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Original Studies |
University Department of Medicine and Western Australia Heart Research Institute (F.M.R., G.F.W.), University of Western Australia, and the Department of Radiology (J.H.), Royal Perth Hospital, Perth, Western Australia 6001; the Faculty of Science (G.R.S.), University of Western Australia, Nedlands, Western Australia 6009; Lipoprotein Team (R.P.N.), Medical Research Council Clinical Sciences Center, Imperial College of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom; and the Department of Bioengineering, University of Washington (P.H.R.B.), Seattle, Washington 98195
Address all correspondence and requests for reprints to: A/Prof G. F. Watts, University Department of Medicine, Royal Perth Hospital, Box X2213, GPO, Perth, Western Australia 6001, Australia. E-mail: gfwatts{at}cyllene.uwa.edu.au
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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+2.5 ± 4.6 vs. -14.7 ±
4.0 mg/kg fat free mass·day; P = 0.010), but did
not significantly alter its fractional catabolism. Weight reduction was
also associated with an increased fractional catabolic rate of LDL apoB
(0.24 ± 0.07 vs. 0.54 ± 0.10 pools/day;
P = 0.002) and conversion of VLDL to LDL apoB
(11.7 ± 2.5% vs. 56.3 ± 11.4%;
P = 0.008). A change in hepatic VLDL apoB secretion
was significantly correlated with a change in visceral adipose tissue
area (r = 0.59; P = 0.043), but not plasma
concentrations of insulin, free fatty acids, or lathosterol. The data
support the hypothesis that a reduction in visceral adipose tissue is
associated with a decrease in the hepatic secretion of VLDL apoB, and
this may be due to a decrease in portal lipid substrate supply. Weight
reduction may also increase the fractional catabolism of LDL apoB, but
this requires further evaluation. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Apolipoprotein B-100 (apoB) is secreted by the liver in very low density lipoprotein (VLDL) (6) and is present in intermediate density lipoprotein (IDL) and low density lipoprotein (LDL). An elevated plasma concentration of apoB is associated with an increased risk of coronary heart disease (7). The precise regulation of the metabolism of VLDL apoB has not been fully elucidated. It has been suggested that visceral adipose tissue increases the portal flux of free fatty acids to the liver (8), possibly due to the effects of insulin resistance (9). In vitro studies have shown that free fatty acids stimulate the synthesis and secretion of VLDL apoB (10). Furthermore, both in vitro (11, 12) and in vivo (13, 14) studies have demonstrated that insulin inhibits the hepatic secretion of VLDL apoB. We have previously shown in men with visceral obesity that cholesterol synthesis is increased (5), and this may be related to insulin resistance (15). Although it is recognized that the synthetic rates of both cholesterol esters and triglycerides are dependent on the availability of free fatty acids (16), there is dispute as to whether the regulatory processes of apoB secretion involve predominately the availability of cholesterol (10, 17, 18) or triglyceride (19, 20). The balance of evidence suggests that the hepatic availability of both cholesterol and triglyceride may be rate limiting for apoB secretion (16), and we would anticipate this to apply in visceral obesity (5).
Previous radiokinetic studies have examined the kinetics of apoB metabolism in obese men (21, 22, 23, 24, 25). However, none of these studies examined men with visceral obesity, nor did they investigate the effect of a reduction in visceral adipose tissue on VLDL, IDL, or LDL apoB metabolism.
In the present study our objective was to employ a stable isotope technique to test the hypothesis that a reduction in visceral obesity decreases the hepatic secretion of VLDL apoB and that reduction in secretion of this apolipoprotein may be a consequence of improved insulin resistance and decreased lipid substrate supply. As an hypothesis-generating exercise, we also investigated the relationship between decreased hepatic secretion of VLDL apoB after weight reduction and the kinetics of IDL and LDL apoB.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Twenty-eight men, aged 18–65 yr, with a body mass index (BMI)
greater than 28 and visceral obesity (waist to hip ratio, 
1.0; waist
circumference, 100 cm) volunteered for the study. None had diabetes
mellitus, proteinuria, hypothyroidism, abnormal liver enzymes, major
systemic illness, or a history of alcohol abuse. None reported a family
history of hyperlipidemia or premature coronary artery disease or was
taking medication known to affect lipid metabolism. All subjects
provided written consent, and the study was approved by the ethics
committee at Royal Perth Hospital.
