0021-972X/07/$15.00/0
Printed in U.S.A.
The Journal of Clinical Endocrinology & Metabolism 92(4):1474 –1478
Copyright © 2007 by The Endocrine Society
doi: 10.1210/jc.2006-1998
Postprandial Lipoprotein Metabolism in Familial
Hypobetalipoproteinemia
Amanda J. Hooper, Ken Robertson, P. Hugh R. Barrett, Klaus G. Parhofer, Frank M. van Bockxmeer,
and John R. Burnett
Department of Core Clinical Pathology and Biochemistry (A.J.H., K.R., F.M.v.B., J.R.B.), PathWest Laboratory Medicine
WA, Royal Perth Hospital, Perth 6000, Australia; School of Medicine and Pharmacology (A.J.H., P.H.R.B., J.R.B.) and
School of Surgery and Pathology (F.M.v.B.), University of Western Australia, Crawley 6009, Australia; and Department of
Internal Medicine II (K.G.P.), Klinikum Grosshadern, Ludwig-Maximilians University, 81377 Munich, Germany
Objective: Familial hypobetalipoproteinemia (FHBL) is an autosomal codominantly inherited disorder of lipoprotein metabolism characterized by decreased plasma concentrations of low-density lipoprotein-cholesterol and apolipoprotein (apo) B. We examined the effect of
truncated apoB variants (⬍apoB-48) causing FHBL on postprandial
triglyceride-rich lipoprotein (TRL) metabolism.
Methods and Results: A standardized oral fat load was given after
a 12-h fast to six heterozygous [apoB-6.9 (n ⫽ 3), apoB-25.8 (n ⫽ 1),
apoB-40.3 (n ⫽ 2)] FHBL subjects and 10 normolipidemic controls.
Plasma was obtained every 2 h for 10 h. Large TRLs [containing
chylomicrons (CM)] and small TRLs (containing CM remnants) were
isolated by ultracentrifugation. Compared with controls, FHBL subjects had significantly decreased fasting plasma cholesterol (2.3 ⫾ 0.5
vs. 4.8 ⫾ 0.5 mmol/liter), triglyceride (0.4 ⫾ 0.3 vs. 1.5 ⫾ 0.5 mmol/
F
AMILIAL hypobetalipoproteinemia (FHBL; OMIM
107730) is a rare autosomal codominant disorder of
lipoprotein metabolism characterized by decreased plasma
concentrations of low-density lipoprotein (LDL)-cholesterol
and apolipoprotein (apo) B (⬍5th percentile for age and sex)
(1–3). Approximately 60 splicing, frameshift, and nonsense
mutations in the APOB gene causing FHBL have been reported, as well as one missense mutation, R463W (4). Most
of these mutations cause the production of a carboxy-terminal truncated apoB molecule. Only truncations larger than
30% of full-length apoB-100 are detectable in plasma; these
truncations seem to have a limited capacity for lipid transport. FHBL heterozygotes are generally asymptomatic. However, fatty liver has been reported in FHBL (5–9).
ApoB is essential for the formation of triglyceride-rich
lipoproteins (TRLs), namely very low-density lipoprotein
(VLDL) by the liver and chylomicrons (CM) by the intestine.
The very low plasma triglyceride concentrations that are
typical of FHBL may be due, at least in part, to defective
assembly and secretion of TRL. However, in vivo apoB turnover studies in heterozygous FHBL due to truncated apoB
First Published Online January 9, 2007
Abbreviations: apo, Apolipoprotein; CM, chylomicrons; FHBL, familial hypobetalipoproteinemia; iAUC, incremental area under the
curve; LDL, low-density lipoprotein; RP, retinyl palmitate; TRL, triglyceride-rich lipoprotein; VLDL, very low-density lipoprotein.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine community.
liter), low-density lipoprotein-cholesterol (0.6 ⫾ 0.4 vs. 3.0 ⫾ 0.5
mmol/liter), and apoB (0.22 ⫾ 0.05 vs. 0.95 ⫾ 0.14 g/liter) concentrations (all P ⬍ 0.001). The postprandial incremental area under the
curve in FHBL subjects was decreased for large TRL-triglyceride
(⫺61%; P ⬍ 0.005), small TRL-cholesterol (⫺86%; P ⬍ 0.001), and
small TRL-triglyceride (⫺86%; P ⬍ 0.001) relative to controls. Multicompartmental modeling analysis showed that the delay time of
apoB-48 was shorter and that apoB-48 production was decreased in
FHBL subjects compared with controls.
