© 1995 American Heart Association, Inc.
Articles |
Apoprotein B-100 Production Is Decreased in Subjects Heterozygous for Truncations of Apoprotein B
From the Division of Atherosclerosis, Nutrition and Lipid Research (C.A.A.-S., K.G.P., D.T., J.B., C.Q., G.S.), Washington University School of Medicine, St Louis, Mo; the Resource Facility for Kinetic Analysis (H.R.B.), University of Washington, Seattle; and The Gladstone Foundation Laboratories for Cardiovascular Disease (S.G.Y.), University of California, San Francisco.
Correspondence to Gustav Schonfeld, MD, Washington University School of Medicine, 660 S Euclid, Box 8046, St Louis, MO 63110.
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Abstract |
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Abstract Among individuals who are heterozygous for familial hypobetalipoproteinemia (FHBL) and who have various truncations of apoprotein (apo) B (ie, FHBL with apoB truncation/apoB-100 genotypes), the plasma concentrations of apoB-100 are typically
30% rather than
the expected 50% of those in unaffected family members. The
metabolic basis for the low apoB-100 levels is unknown. Therefore, we
compared the metabolism of apoB-100 in 8 subjects with heterozygous
FHBL (2 apoB-89/apoB-100, 2 apoB-75/apoB-100, 2 apoB-54.8/apoB-100, 1
apoB-52/apoB-100, and 1 apoB-31/apoB-100) with the metabolism of
apoB-100 in 8 apoB-100/apoB-100 control subjects who were paired with
the heterozygotes by gender, age, height, weight, and race. Endogenous
labeling of apoB-100 with [13C]leucine and a
multicompartmental kinetic model were used to obtain kinetic
parameters. FHBL heterozygotes had significantly reduced VLDL apoB-100
production rates (7.7±3.7 versus 21.2±6.2
mg · kg-1 · d-1,
P=.002) and LDL apoB-100 production rates (4.5±3.12 versus
15.3±1 mg · kg-1 · d-1,
P=.05) compared with control subjects. Fractional conversion
rates of VLDL to LDL were not significantly different (0.67±0.36
versus 0.77±0.17 pools/d), and the respective fractional catabolic
rates of apoB-100 in VLDL, IDL, and LDL also were similar in both
groups. Thus, FHBL heterozygotes produced apoB-100 at about 30% of the
rates of control subjects. We believe these reduced production rates
largely account for the lower than expected levels of apoB-100 and LDL
cholesterol in the plasma of FHBL heterozygotes.
Key Words: hypobetalipoproteinemia • truncation mutations • apolipoprotein B • kinetics
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Introduction |
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Familial hypobetalipoproteinemia (FHBL) is an autosomal codominant disease characterized by decreased plasma levels of total and LDL cholesterol (LDL-C) and apoprotein (apo) B. Heterozygous FHBL subjects are usually asymptomatic, whereas some FHBL homozygotes have intestinal fat malabsorption and complications related to fat-soluble vitamin deficiency. An unknown but small proportion of FHBL cases are associated with truncated forms of apoB-100.1 To date, more than 25 different truncations have been identified.2
Because heterozygotes for FHBL have one normal apoB-100 allele, one might expect them to have half-normal plasma levels of apoB-100 and LDL-C, but this is not usually the case. Instead, the typical plasma concentrations of apoB-100 (and LDL-C) are only 25% to 30% of normal. The objective of this study was to examine the metabolic basis for these less than half-normal levels of apoB-100 in FHBL heterozygotes. For this purpose, the metabolism of VLDL, IDL, and LDL apoB-100 was studied in eight subjects heterozygous for five different apoB truncations (B89, B75, B54.8, B52, and B31) and eight matched control subjects using endogenous labeling of apoB-100 with [13C]leucine. Metabolic parameters for apoB-100 were estimated by multicompartmental modeling. Our data suggest that a reduced apoB-100 production rate (PR) is the mechanism responsible for the lower than expected apoB-100 levels.
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Methods |
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Subjects
Eight healthy heterozygotes for five different truncated forms of apoB and eight healthy apoB homozygotes participated in the study (Table 1
). The clinical characteristics of five of the
heterozygotes have been reported.1 4 5 The detection and
characterization of the truncated forms of apoB-100 were performed as
described.6 The control apoB-100/apoB-100 homozygote
subjects were normolipidemic, non–blood-related members of families
studied in the Lipid Research Clinic of Washington University School of
Medicine, St Louis, Mo. Control subjects were matched to FHBL subjects
by age, sex, race, weight, and height. All subjects were healthy and
taking no medications.
