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Low plasma high-density lipoprotein (HDL) cholesterol is a major abnormality in abdominal obesity. This relates due to accelerated HDL catabolism, but the underlying mechanism requires further elucidation. The relationships between HDL catabolism and other variables that may be modified in abdominal obesity, such as very low-density lipoprotein (VLDL) subspecies (VLDL1, VLDL2) kinetics, liver fat, or visceral adiposity, remain to be investigated.

Objectives:

Our aim was to study the associations between HDL apolipoprotein (apo)-A-I fractional catabolic rate (FCR) and the kinetics of VLDL subspecies and estimates of liver and visceral and sc fat.

Design:

We carried out a multicenter in vivo kinetic study using stable isotopes (deuterated leucine and glycerol) in 62 individuals with abdominal obesity.

Results:

In a multivariate analysis, among the morphological and biological parameters that may predict apoA-I FCR, liver fat (β = .400, P = .003), and VLDL1-apoB (β = .307, P = .020) were independently associated with apoA-I FCR. In a multivariate analysis, among the kinetic parameters, VLDL1-triglycerides (TGs) indirect FCR (β = −.357, P = .001), VLDL1-TG production rate (β = 0.213, P = .048), and apoA-II FCR (β = .667, P < .0001) were independently associated with apoA-I FCR. After adjustment for VLDL1-TG production rate, liver fat was no more correlated with apoA-I FCR. No association between apoA-I FCR and visceral fat was observed.

Conclusions:

We show that VLDL1 is an important independent determinant of apoA-I FCR and more precisely that apoA-I FCR is independently associated with both catabolism and the production of VLDL1-TG. In addition, we show an association between liver fat and apoA-I FCR that is mostly mediated by VLDL1-TG production. These data indicate that, in abdominal obesity, dysfunctional VLDL1 metabolism is an important modulator of HDL apoA-I catabolism.

Abdominal obesity is part of the metabolic syndrome and is strongly associated with insulin resistance, dyslipidemia, and increased cardiovascular risk (1–4). Low high-density lipoprotein (HDL) cholesterol is a main feature of the dyslipidemia associated with abdominal obesity (5) that has been shown to be a main risk factor for cardiovascular disease in metabolic syndrome (3, 6). In vivo kinetic studies performed in abdominally obese individuals have shown that low plasma concentration of HDL cholesterol is the consequence of increased HDL catabolism (7–9). However, among abdominally obese subjects, there is a large variability in apolipoprotein (apo)-A-I fractional catabolic rate (FCR) that requires investigation.

We have previously shown that HDL-apoA-I catabolism is positively correlated with very low-density lipoprotein (VLDL)-apoB production rate (8). However, some questions remained unanswered. Indeed, the link between apoA-I FCR and VLDL subspecies, whose evaluation is critical to the metabolic syndrome or type 2 diabetes, has not been studied. Lipoprotein kinetic studies have shown that VLDL are metabolically heterogeneous, with accumulating evidence demonstrating that both the production and catabolism of large triglyceride-rich VLDL1 (Sf 60–400) and smaller cholesterol-rich VLDL2 (Sf 20–60) are regulated independently of each other (10). The separate evaluation of VLDL1 and VLDL2 metabolism is important in the metabolic syndrome or type 2 diabetes, conditions in which the hepatic oversecretion of VLDLs is mainly due to increased secretion of the triglyceride-rich VLDL1 particles (11, 12). Thus, it is important to analyze precisely the kinetic associations between HDL-apoA-I and both VLDL1 and VLDL2 lipoproteins.

VLDL1 secretion has been shown to be positively correlated with liver fat and visceral fat (11). However, liver fat and visceral fat were not determined in previous kinetics studies of HDL-apoA-I, and it is not clear whether the association between HDL-apoA-I catabolism and the VLDL (or VLDL1) secretion rate is a direct one or is indirectly mediated by the extent of ectopic fat in the liver and visceral/sc regions of the abdomen.

To extend our previous findings on the association between apoA-I and VLDL kinetics, we investigated in a relatively large multicenter tracer study the relationships of apoA-I catabolism with the kinetics of VLDL subspecies and hepatic, visceral, and sc fat compartments in abdominally obese individuals.

