end of the experimental period in those subjects with
the X+ allele. Triglycerides in the small TRL (Fig 2B)
fraction increased over baseline during the first 6 hours of the
postprandial period for both X- and X+ subjects. No significant
genotype effects were observed by ANOVA for repeated measures
(interaction between genotype and time) for
triglyceride levels in either of the TRL fractions.
Subjects with the X- genotype appear to have elevated levels
of large TRL and small TRL triglycerides (Fig 2) and AUC
(Table 2); however, these effects did not
reach statistical significance.
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) and X+
subjects (dotted line, 
) (X+ indicates X+/X- or X+/X+
genotypes). For each group, the levels at each time point were
averaged. P1, genotype effect; P2, time effect; P3,
genotype by time interaction. MANOVA for repeated measures.
Tukeys test for normally distributed variables or Kruskal-Wallis
test for nonparametric variables.
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The distribution of plasma cholesterol within the different
TRL fractions examined is presented in Fig 3. Cholesterol in large TRL
(Fig 3A) was significantly elevated over baseline in X- and X+
subjects during the first 9 hours of the fat load. No significant
genotype effect was observed by ANOVA. Cholesterol
in the small TRL fraction (Fig 3B) increased over the baseline during
the first 6 hours of the postprandial period for both X- and X+
subjects and decreased below the baseline at the 11 hours time point.
No significant differences were noted between genotypes with
regard to postprandial response for this parameter.
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In X- subjects, the plasma LDL cholesterol (Fig 4A) levels showed a significant decrease
for time points 1-6 hours compared with baseline levels. On the other
hand, in X+ subjects, plasma LDL-C levels showed a significant decrease
only at 4 hours. There were no significant differences in postprandial
LDL-Cholesterol response as demonstrated by ANOVA for
repeated measures. In X- subjects, the plasma apo B levels (Fig 4B)
showed a significant decrease for the 3 and 4 hour time points compared
with baseline levels, whereas no significant changes in postprandial
apo B was observed in X+ subjects. There were no significant
differences in postprandial apo B response.
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HDL-Cholesterol levels (Fig 4C) decreased during the first
half of the postprandial period (1-5 hours) in X+ subjects and returned
to the baseline afterward; however, the changes did not reach
statistical significance versus the baseline. In X- subjects, HDL
levels remained unchanged except at the 11 hour time point that was
significantly elevated over the baseline (P=.0007). No
genotype effect could be demonstrated by ANOVA for repeated
measures. The postprandial apo AI changes (Fig 4D) were similar to
those observed for HDL-Cholesterol; however, a significant
genotype effect was seen (P=.047), with X- subjects
having greater apo A-I levels compared with X+ subjects.
RP and apo B-48 were used as markers for intestinal lipoprotein
production. Large and small TRL-RP responses in X- and X+
subjects are shown in Fig 5. RP levels in
large TRL and small TRL were significantly elevated over the baseline
in X- and X+ subjects during the entire period. A significant
genotype effect was also observed by ANOVA for repeated
measures, with X- subjects showing a significantly greater
postprandial response (P=.04) in the large TRL RP (Fig 5A)
and a greater (P=.023) AUC than X+ subjects (Table 2).
Furthermore, a significant genotype by time interaction was
also observed in this fraction (P=.005). The small TRL RP
response (Fig 5B) was also significantly greater in X- than X+
subjects, as suggested by a significant genotype effect
observed by ANOVA (P=.010) and a greater AUC
(P=.007) (Table 2).
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Large and small apo B-48 responses in X- and X+ subjects are shown in
Fig 6. Apo B-48 levels (as determined by
densitometric scanning) in large TRL and small TRL were significantly
elevated over the baseline in X- and X+ subjects during the entire
period. A significant genotype effect was also observed by
ANOVA for repeated measures, with X- subjects showing a significantly
greater postprandial response (P=.016) in the large apo B-48
(Fig 6A) and a greater (P=.030) AUC than X+ subjects (Table 2). The small TRL apo B-48 response (Fig 6B) was also significantly
greater in X- than X+ subjects, as suggested by a significant
genotype effect observed by ANOVA (P=.040) and a
greater AUC (P=.040) (Table 2). No significant
genotype effects were observed for apo B-100 in large or small
TRL particles (Table 2).
