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Microsomal triglyceride transfer protein –493T variant reduces IDL plus LDL apoB production and the plasma concentration of large LDL particles

¹Atherosclerosis Research Unit, King Gustaf V Research Institute, Department of Medicine, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden ²Department of Pathological Biochemistry, University of Glasgow, Royal Infirmary, Glasgow ³Oxford Centre for Diabetes, Endocrinology and Metabolism, Nuffield Department of Clinical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom

Submitted 12 August 2005 ; accepted in final form 14 November 2005

	ABSTRACT

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The microsomal triglyceride transfer protein (MTP) is essential for the synthesis and secretion of apolipoprotein B (apoB)-containing lipoproteins. We investigated the role the MTP –493G/T gene polymorphism in determining the apoB-100 secretion pattern and LDL heterogeneity in healthy human subjects. Groups of carriers of the T and the G variants (n = 6 each) were recruited from a cohort of healthy 50-yr-old men. Kinetic studies were performed by endogenous [²H₃]leucine labeling of apoB and subsequent quantification of the stable isotope incorporation. apoB production rates, metabolic conversions, and eliminations were calculated by multicompartmental modeling (SAAM-II). LDL subfraction distribution was analyzed in the entire cohort (n = 377). Carriers of the MTP –493T allele had lower plasma LDL apoB and lower concentration of large LDL particles [LDL-I: 136 ± 57 (TT) vs. 175 ± 55 (GG) mg/l, P < 0.01]. Kinetic modeling suggested that MTP –493T homozygotes had a 60% lower direct production rate of intermediate-density lipoprotein (IDL) plus LDL compared with homozygotes for the G allele (P < 0.05). No differences were seen in production rates of large and small VLDL, nor were there any differences in metabolic conversion or elimination rates of apoB between the genotype groups. This study shows that a polymorphism in the MTP gene affects the spectrum of endogenous apoB-containing lipoprotein particles produced in humans. Reduced direct production of LDL plus IDL appears to be related to lower plasma concentrations of large LDL particles.

intermediate-density lipoprotein; low-density lipoprotein; apolipoprotein B; very-low-density lipoprotein secretion; lipidation; microsomal triglyceride transfer protein

There is evidence for a link between polymorphisms in the MTP gene and the LDL cholesterol concentration. Some recent studies have shown a link between the presence of the MTP-493T variant and low LDL cholesterol (17, 20, 21), but conflicting or negative evidence has also been observed (5, 15). One possible explanation for the discrepant results is an interaction with visceral obesity (30). It is also possible that there is an interaction with the LDL receptor gene or the hepatocyte cholesterol homeostasis, as the phenotype of the MTP polymorphism switches from modulating LDL concentrations to plasma triglyceride (VLDL) concentrations in subjects with familial hypercholesterolemia (24).

We hypothesize that a common variant in the MTP gene, with presumed effects on the activity state of the MTP protein, is an important regulator of the size spectrum of apoB-containing lipoproteins produced from the human liver and that this might determine some of the aspects of the lipoprotein heterogeneity seen in plasma. To study this we recruited genetically defined healthy carriers of the MTP –493G/T variants and performed apoB turnover studies using endogenous stable isotope labeling to define the production, conversion, and elimination rates of apoB-containing lipoproteins. In addition, we determined the genotype-phenotype relationship between the MTP gene promoter variants and LDL subclass distribution within the entire cohort from which the turnover study subjects were recruited.

	METHODS

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Subjects. A total of 377 healthy 50-year-old men living in Stockholm County, Sweden, were recruited from a randomized population-based screening program. Exclusion criteria were chronic disease of any kind, a history of coronary heart disease or arterial thromboembolic disease, and continuous treatment with antihypertensive or lipid-lowering agents. Only men of northern European descent were included.

The LDL subfraction distribution was measured in the entire cohort. Data on these subjects have recently been presented in relation to genetic variation in the lipoprotein lipase (LPL), hepatic lipase (HL), cholesteryl ester transfer protein (CETP), and apoE genes (28). A total of 12 subjects participated in the turnover studies. Four of these subjects were recruited from a previous collection of healthy men and performed according to the same principles and within the same geographic area (31). This was done to increase the total number of potential volunteers for the study (there are 6 homozygous carriers of the MTP –493T variant for every 100 people). A total of 20 homozygous carriers for the T variant were first invited; 11 were willing, and six were selected to participate. Subjects homozygous for the G variant (50 for every 100 people) were then approached to match the six T carriers. After completion of the study, the genotypes of the 12 subjects were checked by sequencing. It turned out that one subject who was first allocated an MTP –493TT genotype was actually a heterozygote. This subject was still included in the TT group. The study was approved by the Ethics Committee of the Karolinska Hospital, and all subjects gave informed consent to participation.