Research Design and Methods

Study cohort

Sixty-two subjects were recruited at three study centers according to the following inclusion criteria: men or postmenopausal women, 35–65 years of age, BMI greater than 25 kg/m2 and less than 40 kg/m2, abdominal obesity according to National Cholesterol Education Program/Adult Treatment Panel III (waist circumference >88 cm for women and >102 cm for men), and at least one lipid abnormality (plasma triglycerides >1.7 mmol/L and <4.5 mmol/L and/or HDL cholesterol <1.29 mmol/L for women and <1.03 mmol/L for men).

Exclusion criteria were HDL cholesterol below 0.6 mmol/L, total cholesterol above 6.5 mmol/L or genetic hyperlipidemia, apoE2/E2 or apoE4/E4 homozygosity, type 2 diabetes treated with oral agents and/or insulin, a history of cardiovascular disease, systolic blood pressure above 160 mm Hg or diastolic blood pressure above 95 mm Hg, a history of surgical procedures for weight loss, the presence of any clinically significant endocrine disease, severe hepatic impairment (aspartate aminotransferase or alanine aminotransferase greater than 3 times the upper limit of normal) or renal function (creatinine clearance <30 mL/min), or proteinuria (>30 mg/dL). Subjects were not allowed any lipid-lowering drugs, antiobesity drugs, nonselective β-blockers, or agents known to affect lipid metabolism. Individuals with histories of alcohol and/or drug abuse, current smoking, or smoking cessation within the past 3 months were also excluded.

Subjects were advised to follow a weight-maintenance diet for 6 weeks before the kinetic studies. Body weight was measured with participants wearing undergarments or very light clothing and no shoes. Subjects with greater than 3% variation in weight during this period were excluded from the study. Waist circumference was recorded at the midpoint between the lower rib margin and the iliac crest. Three consecutive readings were taken and the mean was recorded.

Study design

The protocol included three study visits comprising a fasting kinetic study, determination of intraabdominal fat depots, and a heparin test on separate dates. The ethics committee at each site approved the study design and each subject gave written informed consent before participation in the study (trial registered as number NCT00408148).

Kinetic protocol, isolation of lipoproteins, and biochemical analyses

The subjects were admitted at 7:30 am and baseline blood samples for the kinetic study and biomarkers (apoA-I, apoA-II, apoB, apoCIII, apoE, lipoprotein A (LpA)-I, glucose, insulin, and LDL particle size) were taken. At 8:00 am, a bolus injection of [1,1,2,3,3-2H5]glycerol (500 mg) and [5,5,5-2H3]leucine (7 mg/kg) was given and blood drawn as previously described (13). Isolation of VLDL1 and VLDL2 and measurements of isotopic enrichment of leucine in apoB and glycerol in triglycerides were performed as previously described (13). Total apoB and triglyceride content in VLDL1 and VLDL2 were determined at 0, 4, and 8 hours after tracer injection. Biochemical analyses were performed and LDL peak size was measured as previously described (14).

Isolation of apolipoproteins and glycerol: measurement of isotopic enrichment

VLDL1 and VLDL2 were isolated from plasma as previously reported (13). HDL-apoA-I and HDL-apoA-II were isolated from plasma by sequential ultracentrifugation, separated by SDS-PAGE, and blotted on to a polyvinylidene fluoride membrane. ApoB (isolated from VLDL1 and VLDL2) and ApoA-I and apoA-II (isolated from HDL) were hydrolyzed, derivatized, and subjected to gas chromatography mass spectrometer to measure tracer leucine enrichment, as previously reported (13, 15).

Triglycerides were isolated from VLDL1 and VLDL2 fractions and the tracer glycerol enrichment determined as previously reported (13).

Modeling

Apoprotein enrichment data were modeled using SAAM-II (The Epsilon Group) (16). The injected amount of [2H3]leucine and [2H5]glycerol, the leucine and glycerol pool sizes in VLDL1 and VLDL2, and the enrichment curves of plasma leucine and glycerol in VLDL1 and VLDL2 leucine and glycerol were used for a multicompartment model that allowed simultaneous modeling of apoB and triglycerides kinetics as previously described (13) and shown in Figure 1. ApoA-I modeling was performed using a multicompartment model as previously detailed (17). Briefly, the apoA-I model includes a four-compartment subsystem (compartments 1–4) that describes plasma leucine kinetics. This subsystem is connected to an intrahepatic delay compartment, compartment 5, that accounts for the time required for the synthesis and secretion of apoA-I into plasma. Compartment 6 describes the kinetics of apoA-I in the plasma HDL fraction. ApoA-II modeling was performed using the apoA-I model. The FCR was equivalent to the loss from compartment 6, and the PR (mg/kg−1 · d−1) was calculated as the product of FCR and apoA-I (or apoA-II) pool sizes.