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Study Protocol
The study protocol was approved by the Human Studies Committee
of Washington University School of Medicine, and all patients gave
written consent. Physical examinations, blood counts, clinical
chemistries, and lipid profiles (Table 2) were done at
the time of enrollment. Subjects were instructed to consume a typical
American diet (caloric distribution: 40% to 50% carbohydrates, 30%
to 40% fat, 15% to 20% protein) during the 5 days before and 5 days
after the primed, constant 8-hour [13C]leucine
infusion. Adherence to the diet was confirmed by using dietary records
from 3 different days. For the [13C]leucine infusion,
patients were admitted to the General Clinical Research Center at
Washington University after fasting for 12 hours. A bolus of
[13C]leucine (0.85 mg/kg) was administered through an
intravenous catheter in one arm followed by 0.85
mg · kg-1 · h-1 as a constant
infusion for 8 hours. During the study, a total of 37 samples were
drawn through a second intravenous catheter in the other arm. All
samples were used for determination of plasma leucine enrichment, and
28 of the samples were used for determination of VLDL, IDL, and LDL
apoB leucine enrichment. After the infusion of
[13C]leucine was stopped, the patients remained fasting
for another 8 hours and then resumed their usual diets. Daily blood
samples were drawn for another 4 days for determination of apoB
enrichment.4 ApoB and lipid concentrations were measured
in five samples during each kinetic study to evaluate the presence of a
steady state, at 1, 4, 8, 12, and 16 hours.
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Analytical Methods
Isolation of Lipoproteins
Blood was collected in EDTA-containing tubes, and plasma was
separated by low-speed centrifugation. VLDL (d<1.006 g/mL),
IDL (d=1.006 to 1.019 g/mL), and LDL (d=1.019 to
1.063 g/mL) were isolated from 4 mL plasma by sequential
ultracentrifugation7 and dialyzed against ammonium
bicarbonate (5 mmol/L) for 24 hours.
Measurements of Lipids and ApoB
ApoB concentrations were measured in VLDL, IDL, and LDL
fractions by radioimmunoassay8 or enzyme-linked
immunosorbent assay, and concentrations were confirmed by protein
assays9 as described.4 Cholesterol and
triglycerides were measured by commercially available tests (WAKO Pure
Chemical Industries, Ltd). Separation of the truncated form of apoB
from apoB-100 was achieved using 3% to 6% gradient sodium dodecyl
sulfate (SDS)–polyacrylamide gels stained with Coomassie
blue.10 The protein bands corresponding to apoB-100 and
the truncated form of apoB were scanned by laser densitometry. Pool
sizes of the truncated forms of apoB and apoB-100 were estimated by
scanning five samples from different time points in each lipoprotein
subfraction and averaging the ratios. VLDL, IDL, and LDL apoB-100 pool
sizes were determined by multiplying the measured apoB concentrations
by the proportion of total apoB represented by apoB-100 and
by plasma volume (body weight multiplied by 0.045).
Isolation of ApoB and Plasma Amino Acids
In the control subjects, apoB-100 was isolated from each
lipoprotein fraction by precipitation with
butanol-isopropylether.19 The precipitated apoB was
dried under nitrogen and hydrolyzed in 6N HCl for 16 hours at 110°C.
The HCl was subsequently evaporated. Plasma amino acids were isolated
from 0.3 mL plasma by cation exchange chromatography.11 In
the heterozygotes, apoB-100 was isolated by SDS-polyacrylamide gel (3%
to 6%) electrophoresis . Aliquots corresponding to 100 to 150 ng total
protein were applied per lane. Coomassie blue–stained apoB-100 bands
were excised and hydrolyzed in 6N HCl for 16 hours at 110°C.
Separations of VLDL apoB-100 by precipitation and by electrophoresis
were compared in a separate study in one control subject. Virtually
identical tracer/tracee ratios were obtained at the various time points
using either the apoB-100 isolated by butanol-isopropylether or the
apoB-100 obtained from SDS-polyacrylamide gel (Pearson correlation,
r=.988, P<.001), and the calculated kinetic
parameters were nearly identical (VLDL apoB-100 fractional catabolic
rate [FCR], 0.36 versus 0.34 pools/h; VLDL apoB-100 PR, 23.4 versus
24.7 mg · kg-1 · d-1). These
differences are very small compared with the much larger differences of
VLDL apoB-100 PR seen between FHBL heterozygotes and control subjects
(Table 3).