Genotyping. The MTP –493G/T polymorphism was genotyped by restriction isotyping as described (17). All amplifications were performed in a 25-µl reaction mix containing 100 ng of genomic DNA, 0.8 µM of each primer, 2 mM of each dNTP (Boehringer Mannheim, Mannheim, Germany), 1 U Taq polymerase (SDS Promega, Madison, WI), 50 mM KCl, 10 mM Tris·HCl, and 0.1% Triton X-100. Subjects were also genotyped for the apoE-2/3/4 polymorphism (13, 28).

Turnover protocol. Subjects arrived at the Clinical Research Unit in the morning after a 10-h fast. Blood samples were taken at times 0, 0.16, 0.33, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 24, and 36 h and daily after that for 14 days. A bolus injection of 0.7 mg/kg body wt of trideuterated [²H₃]leucine was given at time 0 followed by an infusion of 0.7 mg·kg^–1·h^–1 for 10 h. Only noncaloric drinks were allowed during the first 10 h. Then, a light snack was provided, and the subjects went home. The 15-h sample was taken at home. The subjects were asked to maintain a regular life for the following fortnight, which comprised a habitual diet without extremes, limited alcohol intake, and no more exercise than was usually taken.

Kinetic modeling. The change in tracer-to-tracee ratio with time of subfraction (Sf) 60–400 (VLDL₁), Sf 20–60 (VLDL₂), IDL, and LDL apoB together with the apoB pool size was used to derive the kinetic parameters by using the simulation analysis and modeling (SAAM) program II, version 1.1.1, for Windows (SAAM Institute, Seattle, WA). The multicompartmental model has been described before (Fig. 1) (8). It has been applied to various metabolic and hyperlipidemic conditions without modification, which indicates that it can provide solutions to normal as well as extreme metabolic situations (8, 10, 11). The same model was applicable in this study without any need for modification, despite the fact that some of the subjects studied here had lower apoB concentrations than the model had been exposed to before.

View larger version (20K): [in this window] [in a new window]   Fig. 1. Multicompartmental model for apolipoprotein B (apoB) metabolism. Plasma leucine is represented by compartment 1 in equilibrium with an intracellular compartment (compartment 2), which is the theoretical immediate source for apoB synthesis. Compartment 5 is a delay component. Direct input of apoB occurs in VLDL1 (compartment 6), VLDL2 (compartment 8), intermediate-density lipoprotein (IDL; compartment 11), and LDL (compartment 13). Compartments 6, 8, 9, 11, and 13 form a delipidation chain, and compartments 7, 10, and 12 represent theoretical "remnant populations" of particles that are cleared relatively slowly from each density interval. IDL apoB, which is largely restricted to the plasma space, is modeled as 2 intravascular compartments, one of which is delipidated to LDL (compartment 11). LDL apoB, on the other hand, is represented by a single plasma compartment. A biexponential nature of the [2H3]leucine decay curve is accounted for by extravascular exchange with the plasma compartment.

Plasma volumes were calculated using an algorithm based on age and weight as input variables (6). The pool sizes were calculated as the product of the plasma concentration and the plasma volume.

Lipid, lipoprotein, and apolipoprotein methods. Venous blood samples were drawn into precooled sterile tubes (Vacutainer; Becton-Dickinson) containing Na₂EDTA (final concentration 4 mmol/l), and plasma was recovered by low-speed centrifugation (1,750 g, 20 min, 1°C). Phenylmethylsulfonyl fluoride (10 mmol/l, dissolved in isopropanol) and aprotinin (1.4 g/l Trasylol, Bayer) were immediately added to the isolated plasma to final concentrations of 10 µmol/l and 28 µg/ml, respectively. A conventional -quantification was made to measure the concentrations of major plasma and lipid and lipoproteins (4). Fractions of VLDL₁, VLDL₂, IDL, and LDL were isolated by density gradient ultracentrifugation (18). After the removal of the VLDL₂ fraction, the tube was sliced 19 mm from the top to isolate IDL. An additional slice of 57 mm from the top was made to isolate LDL. The apoB content in each fraction in VLDL₁, VLDL₂, and IDL was determined by analytical SDS-PAGE (16). The apoB content in LDL was equated to the total protein content determined by the Lowry et al. method (22), with the addition of 1% SDS to all reagents. apoB was physically isolated by isopropanol extraction (14) for hydrolysis and subsequent analysis of isotope enrichment by gas chromatography-mass spectrometry (8).