Figure 1.
Model for kinetic analysis.
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Model for kinetic analysis.

The model includes separate modules for leucine and glycerol. The free leucine plasma kinetics is modeled by two pools (3 and 4) and a plasma compartment (1), which interchange materials with an intracellular compartment (2). Compartment 2 feeds the apolipoprotein B100 (apoB) synthetic machinery. For glycerol, the plasma compartment (13) is connected to a pooling compartment (12) and feeds TG synthesis, which consists of a fast pathway (14) and a slow pathway (21). The assembly of lipoprotein is modeled by separate delays for apoB and TG. The plasma kinetics of apoB and TG is modeled by a four-compartment hydrolysis chain, consisting of compartments 5, 6, 8, and 10 for apoB. Each apoB compartment, i, has an associated TG compartment, i+10, denoted as 15, 16, etc. Compartments 5/15 and 6/16 are associated with VLDL1, together with a slowly decaying compartment 7/17. Compartments 8/18 and 10/20 together with the slowly decaying compartment 9/19 form the VLDL2 module are shown. Solid arrows show the removal of whole particles and dashed arrows show the removal of TG.

Determination of liver and sc and visceral fat

Liver fat was determined using proton magnetic resonance spectroscopy, and sc abdominal and visceral fat were measured by magnetic resonance imaging as previously described (11).

Analytical procedures

Fasting plasma glucose, triglycerides, HDL cholesterol, LDL cholesterol, and plasma liver enzymes were determined by standard procedures. Plasma apoA-I, apoA-II, apoB, apoE, and adiponectin were measured by an ELISA. Cholesteryl ester transfer protein (CETP) activity was determined as the capacity of a plasma sample to promote the transfer of radiolabeled cholesteryl esters ([3H]cholesteryl ester) from [3H]cholesteryl ester -HDL to apoB-containing lipoproteins (18). Plasma phospholipid transfer protein (PLTP) activity was determined as the capacity of a plasma sample to induce the transfer of radiolabeled [14C]dipalmitoyl phosphatidylcholine from [14C]dipalmitoyl phosphatidylcholine liposomes to an excess of isolated HDL (19). Plasma CETP and PLTP activity levels were related to the activity in a reference plasma analyzed in each run and are expressed in arbitrary units (AU).

Statistical analysis

Data are reported as mean ± SD. Statistical calculations were performed using the SPSS software package (SPSS Inc). For continuous variables, a Kolmogorov-Smirnov analysis was performed to test for normality. The Pearson correlation coefficients (r) were determined by linear regression analysis. Statistical significance of the correlation coefficients was determined by the method of Fisher and Yates. Multivariable analyses were performed by stepwise linear regression, including into the model all the variables that correlated in univariate analysis with P ≤ .10 and potential confounding factors such as age, gender, and study center. For multivariable analyses, data that were not normally distributed were log transformed. A two-tailed probability level of P = .05 was accepted as statistically significant.

Results

Main characteristics of the abdominally obese population

The clinical and biochemical characteristics of the population are shown in Table 1. The subjects were abdominally obese, with a mean BMI of 32.3 ± 3.33 kg/m2, large waist circumference (108 ± 8 cm), and high insulin resistance [mean homeostasis model assessment index of insulin resistance (HOMA-IR) value of 3.14 ± 1.88]. In addition, the subjects also exhibited the typical dyslipidemia of the metabolic syndrome with high plasma triglycerides and low HDL cholesterol (HDL-C) concentrations.

Table 1.