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Multiple regression analyses (Table 3) revealed that the XbaI
polymorphism at the apo B gene was the only significant
(P=.03) predictor of the variability on large TRL-RP
postprandial response (AUC) in our study population, accounting for
10.1% of the variance, whereas the apo B genotype
(P=.01) and baseline plasma cholesterol
(P=.02) were both significant predictors of small TRL-RP
postprandial response, accounting for 14.1 and 10% of the variance,
respectively. When large TRL apo B-48 was used as a dependent
variable using the same variables in the model as for TRL-RP,
only the apo B genotype entered the model as a predictor
(P=.008) accounting for 20.1% of the variance. When small
TRL apo B-48 was introduced in the model as a dependent variable,
the XbaI genotype, age, and BMI were significant predictors,
accounting for 36.4% of the variance (Table 3). The XbaI
polymorphism did not enter the model when large or small TRL-TG
were used as dependent variables.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Interindividual variability in postprandial lipid transport after a standard meal exceeds that observed in the fasting state61 62 and is influenced by numerous environmental and genetic factors affecting the synthesis and catabolism of TRL originating from the liver and intestine. Thus increased postprandial lipemia has been shown in apo A-I Milano carriers,63 and the common variants within the apo E gene locus have also been shown to affect the absorption or clearance of dietary fats,27 28 29 64 with E2 individuals having delayed clearance and E4 individuals having faster clearance as shown by retinyl palmitate concentrations in plasma and the nonchylomicron fraction.32 In order to remove the confounder effect of the variability associated with the apo E gene locus, this study was carried out in subjects homozygous for the apo E3 allele. Using RP and apo B-48 levels to follow clearance of intestinally derived lipoprotein particles, our results show that subjects with the X- genotype at the apo B gene locus have a greater postprandial response to a fat meal than do X+ subjects.
The X+ allele of the XbaI polymorphism has been found associated with increased serum levels of cholesterol and triglycerides by others.39 40 41 45 46 These results could not be confirmed in ours or in other studies,65 possibly due to our reduced sample size or the population studied, young healthy normolipemic males. In agreement with our results, previous studies have shown that in young normolipemic subjects no significant difference was observed between the degradation rate of LDL derived from X- versus X+ subjects.52
Subjects with the X- genotype showed a significantly greater postprandial response in the intestinally derived TRL particles, suggested by the increase in small and large TRL-RP response. Retinyl esters (predominantly RP) are incorporated into the core of chylomicrons in the intestine following the absorption and esterification of vitamin A.66 In the circulation they remain associated with chylomicrons during triglyceride lipolysis and are taken up by the liver within chylomicron remnants.67 Retinyl esters are either stored in the liver or resecreted as unesterified retinol bound to retinol-binding protein.68 The normal liver does not resecrete esterified retinol.69 Since their exchange with other lipoproteins in the circulation is small during the first 8 hours after consumption of a fat load,70 71 retinyl esters have been used as markers for intestinal lipoproteins, thus providing a means for measuring parameters of chylomicrons and chylomicron-remnant metabolism.71 72 73 74 75 In this study we verified the results obtained using retinyl palmitate by determining apo B-48 levels60 in both large and small triglyceride particles. Both markers provided similar results with regard to the XbaI associations with differential postprandial response.
Many factors control the concentration of triglyceride in the circulation. Chylomicron secretion by the intestine, VLDL secretion by the liver, conversion of TRL to triglyceride-depleted lipoproteins, and tissue uptake of triglyceride-depleted lipoproteins are all processes that could be responsible for fluctuations in postprandial triglyceride and lipoprotein concentrations. The greater increases in X- than in X+ subjects in plasma RP concentration in large and small TRL suggest intestinal secretion of TRL as the most plausible mechanism. Since chylomicron catabolism is a relatively fast and efficient process,76 it is unlikely that these phenomena could be due to fluctuations in chylomicron clearance. Several mechanisms can be proposed to explain why TRL secretion by the intestine might not be constant after fat ingestion. Variation in gastric emptying, gastrointestinal motility, or the rate of fat digestion in the intestine,77 potentially could cause postprandial peaks in plasma triglyceride. Postprandial triglyceride peaks could also result from differences in the abilities of the proximal and distal intestine to transport absorbed fat or fluctuations in the availability of phospholipids78 and/or newly synthesized chylomicron apolipoproteins in the enterocyte.79 Alternatively, it has been reported that X+ polymorphism is associated with less efficient binding of LDL to its receptor,50 51 which may result in less efficient down-regulation of the LDL receptor. Consequently, X+ subjects could express more LDL receptor, leading to greater elimination of triglyceride-rich lipoproteins via this receptor and thus to the differences observed with respect to X- carriers.