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Determination of Enrichment and Calculation of Tracer/Tracee Ratio
Amino acids obtained from the hydrolyzed apoB-100 gel bands were
isolated by cation exchange chromatography.11 Plasma amino
acids and amino acids from apoB-100 were derivatized to
N-acetyl-N-propanol esters. Leucine enrichment
was determined by GC-MS using 1.5-mx2.0-mm glass columns (Supelco)
packed with coated material (Amino Acid Packing, Alltech Assoc) and a
Finnigan 3300 quadropule mass spectrometer.12 Isotope
enrichment and tracer/tracee ratio (as percents) were calculated from
the observed ion current ratios m/z 217/216.13 Ratios
varied between peaks of 6 to nadirs of 0.1 at 84 hours for VLDL
apoB. These values are readily detectable on our mass spectrometers.
Because of the nonnegligible mass associated with stable isotope
tracers it is necessary to transform enrichment data to tracer/tracee
ratios. Data in this format are analogous to specific activity in
radiotracer experiments.13
Model of ApoB Metabolism and Calculation of Kinetic Parameters
A simple multicompartmental model (Fig 1) was
used to describe VLDL, IDL, and LDL apoB leucine tracer/tracee ratios.
In multicompartmental modeling, each compartment or pool
represents a group of kinetically homogenous particles. The
CONSAM/SAAM14 programs were used to fit the
model to the observed tracer data. This model is derived from published
models15 16 17 18 and has been shown to describe apoB metabolism
in four normolipidemic control subjects19 who had total
plasma cholesterol levels between the 5th and 50th percentile of age-,
sex-, and race-matched control subjects. The model consists of a
precursor compartment (compartment 1) and an intracellular delay
compartment accounting for the synthesis of apoB and the assembly of
lipoproteins (compartment 2). Compartments 11 and 12 are used to
account for the kinetics of the VLDL apoB fraction and
represent a minimal delipidation chain required to fit the VLDL
tracer data. Compartment 11 represents a pool of VLDL particles
with a rapid turnover, and compartment 12 represents those VLDL
particles that turn over more slowly. IDL apoB (compartment 21) can be
derived from either of the two VLDL compartments. LDL apoB (compartment
31) is derived from the IDL fraction (compartment 21) or directly from
VLDL compartment 11 through a shunt pathway. It is assumed that plasma
leucine (compartment 1) is the source of the leucine that is
incorporated into apoB. Plasma leucine tracer/tracee ratios were
described by a tri-exponential function (described in detail in
Reference 19) that was used as a forcing function20 in the
model. It is further assumed that all apoB enters the plasma via
compartment 11. Thus, transport rates through compartment 11 correspond
to total apoB production. After fitting the model to the observed data,
FCRs and conversion rates were determined for apoB-100. The FCR of VLDL
apoB is the weighted average (related to mass distribution) of the FCRs
of pools 11 and 12. The FCR of each VLDL pool is the sum of individual
rate constants (for compartment 11, the rate constants relate to the
following metabolic pathways: 11
12, 1121, 1131, and
11out; for compartment 12, rate constants relate to 1221
and 12out). The FCR of IDL apoB corresponds to the sum of
individual rate constants of compartment 21 (21out and
2131). The FCR of LDL apoB corresponds to the rate of irreversible
loss from compartment 31 (31out). In this article, the terms
transport rate and PR are used synonymously, as are FCR and turnover
rate. The term rate constant refers to the fractional turnover rate of
a pool related to a specific pathway (eg, the fraction of compartment
11 that is converted to compartment 12 per day).
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ApoE Genotyping
ApoE genotypes were determined by gene amplification and
restriction endonuclease cleavage with HhaI as described by
Hixson and Vernier.21
Statistical Analysis
Results are presented as mean±SD. Paired t tests
were used to compare results obtained in control subjects and
hypobetalipoproteinemic heterozygotes. The Pearson correlation
coefficient was used to analyze the goodness of the pairing process.
All statistical analyses were calculated using INSTAT 2
(GraphPad Software).