Clinical and Biochemical Characteristics of the Abdominally Obese Individuals

Mean ± SD
Age, y51.5 ± 8.1
Gender, M/F50/12
BMI, kg/m232.3 ± 3.33
Waist, cm108 ± 8
Hip, cm110 ± 7
Total fat, %29.7 ± 6.5
Liver fat, %7.7 ± 6.6
Visceral fat, kg2.50 ± 0.85
Subcutaneous fat, kg27.02 ± 6.92
Total cholesterol, mmol/L4.77 ± 0.72
TGs, mmol/L1.98 ± 0.71
LDL cholesterol, mmol/L2.90 ± 0.67
HDL cholesterol, mmol/L0.97 ± 0.15
VLDL1-TG, mg/dL77 ± 34
VLDL1-apoB, mg/dL3.46 ± 1.76
ApoA-I, mg/dL118 ± 14
ApoA-II, mg/dL32 ± 5
Fasting glucose, mmol/L5.63 ± 0.55
Plasma insulin, mU/L12.21 ± 6.74
HOMA-IR3.14 ± 1.88
CETP activity, AU215 ± 32
PLTP activity, AU4948 ± 1091
Mean ± SD
Age, y51.5 ± 8.1
Gender, M/F50/12
BMI, kg/m232.3 ± 3.33
Waist, cm108 ± 8
Hip, cm110 ± 7
Total fat, %29.7 ± 6.5
Liver fat, %7.7 ± 6.6
Visceral fat, kg2.50 ± 0.85
Subcutaneous fat, kg27.02 ± 6.92
Total cholesterol, mmol/L4.77 ± 0.72
TGs, mmol/L1.98 ± 0.71
LDL cholesterol, mmol/L2.90 ± 0.67
HDL cholesterol, mmol/L0.97 ± 0.15
VLDL1-TG, mg/dL77 ± 34
VLDL1-apoB, mg/dL3.46 ± 1.76
ApoA-I, mg/dL118 ± 14
ApoA-II, mg/dL32 ± 5
Fasting glucose, mmol/L5.63 ± 0.55
Plasma insulin, mU/L12.21 ± 6.74
HOMA-IR3.14 ± 1.88
CETP activity, AU215 ± 32
PLTP activity, AU4948 ± 1091

Abbreviations: BMI, body mass index; F, female; M, male.

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Table 1.

Clinical and Biochemical Characteristics of the Abdominally Obese Individuals

Mean ± SD
Age, y51.5 ± 8.1
Gender, M/F50/12
BMI, kg/m232.3 ± 3.33
Waist, cm108 ± 8
Hip, cm110 ± 7
Total fat, %29.7 ± 6.5
Liver fat, %7.7 ± 6.6
Visceral fat, kg2.50 ± 0.85
Subcutaneous fat, kg27.02 ± 6.92
Total cholesterol, mmol/L4.77 ± 0.72
TGs, mmol/L1.98 ± 0.71
LDL cholesterol, mmol/L2.90 ± 0.67
HDL cholesterol, mmol/L0.97 ± 0.15
VLDL1-TG, mg/dL77 ± 34
VLDL1-apoB, mg/dL3.46 ± 1.76
ApoA-I, mg/dL118 ± 14
ApoA-II, mg/dL32 ± 5
Fasting glucose, mmol/L5.63 ± 0.55
Plasma insulin, mU/L12.21 ± 6.74
HOMA-IR3.14 ± 1.88
CETP activity, AU215 ± 32
PLTP activity, AU4948 ± 1091
Mean ± SD
Age, y51.5 ± 8.1
Gender, M/F50/12
BMI, kg/m232.3 ± 3.33
Waist, cm108 ± 8
Hip, cm110 ± 7
Total fat, %29.7 ± 6.5
Liver fat, %7.7 ± 6.6
Visceral fat, kg2.50 ± 0.85
Subcutaneous fat, kg27.02 ± 6.92
Total cholesterol, mmol/L4.77 ± 0.72
TGs, mmol/L1.98 ± 0.71
LDL cholesterol, mmol/L2.90 ± 0.67
HDL cholesterol, mmol/L0.97 ± 0.15
VLDL1-TG, mg/dL77 ± 34
VLDL1-apoB, mg/dL3.46 ± 1.76
ApoA-I, mg/dL118 ± 14
ApoA-II, mg/dL32 ± 5
Fasting glucose, mmol/L5.63 ± 0.55
Plasma insulin, mU/L12.21 ± 6.74
HOMA-IR3.14 ± 1.88
CETP activity, AU215 ± 32
PLTP activity, AU4948 ± 1091

Abbreviations: BMI, body mass index; F, female; M, male.