Subjects entered a randomized, controlled dietary intervention study.
After a 4-week run-in period on an isocaloric diet (weight variation,
<3%), subjects were randomized to continue the isocaloric diet for 16
weeks (n = 14) or to consume a hypocaloric diet for 14 weeks
immediately followed by the isocaloric diet for 2 weeks (n = 14;
Fig. 1
). In seven subjects receiving the
reduction diet, IDL apoB and LDL apoB kinetics were also examined.
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For the first 14 weeks of weight loss, the diet prescribed provided 1200 Cal/day (25% of energy from fat, 55% from carbohydrate, and 20% from protein). This was immediately followed by a 2-week isocaloric diet. We attempted to maintain the composition of the diet (as a percentage of energy intake) during the 2-week weight maintenance period in the intervention group similar to that during the run-in phase. The intervention group was reviewed weekly, and the control group was reviewed every 3 weeks. Three-day dietary diaries were completed every three weeks by both groups. Compliance with the reduction and maintenance diets was checked by dietary diaries. These were analyzed using DIET 4 Nutrient Calculation Software (Xyris Software, Brisbane, Australia) based on the Australian Food Composition Database (NUTTAB 95, Australian Government Nutrient Database, Canberra, Australia).
Clinical protocol
BMI was calculated as weight (kilograms) divided by height2 (meters). Waist circumference (centimeters) was measured at the point midway between the costal margin and iliac crest in the midaxillary line and hip circumference (centimeters) was measured at the widest point around the greater trochanter. Body composition was estimated by a bioelectrical impedance method (Holtain Ltd., Dyfed, Wales, UK), and measurements of fat mass (FM) and fat-free mass (FFM) were recorded. Subjects were requested to keep their level of physical activity constant, and this was assessed by 7-day recall questionnaires (26).
A standard glucose tolerance test (75 g dextrose/200 mL water), magnetic resonance imaging (MRI) scan, and stable isotope infusion study was carried out at week 0 and week 16. For the glucose tolerance test, blood samples were collected through a venous cannula from an anticubital vein at 0 and 120 min to assess glucose intolerance (27). Insulin resistance was assessed from fasting plasma insulin and glucose concentrations using the homeostasis model (28). MRI scans were performed on the subjects using a 1.0T Picker MR scanner (Picker International, Cleveland, OH). The scanner employed a T1 weighted fast spin echo sequence, which gave a high fat to water signal ratio. Ten transverse axial images (field of view, 40–48 cm; 10 mm thick) at various intervertebral levels from T10 to the pubis were acquired from each subject. Software developed within the MRI department was used to calculate sc and visceral adipose tissue area from the images. In two subjects on the weight reduction diet, it was not possible to repeat the MRI scan due to technical difficulties and patient noncompliance, and in these subjects, visceral adipose tissue area at the L3 vertebra was calculated from the subject’s waist circumference [i.e. visceral adipose tissue (cm2) = 6.7 x waist circumference (cm) - 464.1]. This equation was derived from data that showed a significant, positive association between visceral adipose tissue at L3 and waist circumference in 41 male subjects (r = 0.80; P < 0.001; Riches, F. M., et al., unpublished observation).
For the stable isotope infusions, subjects were studied in the semirecumbent position after an overnight fast and were allowed water only. Venous blood was collected for measurements of lipid, lipoprotein, free fatty acids, mevalonic acid, and lathosterol and for the determination of apoE genotype. An indwelling cannula was placed in a superficial vein of each antecubital fossa at the beginning of the study, one for administration of the stable isotope and the other for blood sampling. 1-[13C]Leucine (99.5% enrichment; Tracer Technologies, Somerville, MA) was administered by a primed (1 mg/kg), constant (1 mg/kg·h) iv infusion for 10 h via the left cannula. Blood samples were collected into ethylenediamine tetraacetate at baseline and 30-min intervals for 3 h and hourly thereafter.
