Journal of Clinical Endocrinology & Metabolism
, doi:10.1210/jc.2006-1998
The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 4 1474-1478
Copyright © 2007 by The Endocrine Society
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
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: john.burnett{at}health.wa.gov.au.
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Abstract
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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/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.
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Introduction
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FAMILIAL 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, 2, 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, 6, 7, 8, 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 variants have shown inconsistent results with respect to rates of apoB secretion and catabolism (10, 11, 12, 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.
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Subjects and Methods
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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 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.
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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.
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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 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.
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Results
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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).
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TABLE 1. Summary of fasting lipids and iAUC after a fat load for lipids, RP, and apoB-48 in controls and FHBL subjects
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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).
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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).
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The iAUC in FHBL subjects was decreased for large TRL-triglyceride (–61%; P < 0.005) and small TRL-cholesterol (–86%; P < 0.001) and triglyceride (–86%; P < 0.001) compared 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).
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.
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TABLE 2. Calculated fractional rate constants and delay times in RP and apoB-48 metabolism in control and FHBL subjects
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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.
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Discussion
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FHBL is a rare inherited disorder in which mutations in the APOB gene lead to decreased plasma concentrations of LDL-cholesterol, and apoB (1, 2, 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 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 apoB-48.4 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 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, 22, 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.
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Footnotes
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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.
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.
Received September 11, 2006.
Accepted January 3, 2007.
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References
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Abstract
Introduction