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Table 2 presents the kinetic data for apoA-I, apoA-II, VLDL1-triglycerides (TGs), VLDL2-TGs, VLDL1-apoB, and VLDL2-apoB of the abdominally obese population.

Table 2.

Kinetic Data for apoA-I, apoA-II, VLDL1-TG, VLDL2-TG, VLDL1-apoB and VLDL2-apoB Metabolism in the Abdominally Obese Individuals

Mean ± SD [ranges]
ApoA-I FCR, pool · d−10.29 ± 0.07 [0.14–0.44]
ApoA-I PR, mg · kg−1 · d−115.16 ± 3.88 [8.11–23.53]
ApoA-II FCR, pool · d−10.27 ± 0.08 [0.14–0.54]
ApoA-II PR, mg · kg−1 · d−13.86 ± 1.37 [1.75–8.96]
VLDL1-TG direct FCR, pool · d−17.52 ± 5.50 [1.06–25.33]
VLDL1-TG indirect FCR, pool · d−12.72 ± 1.47 [0.69–7.94]
VLDL1-TG total FCR, pool · d−110.24 ± 5.84 [2.71–30.81]
VLDL1-TG PR, mg · kg−1 · d−1292.92 ± 124.62 [121.96–625.75]
VLDL2-TG FCR, pool · d−114.02 ± 6.79 [5.41–34.63]
VLDL2-TG PR, mg · kg−1 · d−1110.51 ± 53.30 [38.97–274.30]
VLDL1-apoB direct FCR, pool · d−12.90 ± 2.67 [0.00–9.56]
VLDL1-apoB indirect FCR, pool · d−14.63 ± 2.06 [1.14–10.07]
VLDL1-apoB total FCR, pool · d−17.53 ± 3.22 [2.48–18.51]
VLDL1-apoB PR, mg · kg−1 · d−18.22 ± 3.14 [3.60–16.45]
VLDL2-apoB FCR, pool · d−15.68 ± 1.96 [2.57–11.90]
VLDL2-apoB PR, mg · kg−1 · d−17.04 ± 2.76 [1.08–16.91]
Mean ± SD [ranges]
ApoA-I FCR, pool · d−10.29 ± 0.07 [0.14–0.44]
ApoA-I PR, mg · kg−1 · d−115.16 ± 3.88 [8.11–23.53]
ApoA-II FCR, pool · d−10.27 ± 0.08 [0.14–0.54]
ApoA-II PR, mg · kg−1 · d−13.86 ± 1.37 [1.75–8.96]
VLDL1-TG direct FCR, pool · d−17.52 ± 5.50 [1.06–25.33]
VLDL1-TG indirect FCR, pool · d−12.72 ± 1.47 [0.69–7.94]
VLDL1-TG total FCR, pool · d−110.24 ± 5.84 [2.71–30.81]
VLDL1-TG PR, mg · kg−1 · d−1292.92 ± 124.62 [121.96–625.75]
VLDL2-TG FCR, pool · d−114.02 ± 6.79 [5.41–34.63]
VLDL2-TG PR, mg · kg−1 · d−1110.51 ± 53.30 [38.97–274.30]
VLDL1-apoB direct FCR, pool · d−12.90 ± 2.67 [0.00–9.56]
VLDL1-apoB indirect FCR, pool · d−14.63 ± 2.06 [1.14–10.07]
VLDL1-apoB total FCR, pool · d−17.53 ± 3.22 [2.48–18.51]
VLDL1-apoB PR, mg · kg−1 · d−18.22 ± 3.14 [3.60–16.45]
VLDL2-apoB FCR, pool · d−15.68 ± 1.96 [2.57–11.90]
VLDL2-apoB PR, mg · kg−1 · d−17.04 ± 2.76 [1.08–16.91]
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Table 2.