Laboratory methods
The laboratory methods for the isolation and measurement of the isotopic enrichment of apoB have previously been described previously (5) and are outlined below.
Isolation and measurement of isotopic enrichment of VLDL, IDL, and LDL apoB. VLDL (density, <1.006 kg/L), IDL (density, 1.006–1.019 kg/L), and LDL (density, 1.019–1.063 kg/L) were isolated from plasma by sequential ultracentrifugation (Centrikon T-1190, Kontron Instruments Ltd., Milan, Italy). The apoB was separated from each lipoprotein fraction by precipitation with isopropanol (29). In our hands, this technique is highly specific for isolating apoB-100 and was positively associated with VLDL apoB concentration as measured by immunoturbidimetry (r = 0.89; P < 0.001; n = 27; Riches, F. M., et al., unpublished observations, 1996). The precipitate was then delipidated with ether ethanol and hydrolyzed, and the plasma amino acids were isolated by cation exchange chromatography. The VLDL and IDL samples were derivitized for gas chromatography-mass spectrometry analysis (Hewlett-Packard Co. 5890, Wilmington, DE). Leucine enrichment was calculated using the formula of Cobelli (30). Analytical precision of the method, assessed by taking replicate samples (n = 5) at two time points in four of the studies, was less than 8% for isotopic enrichment (E) of VLDL and IDL apoB with leucine. The tracer to tracee ratio (Z(t)) was derived from the enrichment data according to the equation (30): Z(t) = E(t)/(El) - E(t)), where E(t) is the isotopic enrichment of VLDL apoB or IDL apoB at time t, and E(l) is the isotopic enrichment of the infusate.
To determine the isotopic enrichment of LDL apoB, the plasma amino acids were isolated by cation exchange chromatography and analyzed by continuous flow isotope ratio mass spectrometry, using a 20–20 Stable Isotope Analyzer coupled to an automated nitrogen and carbon analyzer (Europa Scientific, Crewe, UK). The combusted samples produced labeled CO2. This method was necessary to measure very small fluctuations in the low isotopic enrichment of LDL apoB.
In the LDL fraction, Z(t) was calculated as: Z(t) = [(R(t) - Ro)/El] x (23067/523) x 100, where R(t) is the 13C/12C ratio at time t, R0 is the 13C/12C ratio at baseline before the infusion of 1-[13C]leucine, and E(l) is the isotopic enrichment of the infusate. This was then multiplied by the total number of carbon atoms in LDL apoB and divided by the total number of leucine residues in LDL apoB (31).
Quantification of VLDL, IDL, and LDL apoB; plasma volume; and other analytes. In each study, plasma samples were combined to yield three pooled samples. After precipitation of apoB with isopropanol, VLDL, IDL, and LDL apoB concentrations were determined by a modified Lowry method (32) [coefficient of variation (CV), <4.0%]. Plasma volume was measured by a standard isotopic dilution technique (33). Plasma lipid concentrations were determined using conventional enzymatic methods, and the genotype for apoE determined as described by Hixson and Vernier (34). Plasma insulin was measured by an immunoenzymometric assay (CV, <7.0%), and plasma glucose was measured by an enzymatic hexokinase reaction (CV, <3.1%). An enzymatic colorimetric assay was used to determine the concentration of plasma free fatty acids (CV, <3.0%). The plasma lathosterol concentration was assayed using gas chromatography-mass spectrometry (Hewlett-Packard Co. 5890; interassay CV, 6.0%) (35). Mevalonic acid was measured by capillary gas chromatography-electron capture mass spectrometry (CV, 5.9%) (36).