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Results |
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The control subjects and FHBL heterozygotes were closely matched for age, sex, weight, height, and race (Table 1
). ApoE genotypes were
identical in six of eight subjects. By definition, significant
differences were found between control subjects and FHBL heterozygotes
in mean total plasma cholesterol and triglycerides, LDL-C, plasma apoB,
VLDL apoB, and LDL apoB (P<.001 for all parameters except
plasma triglycerides [P<.05]). The apoB and LDL-C
levels in FHBL heterozygotes were 0.25 gm/L and 1.1 mmol/L,
representing only 27% to 37% of the levels of control
subjects. This percent reduction in the apoB and LDL-C levels is
comparable to the percent reduction observed between affected and
nonaffected members of these FHBL families.1 6 22 23 The
mean HDL cholesterol levels in the heterozygotes and control subjects
were similar.
During the kinetic studies, apoB concentrations in all subjects
remained constant, indicating that each subject remained in a steady
state during the course of the study (coefficients of variation for the
five samples analyzed during infusion were <10%). Plasma
[13C]leucine tracer/tracee ratios curves are shown in
Figs 2 through 9
for each of the heterozygote/control pairs of individuals in the same
sequence as they are arranged in Table 1, ie, from apoB-89/apoB-100
through apoB-31/apoB-100 heterozygotes and matched control subjects.
The A panels show curves for leucine; the B panels, curves for VLDL
apoB-100; the C panels, curves for IDL apoB-100; and the D panels,
curves for LDL apoB-100. There were sufficient data for modeling all
lipoprotein parameters with the exceptions of LDL FCRs for subjects 5
and 9. As the figures show, there was good agreement between the
model-derived fits and the observed tracer data.
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---) and matched control
subjects (—
—). For heterozygote/control pairs, panels A, B, C,
and D show tracer/tracee ratios for leucine, VLDL, IDL, and LDL,
respectively. Figs 2
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VLDL apoB-100 production was significantly lower in the eight FHBL
heterozygotes than in the control subjects (Table 3) (21.2±6.2 versus
7.7±3.2 mg · kg-1 · d-1,
P<.001). Significant decreases in IDL (9.8±4.6 versus
3.2±3.1 mg · kg-1 · d-1,
P<.05) and LDL (15.3±4.5 versus 4.5±3.4
mg · kg-1 · d-1,
P<.01) PRs were also found. The fractional conversion of
VLDL apoB-100 to LDL apoB-100 was similar in FHBL heterozygotes and
control subjects (0.77±0.17 versus 0. 67±0.36), as were the mean FCRs
of VLDL, IDL, and LDL apoB-100. However, the FCR of VLDL apoB-100 in
one apoB-54.8/apoB-100 heterozygote and in one apoB-52/apoB-100
heterozygote was higher than in the respective control subjects. Also,
one apoB-75/apoB-100 heterozygote and one apoB-52/apoB-100 heterozygote
had higher LDL apoB-100 FCRs compared with their respective control
subjects.
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Discussion |
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FHBL heterozygotes with apoB-100 truncations do not have the one-half normal apoB-100 plasma levels that would be expected from the presence of one normal apoB-100 allele.22 23 24 25 26 27 Rather, their apoB-100 levels are
30% of normal. This suggests that the
metabolism of apoB-100 may be affected by the presence of the mutant
apoB allele. To test this hypothesis, we performed kinetic studies
using endogenous labeling of apoB-100 in eight FHBL heterozygotes with
various apoB truncations and eight matched apoB-100/apoB-100 control
subjects. A multicompartmental model was used for the analysis of
the tracer data. The FHBL heterozygotes and control subjects were
matched by age, sex, weight, height, race, and apoE genotype, thereby
minimizing the effects of those variables and allowing us to compare
the kinetic parameters with confidence. Further confidence was imparted
by the fact that the kinetic parameters in the control subjects were
comparable to those reported by Parhofer et al19 The
technique of endogenous labeling combined with multicompartmental
modeling is very useful for studies of apoB kinetics. It uses
nonradioactive tracers, apoB in all density fractions can be studied
and modeled, and the kinetics of both apoB-100 and apoB truncations can
be examined simultaneously in the same subject.19 The best
fit of the data was obtained using the model in Fig 1, which assumes
that all apoB enters plasma as VLDL particles. Although it has been
suggested that IDL- and LDL-sized particles may be secreted into
plasma, this hypothesis was not required nor was it supported by the
tracer data.
Lower levels of apoB-100–containing particles in plasma could be due
either to decreased apoB-100 PRs or to increased rates of clearance of
these lipoproteins from the plasma. We favor lower PRs, as lower VLDL,
IDL, and LDL apoB-100 PRs were observed in heterozygotes than in their
respective control subjects. The mean VLDL, IDL, and LDL apoB-100 PRs
in the FHBL heterozygotes were 36%, 33%, and 29% of the respective
control values. These values are similar to the percentages in control
subjects for plasma LDL-C and apoB levels (Table 1).