Conclusions: We have demonstrated that heterozygous FHBL subjects with apoB truncations shorter than apoB-48, and therefore only
a single fully-functional apoB-48 allele, have decreased TRL production but normal postprandial TRL particle clearance. (J Clin Endocrinol Metab 92: 1474 –1478, 2007)
variants have shown inconsistent results with respect to rates
of apoB secretion and catabolism (10 –13). Case studies with
apoB-48.4 and apoB-76 have shown “normal” postprandial
responses (14, 15). We therefore investigated the effect of
truncated apoB variants shorter than apoB-48 (that is, having
only one fully functional apoB-48 allele) on postprandial TRL
metabolism.
Subjects and Methods
Subjects
Postprandial studies were performed on six heterozygous [apoB-6.9
(n ⫽ 3), apoB-25.8 (n ⫽ 1), and apoB-40.3 (n ⫽ 2)] FHBL subjects (16) and
10 normolipidemic controls from a previous study (17). All subjects
(FHBL and controls) were male, except for one young woman carrying
the apoB-6.9 mutation. Approval for FHBL studies was obtained from
the Royal Perth Hospital Ethics Committee.
Oral fat tolerance test
After a 12-h fast, subjects ingested a fatty “milk shake” containing 100
ml milk (3.5% fat), 150 ml cream (30% fat), 70 ml corn oil, 90 g egg, 10 g
sugar, and 3.5 g coffee flavoring, taken together with 80,000 U vitamin
A (retinol). This fat load yields 1305 kcal (87% from fat, 7% from carbohydrates, and 6% from protein) and was consumed at 0700 h within
5 min. During the study, the subjects ate no calories, but were allowed
to drink water as required.
Venous blood samples were drawn and collected into tubes containing EDTA-Na2 before the test meal, then every 2 h for the 10-h study.
Samples were kept on ice before isolation of plasma lipoproteins and
protected from light during processing. Plasma was isolated by centrifugation (10 min, 3000 rpm). Ultracentrifugation (20,000 rpm, 30 min, 80
Ti rotor; Beckman, Fullerton, CA) was performed on 5-ml plasma samples in Quick-Seal tubes (Beckman) overlayed with d ⫽ 1.006 kg/liter
1474
Hooper et al. • Postprandial Lipoprotein Metabolism in FHBL
J Clin Endocrinol Metab, April 2007, 92(4):1474 –1478
1475
solution. The top 1 ml containing CM was removed using a Beckman
Tube Slicer and designated the “large TRL” fraction. The infranatant was
again overlaid with d ⫽ 1.006 kg/liter solution, and further ultracentrifugation (40,000 rpm, 18 h) was carried out to obtain CM remnants,
VLDL, and VLDL remnants (designated the “small TRL” fraction).
Analyses
Cholesterol and triglyceride concentrations in plasma and fractions
were measured enzymatically using Roche Diagnostics GmbH (Basel,
Switzerland) reagents on a Hitachi 917 analyzer (Hitachi, Tokyo, Japan).
ApoB was measured on a Behring BN-II Nephelometer (Behring, Marburg, Germany). Retinyl palmitate (RP) concentrations were determined
by HPLC as described, using retinyl acetate as an internal standard (17).
Plasma samples from FHBL subjects were run on precast 3– 8% Novex
NuPage Tris-acetate gels (Invitrogen, Carlsbad, CA) for 1 h at 150 V.