Calculation of apoB kinetics
The fractional secretion rate (FSR) of VLDL, IDL, and LDL apoB (pools per day), equivalent to the fractional catabolic rate (FCR) at steady state concentration was estimated by multicompartmental analysis. The SAAM-II program package (SAAM Institute, Seattle, WA) was used to fit the model to the tracer data. In subjects in whom only VLDL apoB enrichment was measured, the model consisted of three compartments as described previously (5). Briefly, compartment 1 is a plasma leucine compartment, compartment 2 is an adjustable intrahepatic delay, and compartment 3 is a plasma compartment for VLDL apoB secreted by the liver.
The kinetics of VLDL, IDL, and LDL apoB were calculated using a multicompartmental model as described by Parhofer (37). Briefly, compartment 1 is a precursor compartment, and compartment 2 is an adjustable intrahepatic delay. Compartments 3 and 4 represent a minimal delipidation chain. VLDL apoB in compartment 3 is rapidly turning over and is converted to compartment 4, which represents VLDL apoB particles that turn over more slowly, IDL apoB (compartment 5), or LDL apoB (compartment 6) via a shunt pathway. ApoB can be removed from compartments 4, 5, and 6. Due to the uncertainty associated with low concentrations of apoB in VLDL and IDL pools, we made these values adjustable. The measured VLDL and IDL apoB values were added to the analysis as weighted data.
We compared the FSR of VLDL apoB derived from the VLDL multicompartmental model with the values derived from the VLDL, IDL, and LDL model. The absolute secretion rate of VLDL, IDL, and LDL apoB was calculated as the product of FSR and pool size. Pool size was determined by multiplying the mean plasma VLDL, IDL, or LDL apoB concentration by plasma volume.
Statistics
Before statistical manipulation of continuous variables, the normality of their distributions were assessed using Kolmogorov-Smirnov’s test. A paired t test was used to analyze within-patient changes for normally distributed data, and a Wilcoxon signed ranks test was used for nonnormally distributed data. The differences between each group were compared by unpaired t tests for normally distributed data and by Mann-Whitney tests for nonnormally distributed data. Associations between the hepatic secretion of VLDL apoB and other variables were examined by simple and multiple linear regression analyses. The apoE genotype was described as a binary variable (i.e. 0 = E2/E2, 1 = E3E3, 2 = E4/E3, 3 = E4/E2).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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shows the
clinical characteristics of the subjects before and after the weight
reduction or weight maintenance diet. The men were middle-aged, and
none of the baseline characteristics were significantly different
between the two groups. In subjects on the weight reduction diet, there
was a significant decrease (P < 0.001) in body weight,
BMI, waist circumference, waist to hip ratio, fat mass, and visceral
adipose tissue area at the L3 vertebra. The clinical characteristics of
subjects receiving the weight maintenance diet did not change
significantly from week 0 to week 16. Of the subjects on the weight
reduction diet, five were apoE3/E3, three were apoE4/E3, three were
apoE2/E3, and one was apoE4/E2. One subject in the weight maintenance
group was apoE4/E4, eight were apoE3/E3, three were apoE4/E3, and two
were apoE2/E3. The frequency distributions of apolipoprotein E
genotypes were not significantly different between the groups.
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).
Subjects in the weight reduction group significantly reduced their
total energy and fat intake (percentage of energy) and significantly
increased their carbohydrate intake (percentage of energy). Energy and
nutrient intake did not change in the subjects on the weight
maintenance diet. That subjects randomized to the reduction diet were
consuming an isocaloric diet from week 14 to week 16 is supported by
our observation that body weight did not vary by more than 2% during
this period. There was no significant difference before and after
(weeks 14–16) the reduction diet between the percent intakes of fat
(37.3 ± 6.6% vs. 34.5 ± 8.8%;
P = 0.253), carbohydrate (34.4 ± 8.3%
vs. 38.7 ± 11.7%; P = 0.138), protein
(19.3 ± 3.2% vs. 20.2 ± 2.9%;
P = 0.282), and alcohol (9.2 ± 8.0%
vs. 6.5 ± 5.3%; P = 0.125) or the
polyunsaturated to saturated fat ratio (0.43 ± 0.15
vs. 0.46 ± 0.36; P = 0.784). There was
no change in the reported level of physical activity from week 0 to
week 16 in subjects on the reduction diet (38.7 ± 2.1
vs. 36.3 ± 1.2 Cal/kg·day; P =
0.314).