Protein pellets were hydrolyzed to amino acids at 110°C for 24 h in 6 M HCl and evaporated to dryness. Amino acids were finally isolated by cation exchange chromatography, using Dowex AG 50W-X8 resin (H⁺ form, 50–100 mesh; Bio-Rad, Richmond, CA) and eluted in 4 M NH₄OH. Samples were analyzed for isotope enrichments as previously described (8).

LDL subfraction distribution. The plasma concentrations of LDL subfractions were determined by subjecting a sample of isolated LDL to high-resolution, nondenaturing polyacrylamide gradient (3–7.5%) gel electrophoresis (GGE). A detailed description of the GGE procedure has been published (29). This procedure provides quantification of the plasma concentrations of predefined subfractions of LDL with the following cutoffs: LDL-I (27.0–25.0 nm), LDL-II (25.0–23.5 nm), LDL-III (23.5–22.5 nm), and LDL-IV (22.5–21.0 nm).

Statistics. Statistical calculations were performed by using the statistical software package StatView (SAS, Cary, NC). Skewed variables were log₁₀-transformed before analysis. One-way analysis of variance and Scheffé’s post hoc test were used to compare differences between means. Statistical differences in kinetic parameters between the groups were calculated using the Mann-Witney U-test.

	RESULTS

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Plasma lipids and body mass index in the cohort. The average total plasma concentration of cholesterol and triglycerides was within the expected range for a healthy population (Table 1). The body mass index (BMI) was marginally lower among the subjects selected for the turnover study (Table 1 compared with data in Table 2, not statistically significantly different).

Production, conversion, and elimination of apoB-containing lipoproteins. Pool sizes and production rates of VLDL₁ and VLDL₂ were similar between the groups (Table 3). The rate constants for each individual derived from the multicompartmental modeling is shown in Table 4. Except for one subject the direct catabolism of VLDL₁ was in the same order of magnitude, and so was the transfer of material from VLDL₁ to VLDL₂ (Table 3). IDL and LDL apoB direct production was generally much lower than the direct production of VLDL. The IDL and LDL direct production tended to be lower in the MTP –493T carriers. Therefore, the production rates of IDL and LDL apoB were added to give an estimate of the direct secretion of the non-triglyceride-rich apoB-containing lipoproteins. This showed that the production rate was only one-third in the carriers of the MTP –493T variant compared with the –493G homozygotes (149 ± 78 vs. 493 ± 342 mg/day, P < 0.05). If subject 7 (genotype MTP –493GT) is excluded from the analysis, the level of statistical significance changes to P = 0.06. The lower LDL levels in carriers of the MTP –493T variant could not be explained by higher LDL catabolism because the fractional catabolic rate of LDL was very similar between the genotypic groups.

View larger version (12K): [in this window] [in a new window]   Fig. 2. Incorporation rate of [2H3]leucine into apoB, shown as tracer-to-tracee ratio (TTR), with time, is shown for IDL and LDL apoB in 2 representative subjects (subjects 2 and 12).

LDL subfractions. In the entire cohort (n = 377), the allele frequency of the less common MTP promoter variant (–493T) was 0.25. Genotype frequencies were in Hardy-Weinberg equilibrium. In general, the LDL-II subfraction contained 50% of total LDL apoB, whereas the small dense LDL (LDL-III and -IV) comprised, on average, 33% of total LDL apoB.

Mean plasma concentrations of total LDL apoB and apoB in the LDL subfractions are shown according to the MTP –493G/T genotypes in Table 5. Subjects homozygous for the uncommon MTP –493T allele had significantly decreased plasma LDL apoB concentration (740 ± 191 vs. 861 ± 185 mg/l, P < 0.05) compared with MTP –493G homozygotes. The decrease in plasma LDL apoB concentration was most pronounced in the LDL subfractions containing larger, more buoyant LDL (LDL-I and -II), with a significant reduction in the plasma concentration of LDL-I (136 ± 57 vs. 175 ± 55 mg/l, P < 0.001) in MTP –493T homozygotes compared with MTP –493G homozygotes. There was no corresponding increase in the plasma concentration of small dense LDL particles, nor was there a significant shift in the LDL peak particle size. There was no statistically significant difference in plasma triglycerides between the groups.