Western blotting was then performed using the monoclonal anti-apoB
antibody 1D1 (a gift of Dr. Ross Milne, University of Ottawa Heart
Institute, Ottawa, Ontario, Canada) that recognizes an epitope of apoB
in amino acids 401–582. ApoB-48 concentrations were determined by
densitometry and comparison to an apoB-48 standard of known concentration. ApoB-48 concentrations for control subjects were measured
as described (17), and total plasma apoB-48 was estimated by adding the
large TRL and small TRL fractions. Concentrations for all analytes in
large and small TRL fractions were corrected back to plasma
concentrations.
The incremental area under the curve (iAUC) was calculated for plasma
cholesterol, triglyceride, RP, and apoB-48, and for large- and small-TRL
cholesterol, triglyceride, and RP using SAAM II. Statistical significance of
differences in lipid and RP concentrations and kinetic parameters between
FHBL heterozygotes and control subjects were compared by unpaired t test.
A P value ⬍ 0.05 was considered significant.
Kinetic analysis of RP and apoB-48 data
Compartmental models describing the dynamics of apoB-48 and RP
were developed by use of the multicompartmental modeling program
SAAM II (Resource Facility for Population Kinetics, University of Washington, Seattle, WA). Two models were developed using apoB-48 and RP
mass concentration data, assuming that the fractional rate constants
[k(i,j)] were time invariant and first order. The adjustable parameters in
the apoB-48 and RP models were determined independently of each
other, i.e. there were no parameter constraints between the models.
The model developed to describe the plasma apoB-48 data are shown
in Fig. 1, model A. Compartment 1 represents the dosing compartment
that accounts for the increased synthesis of apoB-48 when the fat meal
is provided. Compartment 2, the delay compartment, contains five compartments in series. In the absence of experimental data, it was assumed
that the residence time of material in compartment 1 and in the delay
compartments (compartment 2) were equal. The function of this compartment was to provide a delay that corresponds to the time required
for the synthesis of CMs and appearance in plasma. From the delay
compartment, material enters the plasma, represented by compartment
3. Plasma apoB-48-containing particles are hydrolyzed and cleared from
the plasma, described by the parameter k(0, 3), the fractional catabolic
rate of plasma apoB-48. The apoB-48 compartmental model was fitted
to each individual data set. To take into account the fasting plasma
concentration of apoB-48, the initial condition (mass of material at t ⫽
0) of compartment 3 was an adjustable, non-zero parameter. Furthermore, the initial condition of the compartments within the delay was
defined as a function of the rate constants and the initial plasma apoB-48
concentration. This relationship assumes that some apoB-48 is preformed and is in the secretory pathway awaiting lipidation before secretion into the lymph and plasma. The magnitude of the dose to compartment 1 was an adjustable parameter, called Input. The program
estimate of this dose is a measure of the number of apoB-48 particles
secreted into plasma.
The model developed to describe the plasma RP data are shown in
Fig. 1, model B. Compartment 4 represents the dosing compartment that
accounts for the transport of retinol into the enterocyte for esterification
to RP. Compartment 5, the delay compartment, contains five compartments in series. It was assumed that the residence time of material in
compartment 4 and in the delay compartments (compartment 5) were
FIG. 1. Multicompartmental kinetic models used for analysis of
plasma apoB-48 and retinol metabolism, models A and B, respectively. In the apoB-48 model, compartment 1 represents the dosing
compartment; compartment 2, a delay compartment consisting of
compartments in series, included in the model to account for the time
required for synthesis and secretion of apoB-48 into plasma; compartment 3, the plasma apoB-48 compartment, from which apoB-48
samples are collected. In the retinol model, compartment 4 represents
the dosing compartment; compartment 5, a delay compartment that
accounts for the time required for the esterification of retinol into RP,
packaging into CMs, and secretion into plasma. A loss pathway from
compartment 5 was required to fit the model, suggesting that not all
of the retinol administered is converted to RP or appears in plasma.
The fraction of retinol absorbed was described by the parameter Fabs.