Kinetic Data for apoA-I, apoA-II, VLDL1-TG, VLDL2-TG, VLDL1-apoB and VLDL2-apoB Metabolism in the Abdominally Obese Individuals

Mean ± SD [ranges]
ApoA-I FCR, pool · d−10.29 ± 0.07 [0.14–0.44]
ApoA-I PR, mg · kg−1 · d−115.16 ± 3.88 [8.11–23.53]
ApoA-II FCR, pool · d−10.27 ± 0.08 [0.14–0.54]
ApoA-II PR, mg · kg−1 · d−13.86 ± 1.37 [1.75–8.96]
VLDL1-TG direct FCR, pool · d−17.52 ± 5.50 [1.06–25.33]
VLDL1-TG indirect FCR, pool · d−12.72 ± 1.47 [0.69–7.94]
VLDL1-TG total FCR, pool · d−110.24 ± 5.84 [2.71–30.81]
VLDL1-TG PR, mg · kg−1 · d−1292.92 ± 124.62 [121.96–625.75]
VLDL2-TG FCR, pool · d−114.02 ± 6.79 [5.41–34.63]
VLDL2-TG PR, mg · kg−1 · d−1110.51 ± 53.30 [38.97–274.30]
VLDL1-apoB direct FCR, pool · d−12.90 ± 2.67 [0.00–9.56]
VLDL1-apoB indirect FCR, pool · d−14.63 ± 2.06 [1.14–10.07]
VLDL1-apoB total FCR, pool · d−17.53 ± 3.22 [2.48–18.51]
VLDL1-apoB PR, mg · kg−1 · d−18.22 ± 3.14 [3.60–16.45]
VLDL2-apoB FCR, pool · d−15.68 ± 1.96 [2.57–11.90]
VLDL2-apoB PR, mg · kg−1 · d−17.04 ± 2.76 [1.08–16.91]
Mean ± SD [ranges]
ApoA-I FCR, pool · d−10.29 ± 0.07 [0.14–0.44]
ApoA-I PR, mg · kg−1 · d−115.16 ± 3.88 [8.11–23.53]
ApoA-II FCR, pool · d−10.27 ± 0.08 [0.14–0.54]
ApoA-II PR, mg · kg−1 · d−13.86 ± 1.37 [1.75–8.96]
VLDL1-TG direct FCR, pool · d−17.52 ± 5.50 [1.06–25.33]
VLDL1-TG indirect FCR, pool · d−12.72 ± 1.47 [0.69–7.94]
VLDL1-TG total FCR, pool · d−110.24 ± 5.84 [2.71–30.81]
VLDL1-TG PR, mg · kg−1 · d−1292.92 ± 124.62 [121.96–625.75]
VLDL2-TG FCR, pool · d−114.02 ± 6.79 [5.41–34.63]
VLDL2-TG PR, mg · kg−1 · d−1110.51 ± 53.30 [38.97–274.30]
VLDL1-apoB direct FCR, pool · d−12.90 ± 2.67 [0.00–9.56]
VLDL1-apoB indirect FCR, pool · d−14.63 ± 2.06 [1.14–10.07]
VLDL1-apoB total FCR, pool · d−17.53 ± 3.22 [2.48–18.51]
VLDL1-apoB PR, mg · kg−1 · d−18.22 ± 3.14 [3.60–16.45]
VLDL2-apoB FCR, pool · d−15.68 ± 1.96 [2.57–11.90]
VLDL2-apoB PR, mg · kg−1 · d−17.04 ± 2.76 [1.08–16.91]
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Correlations between main lipid, morphological, and kinetic parameters

The correlation coefficients between the main lipid, morphological, and kinetic parameters are shown in Table 3. apoA-I FCR was positively correlated with BMI, sc fat, liver fat, HOMA-IR, plasma TGs, VLDL1-TGs and VLDL1-apoB concentrations and negatively with HDL-C, HDL-C to apoA-I ratio, and HDL-C to apoA-II ratio. As far as kinetic parameters are concerned, apoA-I FCR was positively correlated with apoA-I production rate (PR), apoA-II FCR, apoA-II PR, VLDL1-triglycerides PR, and VLDL1-apoB PR. A borderline negative correlation was observed between apoA-I FCR and VLDL1-TG indirect FCR (r = −0.247, P = .054).

Table 3.