Fractional conversions of VLDL apoB-100 to LDL apoB-100 and FCRs did
not consistently or significantly differ between subject-control pairs
(Table 3), suggesting that these could not account for the low apoB-100
levels of heterozygotes as a group. However, differences were observed
between individual subject-control pairs in VLDLLDL conversion that
could be due to differences in removal from plasma of the LDL
precursors, VLDL and/or IDL, before they reached LDL. This would be the
case if, in FHLB subjects compared with control subjects, the content
of apoE or apoC-III per VLDL particle differed, the conformation of
apoB-100 were altered, or the expression of LDL receptors were
disparate. VLDL conversion to LDL also could differ between FHLB and
control subjects if VLDLs differed as substrates for lipolysis. We
cannot distinguish between these possibilities on the basis of the
present experiments, but differences in VLDLLDL conversion could
have contributed to low apoB-100 levels in a few of our subjects.
Our data significantly extend those previously reported because we used more subjects with well defined truncations, matched FHLB and control subjects, and separated apoB-100 from truncated apoBs for analysis.19 Previous studies include one patient with FHBL and retinitis pigmentosa whose low cholesterol levels Converse et al29 attributed to a half-normal LDL PR and another FHBL subject from another kindred who had a normal LDL PR. Sigurdsson et al30 reported VLDL apoB production to be low in two subjects with FHBL. It is not clear whether any apoB truncation was present in these subjects. A decreased VLDL apoB PR was also reported in one compound apoB-37/apoB-86 heterozygote31 and an increased catabolic rate and low PR were noted in one apoB-50 homozygote.32 These studies used historical control subjects, exogenous labels, and in References 29 and 30, lipoprotein fractions that were analyzed without differentiating between the metabolisms of apoB-100 and any truncated forms of apoB.
The cellular mechanisms underlying the decreased VLDL apoB-100
production in the hypobetalipoproteinemic heterozygotes are unclear. In
part this is because VLDL apoB-100 production has not been completely
elucidated even for normal subjects.33 In studies of
cultured hepatoma cells or hepatocytes secreting apoB-100 as the only
form of apoB,34 35 36 37 38 39 40 apoB-100 appears to be under
posttranscriptional control. The amount ultimately secreted from the
cell is determined not by the amount synthesized but by the
partitioning of newly synthesized apoB-100 between degradation in the
endoplasmic reticulum and progression through the cell to ultimate
secretion. The availability of fatty acids and/or cholesterol in the
endoplasmic reticulum seems to favor secretion over degradation. In
apoB-100/apoB-truncation heterozygotes, the secretion of decreased
numbers of apoB-100 particles could be due to alterations at one or
more sites of regulation, eg, changes in apoB-100 mRNA levels or mRNA
translation rates or to events beyond translation, such as
translocation into the RER, degradation in the endoplasmic reticulum,
lipid assembly with apoB-100, or rates of progression of apoB-100
through the rough endoplasmic
reticulumGolgisecretory vesicle pathway to
secretion. It is also possible the reuptake rates in the space of Disse
of apoB-100–containing nascent VLDL particles is affected by the
presence of truncated forms of apoB. There is no information available
at this time to distinguish between these various possibilities.
In summary, decreased VLDL apoB-100 PR seems to be the primary mechanism responsible for the lower than expected apoB plasma levels found in heterozygotes for FHBL. Studies in genetically modified cultured hepatocytes40 and transgenic mice41 are needed to provide further insights into the cellular and molecular events that lead to decreased apoB-100 production in FHBL heterozygotes.
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Acknowledgments |
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This work is partially supported by a General Clinical Research Center (GCRC) grant (US Public Health Service) MO1 RR00036, National Institutes of Health (NIH) National Center for Research Resources (NCRR) grant RR02176, and NIH grants HL 42460 and HL 41633. Dr Aguilar-Salinas is supported by a fellowship from the Programa Universitario de Investigacion en Salud of the Universidad Nacional Autonoma de Mexico. The authors thank Tish Kettler and the personnel of the Core Laboratory of the Lipid Research Center for their expert technical assistance and the personnel of the Lipid Research Clinic and the GCRC of Washington University for their expert help. We express our gratitude to Cheryl Doyon for typing the manuscript.
Received April 5, 1994; accepted October 5, 1994.
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