Compartment 6 is the plasma RP compartment from which samples
are collected. The arrows connecting compartments describe paths by
which material moves from one compartment to another.
equal. The function of this compartment is to provide a delay that
corresponds to the time required for the esterification of retinol, packaging into CMs, and appearance of CM RP in plasma. From the delay
compartment, a fraction of the material (Fabs) enters the plasma, represented by compartment 6. Alternatively, not all of the retinol or RP may
be incorporated onto CMs, as represented by the loss pathway from the
delay compartment. The time course of RP in plasma is used as a marker
of CM metabolism and clearance from plasma. The parameter k(0, 6)
represents the fractional catabolic rate of plasma RP. As for apoB-48, the
RP model was fit to each individual data set. Because RP is not generally
present in measurable concentrations in plasma, the initial conditions
(mass of material at t ⫽ 0) of compartments 5 and 6 were set to zero.
Fitting each model to the respective data provided estimates of the
adjustable parameters from which the fractional catabolic rates could be
derived. In addition, the model provided estimates for all adjustable
parameters, including delay times.
Results
Compared with controls, FHBL subjects had significantly decreased fasting plasma total cholesterol (2.3 ⫾ 0.5
vs. 4.8 ⫾ 0.5 mmol/liter), triglyceride (0.4 ⫾ 0.3 vs. 1.5 ⫾
0.5 mmol/liter), LDL-cholesterol (0.6 ⫾ 0.4 vs. 3.0 ⫾ 0.5
mmol/liter), and apoB (0.22 ⫾ 0.05 vs. 0.95 ⫾ 0.14 g/liter)
concentrations (all P ⬍ 0.001; Table 1). Plasma cholesterol
did not change over the 10-h postprandial study period in
either group; large TRL cholesterol peaked at 8 h in FHBL
subjects compared with 6 h in controls (Fig. 2). The peak
postprandial plasma and TRL-triglyceride was earlier (2
vs. 4 h) in FHBL subjects. Plasma RP concentrations peaked
early at 2 h in FHBL subjects and did not decrease considerably over the study period, whereas controls peaked
at 8 h. Plasma apoB-48 concentrations mirrored plasma
triglycerides with an earlier peak (2 vs. 4 h) in FHBL
subjects (Fig. 3).
The iAUC in FHBL subjects was decreased for large TRLtriglyceride (⫺61%; P ⬍ 0.005) and small TRL-cholesterol
(⫺86%; P ⬍ 0.001) and triglyceride (⫺86%; P ⬍ 0.001) com-
1476
J Clin Endocrinol Metab, April 2007, 92(4):1474 –1478
Hooper et al. • Postprandial Lipoprotein Metabolism in FHBL
TABLE 1. Summary of fasting lipids and iAUC after a fat load
for lipids, RP, and apoB-48 in controls and FHBL subjects
Controls
n
Age (yr)
Body mass index (kg/m2)
Total cholesterol (mmol/liter)
Triglyceride (mmol/liter)
LDL-cholesterol (mmol/liter)
HDL-cholesterol (mmol/liter)
ApoB (g/liter)
iAUC
Plasma total cholesterol
Large TRL-cholesterol
Small TRL-cholesterol
Plasma triglyceride
Large TRL-triglyceride
Small TRL-triglyceride
Plasma RP
Large TRL-RP
Small TRL-RP
Plasma apoB-48
FHBL
10
30 ⫾ 2
22 ⫾ 3
4.8 ⫾ 0.5
1.5 ⫾ 0.5
3.0 ⫾ 0.5
1.2 ⫾ 0.2
0.95 ⫾ 0.14
6
37 ⫾ 12
26 ⫾ 2
2.3 ⫾ 0.5a
0.4 ⫾ 0.3a
0.6 ⫾ 0.4a
1.4 ⫾ 0.3
0.22 ⫾ 0.05a
1.27 ⫾ 0.86
0.43 ⫾ 0.23
0.86 ⫾ 0.39
10.24 ⫾ 4.31
6.47 ⫾ 2.18
2.68 ⫾ 1.40
2.87 ⫾ 1.55
2.12 ⫾ 1.40
0.79 ⫾ 0.55
1155 ⫾ 411
0.65 ⫾ 0.55
0.29 ⫾ 0.24
0.12 ⫾ 0.27a
4.58 ⫾ 3.11b
2.52 ⫾ 1.85b
0.37 ⫾ 0.67a
4.07 ⫾ 3.06
2.55 ⫾ 1.59
0.91 ⫾ 1.09
171 ⫾ 260a
Data shown are mean ⫾ SD. HDL, High-density lipoprotein.
a
P ⬍ 0.001; b P ⬍ 0.01 compared with controls.
pared with controls (Table 1). However, neither large nor
small TRL-RP parameters were affected. Although fasting
apoB-48 concentrations were not different between FHBL
and controls, the iAUC was significantly lower in FHBL
subjects (⫺85%; P ⬍ 0.001).