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shows the biochemical
characteristics of the men studied. At week 0, the biochemical data did
not differ significantly between the groups. Subjects on the weight
reduction diet showed a significant decrease in the concentrations of
cholesterol, triglycerides, insulin, and lathosterol and a reduction in
insulin resistance as measured by the homeostasis model (28).
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describes the isotopic
enrichment curve (mean ± SEM) for plasma leucine and
VLDL apoB during the infusion of 1-[13C]leucine in the
subjects before (Fig. 2A) and after (Fig. 2B) weight reduction. In all
subjects, steady state leucine enrichment was attained within 30 min of
infusion. Table 4 shows the metabolism of
VLDL apoB in the subjects studied. Compared with weight maintenance,
weight reduction was associated with a significant decrease in VLDL
apoB concentration, pool size, and hepatic secretion rate of VLDL apoB
(Fig. 3), but did not significantly alter
its fractional catabolism.
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). After adjusting for
change in insulin resistance and change in percent fat intake or
percent carbohydrate intake (to weeks 14–16), the association remained
significant. However, if either the change in lathosterol or that in
VLDL triglycerides concentration was added to the regression model, the
association became nonsignificant. The association between VLDL apoB
secretion and visceral adipose tissue remained significant (r =
0.667; P = 0.035; n = 10) after removing the two
subjects who did not have a MRI scan at week 16. The change in hepatic
secretion of VLDL apoB was also associated with a change in VLDL
triglycerides concentration (r = 0.58; P = 0.048).
The change in VLDL apoB FCR was significantly correlated with plasma
triglycerides concentration (r = -0.64; P =
0.024). There were no other significant correlations between the change
in hepatic secretion of VLDL apoB or FCR and subcutaneous fat or any of
the physical, biochemical, or dietary variables measured.
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shows the 13C
enrichment of plasma leucine and VLDL, IDL, and LDL apoB before and
after the weight reduction diet. Kinetic parameters for VLDL, IDL, and
LDL apoB metabolism are shown in Table 5.
Similar VLDL apoB FCR values were obtained when the data were analyzed
by both multicompartmental models; however, the more complex VLDL model
was required to fit the IDL and LDL apoB data. After weight reduction,
there was a significant decrease in VLDL and LDL apoB pool sizes and a
trend to a significant decrease in the pool size of IDL apoB. There was
a significant increase in the fractional catabolism of LDL apoB, but no
change in the catabolic rate of VLDL or IDL apoB. The secretion rate of
VLDL apoB decreased significantly, but there was no change in
production of IDL or LDL apoB. Table 6
summarizes the channeling of apoB from VLDL to LDL. Weight reduction
was associated with an increase in the percent conversion of VLDL apoB
to LDL apoB, and this was chiefly attributed to channeling via IDL.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Many of the previous studies investigating the metabolism of VLDL apoB in obesity have used radioisotope techniques (21, 22, 23, 24, 25). However, none of these studies selected subjects for having visceral obesity, and no controlled intervention trials of dietary treatment of visceral obesity and its impact on VLDL apoB metabolism have been carried out. A study by Ginsberg et al. (25) examined VLDL apoB metabolism in six male subjects using a radioactive tracer, exogenously labeling VLDL with 131I. They reported that after weight reduction, there was a significant reduction in the hepatic secretion of VLDL apoB. However, this study was uncontrolled, only a limited number of subjects were examined, and no information about changes in visceral adipose tissue levels was provided. We have extended previous data by examining a larger number of subjects studied in a controlled dietary intervention trial.