The DNA change that results in the absence of the XbaI restriction site
in the apo B gene occurs at the third base of triplet coding for
threonine at amino acid 2488. No amino acid changes result from this
base change in apo B-100.47 This polymorphism is in
strong linkage disequilibrium with the apo B Val591Ala
polymorphism (Ag a1/d), however, which may be the functional
sequence change.80 Another tentative hypothesis relates to
the fact that this mutation is close to the editing site at position
2153. In humans, Apo B-48 is synthesized only in the
intestine81 and is the product of an intestinal mRNA
identical in structure to apo B-100 mRNA except for a single C to U
base substitution, the first base of the codon CAA for Gln-2153,
changing it to UAA, a stop codon.82 83 The mechanism
behind the C to U conversion or editing could involve a form of
cytidine deaminase,84 although other possibilities have
not been ruled out. The mooring sequence model for the editosome
suggests that the recognition and binding sequences of nuclear factors
that both identify the specific site for editing and "moor" the
editing activity are distal to and different from the sequences in the
immediate vicinity of the editing site.84 85 86 The mooring
sequences might be a specific primary sequence or a unique secondary
structure of apo B mRNA. It is possible that the XbaI mutation, close
to the editing site, could affect these "mooring sequences" and
modify the editing activity of apo B mRNA that results in changes of
apo B-48 and intestinal TRL secretion observed in this study.
Alternatively, the XbaI polymorphism may be functionally silent and
may be in linkage disequilibrium with a functionally important sequence
change in the coding or the regulating regions of the apo B
gene.80 Both kinetic and in vitro studies favor the latter
hypothesis.
Previous studies have shown that the X- allele was found significantly more frequently among patients with CAD and with peripheral arterial disease than among healthy control subjects.87 88 89 Nevertheless, in some studies, the X- subjects have lower LDL-C and apo B levels than the X+ subjects, although this effect may be dependent on age and sex.90 It is possible that the higher postprandial response observed in this study in subjects with the X- genotype compared with subjects with the X+ genotype could be involved in the higher risk of CAD previously reported in X- subjects. At least five lines of evidence implicate postprandial lipoprotein metabolism in the genesis of CAD. First, receptor-mediated uptake of TRL remnant particles by monocyte-derived macrophages promotes the formation of lipid-laden foam cells in the vessel wall.91 Second, chylomicron and VLDL remnants make a substantial contribution to the lipid content of the vessel wall in cholesterol-fed rabbits.92 Third, the level of HDL-C, an established risk factor for CAD, is dependent on both the metabolism of TRL particles and the extent of postprandial lipemia.93 Fourth, patients with familial dysbetalipoproteinemia are at high risk of CAD and show a build up of TRL remnants of both intestinal and hepatic origin.94 Fifth, cross-sectional case-control studies have found that increased postprandial triglycerides and RP concentrations are associated with angiographically verified CAD and carotid artery wall thickness.5 6
In conclusion, subjects with the X- genotype of the XbaI polymorphism of apo B have a higher postprandial response than do X+ subjects. These differences observed in postprandial lipoprotein metabolism could be involved in the higher risk of coronary heart disease observed in these subjects.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grants from the Consejeria de Agricultura y Pesca, Consejeria de Educacion y Ciencia, Junta de Andalucia, and the Spanish Ministry of Health (FIS 95/1144) and HL54776 (to J.M.O.) from the National Institutes of Health.
Received January 9, 1996; accepted January 20, 1997.
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