FIG. 3. Plasma apoB-48 response to a fatty meal in FHBL subjects
and controls. Squares indicate FHBL subjects, whereas triangles represent controls (mean ⫾ SEM).
The calculated delay times and fractional rate constants
estimated by the model are shown in Table 2. The delay time
for RP was shorter in FHBL subjects compared with controls
(2.68 vs. 6.71 h; P ⫽ 0.001). The fraction of retinol absorbed,
Fabs, was lower in FHBL subjects compared with controls
(0.16 vs. 0.38), although this failed to reach statistical significance (P ⫽ 0.096). ApoB-48 production (represented by “Input”) was significantly decreased in FHBL subjects, accompanied by a shorter delay time compared with controls (0.90
vs. 3.01 h; P ⬍ 0.01). The fractional rate constant for apoB-48
was 52% lower in the FHBL subjects, but this was not statistically significant. Examples showing the fit of the model
to the data are shown in Fig. 4.
FIG. 2. Postprandial cholesterol, triglyceride, and RP responses in FHBL subjects and controls. Left, Plasma, large TRL, and small TRL
cholesterol response to a fatty meal in FHBL subjects and controls; middle, plasma, large TRL, and small TRL triglyceride response; right,
plasma, large TRL, and small TRL RP response. Squares indicate FHBL subjects, whereas triangles represent controls (mean ⫾ SEM).
Hooper et al. • Postprandial Lipoprotein Metabolism in FHBL
J Clin Endocrinol Metab, April 2007, 92(4):1474 –1478
1477
TABLE 2. Calculated fractional rate constants and delay times in
RP and apoB-48 metabolism in control and FHBL subjects
RP
Controls
1
2
3
4
5
6
7
8
9
10
Mean
SD
FHBL subjects
1
2
3
4
5
6
Mean
SD
P
ApoB-48
DT
(h)
Fabs
5.09
6.10
7.98
0.08
0.38
0.08
0.06
0.43
0.28
6.84
7.00
5.78
7.96
7.87
5.72
6.71
1.09
0.41
0.37
0.16
0.64
0.89
0.38
0.38
0.27
0.41
0.43
0.30
1.00
0.77
0.52
0.47
0.28
2.32
0.12
0.25
1.55 0.17
0.92 0.25
1.60 0.06
7.03 0.18
2.68 0.16
2.48 0.07
0.001 0.096
0.65
0.18
0.05
0.35
0.30
0.23
0.264
k(0,2)
(pools/h)
DT
(h)
Input
(mmol/liter)
k(0,3)
(pools/h)
2.20
4.39
0.83
3.81
4.69
1.98
1.38
2.27
4.44
4.07
3.01
1.42
406
1461
302
544
1387
422
243
1004
283
1420
747
513
0.29
1.13
0.50
0.49
1.06
0.48
0.25
0.39
0.28
1.23
0.61
0.38
1.62
0.34
1.36
0.67
0.99
0.42
0.90
0.52
0.004
161.9
92.9
94.9
10.0
39.2
8.3
67.8
60.0
0.007
0.29
0.51
0.23
0.14
0.39
0.20
0.29
0.14
0.073
DT, Delay time; Fabs, fraction of retinol absorbed; Input, input into
compartment 4 of the apoB-48 model. Data from control subject 4 and
FHBL subject 2 was unable to be modeled for RP.