MRI provides an accurate and precise estimate of visceral adipose tissue mass. This fat depot is associated with dyslipidemia (including elevated plasma apoB levels) (3), insulin resistance (2), and hypertension (4). Visceral fat at the L3 vertebra is considered a surrogate for visceral adipose tissue volume (38). In the present study, a change in visceral fat at the L3 vertebra was associated with a change in the hepatic secretion of VLDL apoB. Abdominal adipocytes have a high lipolytic capacity, possibly due to reduced sensitivity to the antilipolytic effect of insulin (39, 40). This may increase the flux of free fatty acids in the portal vein to the liver (40) and stimulate hepatic secretion of apoB (10) by increasing the synthetic rates of both cholesteryl esters (41) and triglycerides (19). Acute hyperinsulinemia has been shown to decrease apoB secretion in the nondiabetic state (13, 14). However, in subjects who are insulin resistant, such as those with increased visceral adipose tissue mass, hepatic apoB secretion may be increased as a result of a loss of sensitivity to the normal insulin-mediated suppression of apoB. Insulin may also inhibit directly the synthesis of apoB and stimulate its catabolism before assembly of the VLDL particle (42). That we did not find a correlation between the change in the hepatic secretion of VLDL apoB and the change in the plasma free fatty acid concentration may be attributed to the portal vein concentration of free fatty acid decreasing to a greater extent than the peripheral concentration of free fatty acid. This may be a result of the larger proportional decrease in visceral fat compared with total body fat. Our data suggest that lathosterol and VLDL triglycerides concentrations may play a role in determining the hepatic output of apoB, as the association between the change in VLDL apoB secretion and the change in visceral adipose tissue was not significant after adjusting for insulin resistance, as determined by the homeostasis model (28), and either lathosterol or VLDL triglycerides.
Given that apoB is attached to VLDL, it was anticipated that the change in the hepatic secretion rate of VLDL apoB would be associated with the change in the fasting VLDL triglyceride concentration. This association may also be explained on the basis of triglyceride-rich VLDL driving apoB output. In vitro studies (19, 20) have suggested that the availability of triglycerides is the rate-limiting step in the production of apoB-containing lipoproteins. However, this idea has been challenged by a number of investigators (41, 17, 18). Both in vitro experiments (41) and observations performed in human subjects (17, 18) support the hypothesis that the hepatic secretion rate of apoB is in part controlled by cholesterol substrate availability (10, 16). In subjects with visceral obesity, it is possible that both neutral lipids, cholesterol ester and triglyceride, are essential for the initiation and completion of lipoprotein assembly. In the present study, there was no association between the hepatic secretion rate of VLDL apoB and either plasma concentrations of mevalonic acid and lathosterol or the lathosterol to cholesterol ratio. However, because weight reduction potentially has other effects in addition to a reduction in visceral adipose tissue mass (e.g. reduction in plasma triglyceride concentration and improvement in insulin resistance), it is difficult to dissociate the independent effects of different lipid substrates on apoB secretion. In the present study, the reduction in visceral adipose tissue only partially accounted for the variance in VLDL apoB secretion, suggesting that other regulatory mechanisms are involved. Genetic polymorphisms (16, 43, 44) may also play a role in regulating apoB metabolism in men with visceral obesity.
The observation that the FCR of LDL apoB increases after weight reduction may be due to an up-regulation of the LDL receptor (45). The rate of synthesis of LDL receptors is regulated by a feedback mechanism linked to the cholesterol content of the cell (45). An improvement in insulin resistance, decreases cholesterol synthesis (15), possibly due to an increase in LDL receptor activity (46). It has been demonstrated that insulin stimulates LDL receptor activity in vitro (47) and increases LDL receptor messenger ribonucleic acid levels (48). Despite a reduction in the hepatic secretion rate of VLDL apoB, there was no change in the production of IDL or LDL apoB. This may be explained by the increased conversion of VLDL apoB to LDL apoB via the IDL pathway and may be a consequence of increased lipoprotein lipase activity (49). However, these results need to be confirmed in a controlled trial with a larger number of subjects.