	DISCUSSION

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We can only speculate as to how the MTP –493T variant reduces the production of the smallest apoB-containing lipoproteins. Very little is known regarding the molecular effect of this polymorphism, but initial studies using in vitro constructs of the MTP promoter have indicated that the T variant enhances the transcriptional activity. In contrast, a recent quantification of MTP mRNA content in myocardial tissue showed that T variant carriers had significantly less of the transcript than G variant carriers (21). It could be hypothesized that the low MTP activity seen in T variant carriers does not sufficiently fill the smallest apoB-containing particles. Hence, poorly lipidated lipoproteins would then undergo intracellular degradation (1), and we postulate that the smallest lipoproteins would be the most vulnerable in this process. It could also be that a lower number of particles in the lipidation cascade favor lipidation of the few remaining particles, consequently observed as a lower number of small particles being secreted. Alternatively, the MTP –493G/T polymorphism is in linkage disequilibrium with another yet unknown genetic variant that influences MTP activity or function. We have previously reported (23) on the phenotype of this genetic variant on postprandial apoB-48 concentrations. In that study, the smallest apoB-48-containing lipoproteins increased almost 100% in homozygous carriers of the T variant compared with the G variant. We have no explanation for this apparent paradox in relation to the present results, but it is quite likely that the role of MTP differs between the VLDL production by the hepatocyte and the chylomicron production by the enterocyte.

Few previous studies have examined the role of common genetic variability on apoB production. In a study by Watts et al. (32), a cohort of 29 obese subjects who had undergone stable isotope turnover studies to determine the VLDL apoB production rate were genotyped for variants in the apoB, apoE, CETP, HL, and MTP genes. They concluded that variation in the apoB and CETP genes modulated the VLDL production. The effect of the MTP –493G/T gene variant was not statistically significant on its own, but in combination with other genetic variants, carriers of the MTP –493T variants tended to have lower VLDL apoB production rate, which is a finding in the same direction as ours. The production rates of the non-triglyceride-rich apoB-containing lipoproteins (IDL and LDL) were not estimated in that study. In addition, variation in the apoB gene has been associated with the fractional clearance of LDL, but the original study does not provide a potential mechanism (7).

Genetic factors determining the LDL subclass distribution are overwhelmed by the strong association between plasma triglycerides and the relative abundance of small dense LDL (3). Still, there is strong evidence that the LDL subclass distribution is under genetic influence, although the major genes for this regulation remain unknown (19). Variability in a range of genes coding for proteins that are known to regulate the compositional characteristics of LDL is only weakly associated with LDL heterogeneity (28). However, very little is known of how variability in genes involved in apoB secretion influences LDL heterogeneity. The MTP gene could be such a candidate, but the present results appear to show that the impact of MTP genetic variability is rather limited. Instead, the interesting link between the apoB production rate of the various subclasses of apoB-containing lipoproteins and LDL heterogeneity is on a physiological level. The consequence of reduced direct production of IDL and LDL, as observed in the MTP –493TT carriers, seems to lower the absolute abundance of large LDL. This relationship suggests that a certain proportion of the large LDL particles in plasma are nascent particles that have not been formed from VLDL precursors. From a clinical point of view the abundance of small dense LDL has been associated with atherosclerosis, but these particles are likely to be formed as a consequence of sequential lipid exchanges and lipolytic processes of the LDL triglycerides, cholesteryl esters, and phospholipids. Here, we are most likely dealing with an issue of altered direct production of nascent apoB-containing lipoproteins, which does not appear to affect the abundance of small dense LDL.

A limitation of this study is the small size of the groups taking part in the turnover study. However, it should be recognized that the "recruit-by-genotype" design is used to address a very specific issue and that the results are biologically plausible and consistent in the context of the larger cohort studied. Possibly, the heterogeneity within the study groups could have been reduced if the participants had been on strict diets or observed under stricter metabolic conditions, but such conditions are difficult to maintain over a 14-day period. The VLDL apoB kinetic data showed a high degree of heterogeneity, but this is normally seen with the use of multicompartmental modeling. In this study the participants were asked to avoid excesses in the form of alcohol intake, special meals, and particularly strenuous exercise that was not part of regular life.

In summary, this study shows that the pattern of apoB secretion from the human liver is partly genetically regulated. In particular, the direct production of the smallest apoB-containing lipoproteins (IDL and LDL) appears to be influenced by variability in the MTP gene, and this has direct consequences for the LDL subclass pattern observed in plasma.

	GRANTS

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This study was supported by the Swedish Heart-Lung Foundation. F. Karpe is a Wellcome Trust Senior Clinical Research Fellow.

	FOOTNOTES

 

Address for reprint requests and other correspondence: F. Karpe, Oxford Centre for Diabetes, Endocrinology and Metabolism, Nuffield Department of Clinical Medicine, Univ. of Oxford, Churchill Hospital, OX3 7LJ Oxford, UK (e-mail: fredrik.karpe{at}ocdem.ox.ac.uk)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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This Article Abstract Full Text (PDF) All Versions of this Article: 290/4/E739    most recent 00376.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Lundahl, B. Articles by Karpe, F. Search for Related Content PubMed PubMed Citation Articles by Lundahl, B. Articles by Karpe, F.