Discussion
FHBL is a rare inherited disorder in which mutations in the
APOB gene lead to decreased plasma concentrations of LDLcholesterol, and apoB (1–3). Individuals heterozygous for
FHBL are usually asymptomatic but have plasma LDL-cholesterol and apoB concentrations that are about one fourth of
normal. Our experiments were designed to assess postprandial lipoprotein metabolism in heterozygous FHBL subjects
carrying apoB truncations shorter than apoB-48, and therefore only one fully functional apoB-48 allele. In these studies
retinol was used, given with an oral fat load, to endogenously
label CMs and their remnants. The results obtained using a
multicompartmental model clearly demonstrate that compared with normolipidemic controls, heterozygous FHBL
subjects have decreased TRL production but normal postprandial TRL particle clearance.
FHBL subjects had significantly lower fasting total cholesterol, LDL-cholesterol, triglyceride, and apoB concentrations compared with normolipidemic controls, consistent
with and qualitatively similar to those previously reported
(18). In addition, the postprandial iAUC in FHBL subjects
was decreased for plasma (⫺55%), large TRL (⫺61%), and
small TRL (⫺86%) triglyceride; small TRL-cholesterol (-86%);
and plasma apoB-48 (⫺85%). The low plasma apoB-48 iAUC
and peak concentrations observed in the FHBL heterozygotes were consistent with either a decreased production or
increased catabolism of apoB-48-containing lipoproteins. We
developed compartmental models to describe the apoB-48
and RP mass concentration data. Analysis of the apoB-48 and
RP data revealed that the delay time of RP and apoB-48 was
FIG. 4. Plasma RP and apoB-48 concentration curves. Data points
represent observed data (control subject 7, squares; FHBL subject 5,
diamonds). The curves are those predicted by the model. Subjects
chosen were representative of each group.
less in FHBL subjects and that apoB-48 production was significantly lower (⫺92%).
Previous in vivo studies have suggested that subjects with
truncations of apoB have normal postprandial lipoprotein
metabolism (14, 15, 19). Two single case reports with apoB48.4 and apoB-76 have shown normal postprandial responses; however, this finding is perhaps to be expected because
both subjects would have two functioning apoB-48 alleles
(14, 15). The FHBL subjects in our study were all heterozygous for truncations shorter than apoB-48 and therefore only
had one fully functional apoB-48 allele. However, in two
subjects, apoB-40 was detectable in fasting plasma samples
by Western blotting. ApoB truncations seem to have a limited
capacity for lipid export, and only those larger than apoB-30
are detectable in plasma. The shorter the apoB truncation, the
more dense and lipid-poor the lipoprotein particle (20).
A more extensive study has examined postprandial lipids
and RP in FHBL heterozygotes carrying a range of apoB
truncations ranging from apoB-31 to apoB-89 (19). However,
in contrast to our studies, no differences were observed between FHBL subjects and controls in AUC (minus baseline
values) for apoB-48 or the AUC, peak concentrations or peak
times for triglyceride, CM-RP, and CM-remnant RP. Triglyceride peak time was 5.5 h compared with 6 h in controls; the
RP peak occurred later at about 8 h in both subjects and
controls. The heterozygous FHBL subjects in our study had
a mean peak time of 3.3 h for plasma triglyceride and 6 h for
large TRL-RP (results not shown), and the iAUC for apoB-48
1478
J Clin Endocrinol Metab, April 2007, 92(4):1474 –1478
was lower in FHBL subjects compared with controls. This
could, in part, reflect differences in methods; in the age,
gender, and body mass index of subject groups; or in calculating the peak times. In agreement with previous observations (19), an effect of apoB truncation length on postprandial lipemia could not be demonstrated (results not
shown) in our study.
A potential limitation of our study relates to the small
number of subjects and interindividual variability. Postprandial response is affected by gender, APOE genotype, age, and
the time of day of testing (21–23). To assess the reproducibility of the oral fat tolerance test in FHBL subjects, a repeat
fat tolerance test was performed on one of the apoB-6.9
subjects 3 months later. Our findings (data not shown) were
consistent with the concept that the variation in postprandial
studies is due to interindividual variability rather than poor
oral fat tolerance test reproducibility (19). An additional limitation relates to the use of apoB-48 and RP concentration
data to estimate postprandial TRL kinetic parameters. Although compartment models have been used to describe RP
data previously (19), assumptions regarding the time-invariance of the rate constants have not been tested. Future studies
employing tracers to determine CM kinetics should be
performed.