Our study does have limitations. Although it might have been preferable to assess insulin resistance using a hyperinsulinemic, euglycemic clamp (50), the estimate of insulin resistance measured by this technique is well correlated with the estimate obtained by homeostasis model assessment (28). In this study design, it is difficult to dissociate the independent effects of different lipid substrates on apoB metabolism, because a reduction in visceral adipose tissue results in several metabolic alterations. Human studies investigating the independent effects of cholesterol and triglycerides synthesis on apoB secretion with a dual isotope labeling technique (d3-leucine and d5-glycerol) may help to clarify the contribution of these substrates to apoB metabolism. We also did not distinguish VLDL1, VLDL2, LDL2, and LDL3 subspecies, but would anticipate a reduction in VLDL1 secretion (51) and subsequent production of LDL3 (52) with weight reduction. Although there was no significant difference before and after (weeks 14–16) the reduction diet in the percent nutrient intake, the mean percent intakes were lower for fat and higher for carbohydrate at weeks 14–16 compared with week 0. However, Cortese et al. (53) demonstrated that VLDL apoB secretion and FCR were not significantly altered in subjects consuming a low fat, isocaloric diet compared with those in subjects given a high fat, isocaloric diet of similar fatty acid composition. Although the polyunsaturated to saturated fat ratio has been shown to affect the hepatic secretion rate of VLDL apoB (53), in the present study the ratio did not differ before and after weight reduction. In interpreting these stable isotope studies, it is assumed that subjects were in a metabolic steady state with respect to apoB metabolism, the kinetics of leucine in plasma are representative of the kinetics of leucine in the precursor pool before its incorporation into apoB, and all apoB enters the plasma as VLDL particles. In addition, we concede that the correlation between the change in hepatic secretion of VLDL apoB and the change in visceral adipose tissue area at the L3 vertebra does not necessarily demonstrate a casual link between the two metabolic pathways.
In conclusion, our data support the hypothesis that a reduction of visceral adipose tissue decreases the hepatic secretion rate of VLDL apoB. A decreased lipid substrate supply to the liver and increased insulin sensitivity may be two of the mechanisms underlying this relationship. Our results have important therapeutic implications for men with visceral obesity and hepatic oversecretion of apoB.
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Acknowledgments |
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Footnotes |
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2 Recipient of a postgraduate award from the University of Western
Australia.
3 Supported by the Raine Foundation, a Fogarty Senior International
Fellowship, and NIH Grants HL-49110 and RR-12609.
Received August 26, 1998.
Revised April 15, 1999.
Accepted April 21, 1999.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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L. F. Donnelly, K. J. O'Brien, B. J. Dardzinski, S. A. Poe, J. A. Bean, S. K. Holland, and S. R. Daniels Using a Phantom to Compare MR Techniques for Determining the Ratio of Intraabdominal to Subcutaneous Adipose Tissue Am. J. Roentgenol., April 1, 2003; 180(4): 993 - 998. [Abstract] [Full Text] [PDF]
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 G. F. Watts, P. H. R. Barrett, J. Ji, A. P. Serone, D. C. Chan, K. D. Croft, F. Loehrer, and A. G. Johnson Differential Regulation of Lipoprotein Kinetics by Atorvastatin and Fenofibrate in Subjects With the Metabolic Syndrome Diabetes, March 1, 2003; 52(3): 803 - 811. [Abstract] [Full Text] [PDF]
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 B. Mittendorfer, B. W. Patterson, and S. Klein Effect of weight loss on VLDL-triglyceride and apoB-100 kinetics in women with abdominal obesity Am J Physiol Endocrinol Metab, March 1, 2003; 284(3): E549 - E556. [Abstract] [Full Text] [PDF]