In summary, we have performed postprandial studies to
investigate retinol and apoB-48 metabolism in heterozygous
FHBL subjects. Our results show that persons with heterozygous FHBL due to short truncated variants have decreased
TRL production but normal postprandial TRL particle
clearance.
Acknowledgments
Received September 11, 2006. Accepted January 3, 2007.
Address all correspondence and requests for reprints to: Dr. John R.
Burnett, Department of Core Clinical Pathology and Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital, Wellington Street,
GPO Box X2213, Perth, Western Australia 6847, Australia. E-mail:
[email protected].
This work was supported by grants from the Royal Perth Hospital
Medical Research Foundation, Raine Medical Research Foundation, National Health and Medical Research Council (Grant 403908), and National Heart Foundation of Australia (Grant G 139 1155).
A preliminary report of this work was presented at the 6th Annual
Conference on Arteriosclerosis, Thrombosis and Vascular Biology,
Washington, D.C., and printed in abstract form in Arterioscler Thromb
Vasc Biol 25:E50 (2005). P.H.R.B is a Research Fellow of the National
Health and Medical Research Council and is supported in part by National Institutes of Health/National Institute of Biomedical Engineering
and Bioengineering Grant EB-001975.
Disclosure Statement: A.J.H., K.R., P.H.R.B., F.M.v.B., J.R.B have
nothing to declare. K.G.P. consults for Merck Pharma Germany and
received lecture fees from Merck Pharma Germany, Bayer-Vital Germany, Sanofi-Aventis, Merck Sharp & Dohme, and Essex.
References
1. Hooper AJ, van Bockxmeer FM, Burnett JR 2005 Monogenic hypocholesterolaemic lipid disorders and apolipoprotein B metabolism. Crit Rev Clin Lab
Sci 42:515–545
Hooper et al. • Postprandial Lipoprotein Metabolism in FHBL
2. Schonfeld G, Lin X, Yue P 2005 Familial hypobetalipoproteinemia: genetics
and metabolism. Cell Mol Life Sci 62:1372–1378
3. Whitfield AJ, Barrett PHR, van Bockxmeer FM, Burnett JR 2004 Lipid disorders and mutations in the APOB gene. Clin Chem 50:1725–1732
4. Burnett JR, Shan J, Miskie BA, Whitfield AJ, Yuan J, Tran K, McKnight CJ,
Hegele RA, Yao Z 2003 A novel nontruncating APOB gene mutation, R463W,
causes familial hypobetalipoproteinemia. J Biol Chem 278:13442–13452
5. Whitfield AJ, Barrett PHR, Robertson K, Havlat MF, van Bockxmeer FM,
Burnett JR 2005 Liver dysfunction and steatosis in familial hypobetalipoproteinemia. Clin Chem 51:266 –269
6. Tarugi P, Lonardo A, Ballarini G, Grisendi A, Pulvirenti M, Bagni A, Calandra S 1996 Fatty liver in heterozygous hypobetalipoproteinemia caused by
a novel truncated form of apolipoprotein B. Gastroenterology 111:1125–1133
7. Ogata H, Akagi K, Baba M, Nagamatsu A, Suzuki N, Nomiyama K, Fujishima M 1997 Fatty liver in a case with heterozygous familial hypobetalipoproteinemia. Am J Gastroenterol 92:339 –342
8. Schonfeld G, Patterson BW, Yablonskiy DA, Tanoli TS, Averna M, Elias N,
Yue P, Ackerman J 2003 Fatty liver in familial hypobetalipoproteinemia:
triglyceride assembly into VLDL particles is affected by the extent of hepatic
steatosis. J Lipid Res 44:470 – 478
9. Tanoli T, Yue P, Yablonskiy D, Schonfeld G 2004 Fatty liver in familial
hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose
tissue, and insulin sensitivity. J Lipid Res 45:941–947
10. Aguilar-Salinas CA, Barrett PHR, Parhofer KG, Young SG, Tessereau D,
Bateman J, Quinn C, Schonfeld G 1995 Apoprotein B-100 production is
decreased in subjects heterozygous for truncations of apoprotein B. Arterioscler Thromb Vasc Biol 15:71– 80
11. Elias N, Patterson BW, Schonfeld G 1999 Decreased production rates of VLDL
triglycerides and apoB-100 in subjects heterozygous for familial hypobetalipoproteinemia. Arterioscler Thromb Vasc Biol 19:2714 –2721
12. Parhofer KG, Barrett PHR, Bier DM, Schonfeld G 1992 Lipoproteins containing the truncated apolipoprotein, Apo B-89, are cleared from human
plasma more rapidly than Apo B-100-containing lipoproteins in vivo. J Clin
Invest 89:1931–1937
13. Welty FK, Lichtenstein AH, Barrett PHR, Dolnikowski GG, Ordovas JM,
Schaefer EJ 1997 Decreased production and increased catabolism of apolipoprotein B-100 in apolipoprotein B-67/B-100 heterozygotes. Arterioscler
Thromb Vasc Biol 17:881– 888
14. Ruotolo G, Zanelli T, Tettamanti C, Ragogna F, Parlavecchia M, Vigano F,
Catapano AL 1998 Hypobetalipoproteinemia associated with apo B-48.4, a
truncated protein only 14 amino acids longer than apo B-48. Atherosclerosis
137:125–131
15. Takahashi K, Hikita M, Taira K, Kobayashi J, Bujo H, Saito Y 2001 Clinical
characterization of a case with familial hypobetalipoproteinemia caused by
apo B-76, a new truncation of apolipoprotein B, combined with apo E2/E2
phenotype. Intern Med 40:1015–1019
16. Whitfield AJ, Marais AD, Robertson K, Barrett PHR, Bockxmeer FM, Burnett
JR 2003 Four novel mutations in APOB causing heterozygous and homozygous
familial hypobetalipoproteinemia. Hum Mutat 22:178
17. Parhofer KG, Barrett PHR, Schwandt P 2000 Atorvastatin improves postprandial lipoprotein metabolism in normolipidemic subjects. J Clin Endocrinol
Metab 85:4224 – 4230
18. Fouchier SW, Sankatsing RR, Peter J, Castillo S, Pocovi M, Alonso R, Kastelein JJ, Defesche JC 2005 High frequency of APOB gene mutations causing
familial hypobetalipoproteinaemia in patients of Dutch and Spanish descent.
J Med Genet 42:e23
19. Averna M, Seip RL, Mankowitz K, Schonfeld G 1993 Postprandial lipemia
in subjects with hypobetalipoproteinemia and a single intestinal allele for
apoB-48. J Lipid Res 34:1957–1967
20. Young SG, Pullinger CR, Zysow BR, Hofmann-Radvani H, Linton MF,
Farese Jr RV, Terdiman JF, Snyder SM, Grundy SM, Vega GL, Malloy MJ,
Kane JP 1993 Four new mutations in the apolipoprotein B gene causing
hypobetalipoproteinemia, including two different frameshift mutations that
yield truncated apolipoprotein B proteins of identical length. J Lipid Res
34:501–507
21. Cohn JS, McNamara JR, Cohn SD, Ordovas JM, Schaefer EJ 1988 Postprandial plasma lipoprotein changes in human subjects of different ages. J Lipid Res
29:469 – 479
22. Hadjadj S, Paul JL, Meyer L, Durlach V, Verges B, Ziegler O, Drouin P,
Guerci B 1999 Delayed changes in postprandial lipid in young normolipidemic
men after a nocturnal vitamin A oral fat load test. J Nutr 129:1649 –1655
23. Weintraub MS, Eisenberg S, Breslow JL 1987 Dietary fat clearance in normal
subjects is regulated by genetic variation in apolipoprotein E. J Clin Invest
80:1571–1577
JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the
endocrine community.