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 D. C Chan, G. F Watts, T. A Mori, P H. R Barrett, T. G Redgrave, and L. J Beilin Randomized controlled trial of the effect of n-3 fatty acid supplementation on the metabolism of apolipoprotein B-100 and chylomicron remnants in men with visceral obesity Am. J. Clinical Nutrition, February 1, 2003; 77(2): 300 - 307. [Abstract] [Full Text] [PDF]
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D. C. Chan, G. F. Watts, P. H. R. Barrett, L. J. Beilin, T. G. Redgrave, and T. A. Mori Regulatory Effects of HMG CoA Reductase Inhibitor and Fish Oils on Apolipoprotein B-100 Kinetics in Insulin-Resistant Obese Male Subjects With Dyslipidemia Diabetes, August 1, 2002; 51(8): 2377 - 2386. [Abstract] [Full Text] [PDF]
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A. Carpentier, B. W. Patterson, N. Leung, and G. F. Lewis Sensitivity to Acute Insulin-Mediated Suppression of Plasma Free Fatty Acids Is Not a Determinant of Fasting VLDL Triglyceride Secretion in Healthy Humans Diabetes, June 1, 2002; 51(6): 1867 - 1875. [Abstract] [Full Text] [PDF]
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D. C. Chan, G. F. Watts, P. H. R. Barrett, I. J. Martins, A. P. James, J. C. L. Mamo, T. A. Mori, and T. G. Redgrave Effect of atorvastatin on chylomicron remnant metabolism in visceral obesity: a study employing a new stable isotope breath test J. Lipid Res., May 1, 2002; 43(5): 706 - 712. [Abstract] [Full Text] [PDF]
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D. C. Chan, G. F. Watts, P. H. R. Barrett, T. A. Mori, L. J. Beilin, and T. G. Redgrave Mechanism of Action of a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor on Apolipoprotein B-100 Kinetics in Visceral Obesity J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2283 - 2289. [Abstract] [Full Text] [PDF]
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K. P. Dwyer, P. H. R. Barrett, D. Chan, J. I. Foo, G. F. Watts, and K. D. Croft Oxazolinone derivative of leucine for GC-MS: a sensitive and robust method for stable isotope kinetic studies of lipoproteins J. Lipid Res., February 1, 2002; 43(2): 344 - 349. [Abstract] [Full Text] [PDF]
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E. T.P. Keulen, M. Kruijshoop, N. C. Schaper, A. P.G. Hoeks, and T. W.A. de Bruin Increased Intima-Media Thickness in Familial Combined Hyperlipidemia Associated With Apolipoprotein B Arterioscler Thromb Vasc Biol, February 1, 2002; 22(2): 283 - 288. [Abstract] [Full Text] [PDF]
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J. Q. Purnell, S. E. Kahn, J. J. Albers, D. N. Nevin, J. D. Brunzell, and R. S. Schwartz Effect of Weight Loss with Reduction of Intra-Abdominal Fat on Lipid Metabolism in Older Men J. Clin. Endocrinol. Metab., March 1, 2000; 85(3): 977 - 982. [Abstract] [Full Text]
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 G.F. WATTS, S. HERRMANN, and F.M. RICHES Effects of diet and serotonergic agonist on hepatic apolipoprotein B-100 secretion and endothelial function in obese men QJM, March 1, 2000; 93(3): 153 - 161. [Abstract] [Full Text] [PDF]
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 M. Barton, R. Carmona, H. Morawietz, L. V. d'Uscio, W. Goettsch, H. Hillen, C. C. Haudenschild, J. E. Krieger, K. Munter, T. Lattmann, et al. Obesity Is Associated With Tissue-Specific Activation of Renal Angiotensin-Converting Enzyme In Vivo : Evidence for a Regulatory Role of Endothelin Hypertension, January 1, 2000; 35(1): 329 - 336. [Abstract] [Full Text] [PDF]
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) and VLDL apoB (•) during
the infusion of 1-[13C]leucine in the subjects before (A)
and after (B) weight reduction.
), and LDL apoB
(
) during an infusion of 1 13C-leucine (mean ±
SEM) in the seven subjects before (A) and after (B) the
weight reduction diet.