Pearson Correlation Coefficients in the 62 Abdominally Obese Individuals

Age, yBMI, kg/m2Visceral FatSubcutaneous FatLiver FatHOMA-IRTGsHDL-CHDL-C/apoA-IHDL-C/apoA-IIVLDL1-TGVLDL1-apoBapoA-I PoolapoA-I FCRapoA-I PRapoA-II Pool
Age, y
BMI, kg/m20.126
Visceral fat0.0350.461a
Subcutaneous fat0.0210.813b0.310c
Liver fat−0.0530.567b0.390d0.481b
HOMA-IR0.1730.490b0.509b0.469a0.539b
TGs−0.0400.385d0.345d0.2460.353d0.357d
HDL-C−0.042−0.164−0.148−0.012−0.50−0.187−0.312c
HDL-C/apoA-I−0.122−0.453a−0.340d−0.330d−0.413a−0.414a−0.595b0.646b
HDL-C/apoA-II−0.143−0.298c−0.309c−0.283c−0.199−0.385d−0.637b0.560b0.622b
VLDL1-TG−0.0640.420a0.461a0.1880.335d0.403d0.826b−0.213−0.483b−0.575b
VLDL1-apoB0.0160.411a0.300c0.259c0.355d0.300c0.574b−0.105−0.326d−0.344d0.706b
apoA-I pool−0.340d0.486b0.338c0.474a0.284c0.1170.266c0.328d−0.056−0.1000.287c0.299c
apoA-I FCR−0.1250.410a0.1290.334d0.427a0.271c0.422a−0.340d−0.512b−0.385d0.443a0.455a−0.223
apoA-I PR−0.1540.396d0.0310.367d0.415a0.2350.434a−0.029−0.380d−0.281c0.414a0.481b0.2060.900
apoA-II pool−0.355d0.435a0.412a0.471a0.284c0.2480.380d0.247−0.087−0.460a0.433a0.326d0.824b0.1770.279c
apoA-II FCR−0.1580.310c0.1560.266c0.307c0.1290.191−0.150−0.292c0.2300.1360.244−0.1210.672b0.612b0.303c
apoA-II PR0.267c0.336d0.1710.343d0.329d0.1400.297c−0.226−0.226−0.352d0.2300.290c0.1230.606b0.652b0.580b
VLDL1-TG PR0.0490.440a0.348d0.509b0.664b0.377d0.333d−0.205−0.480b−0.305c0.307c0.287c0.1270.512b0.404d0.248
VLDL2-TG PR−0.259c0.280c0.442a0.2300.1790.1560.142−0.065−0.268c−0.291c0.336d0.0640.325d0.0830.0080.397d
VLDL1-TG direct FCR0.145−0.048−0.2130.1900.250−0.097−0.271c−0.098−0.0200.121−0.458a−0.253c−0.2470.054−0.019−0.219
VLDL1-TG indirect FCR−0.153−0.0860.0310.018−0.143−0.147−0.537b0.0830.1950.181−0.518b−0.480b0.047−0.247−0.281c0.015
VLDL1-TG total FCR0.097−0.067−0.1930.1830.200−0.128−0.390d−0.0710.0300.159−0.562b−0.359d−0.221−0.012−0.089−0.202
VLDL2-TG FCR−0.316c0.0600.1190.0540.1340.051−0.2390.058−0.051−0.021−0.085−0.1080.293c0.0530.0170.275c
VLDL1-apoB PR−0.1050.400d0.323c0.431a0.574b0.322d0.430d−0.184−0.401d−0.302c0.437a0.367d0.0810.422a0.347d0.191
VLDL2-apoB PR−0.1660.271c0.335d0.1920.348d0.1650.255c−0.242−0.307c−0.1930.360d0.307c0.0680.1900.0880.038
VLDL1-apoB direct FCR0.112−0.005−0.2320.1970.122−0.053−0.0800.066−0.0930.079−0.277c−0.288c−0.1040.0750.094−0.073
VLDL1-apoB indirect FCR0.021−0.204−0.122−0.093−0.163−0.275c−0.573b0.0020.2470.330d−0.640b−0.521b−0.211−0.224−0.292c−0.306c
VLDL1-apoB total FCR0.106−0.135−0.272c0.102−0.003−0.219−0.434a0.0560.0810.277c−0.613b−0.547b−0.222−0.082−0.109−0.256c
VLDL2-apoB FCR−0.0890.0270.257c−0.0640.1950.116−0.112−0.161−0.1290.027−0.067−0.056−0.0360.059−0.073−0.117
CETP activity0.336#−0.028−0.0910.009−0.0810.177−0.033−0.177−0.215−0.106−0.140−0.072−0.205−0.076−0.124−0.149
PLTP activity−0.007−0.018−0.121−0.027−0.177−0.1200.145−0.057−0.055−0.2160.1300.1800.048−0.0010.0850.026
Age, yBMI, kg/m2Visceral FatSubcutaneous FatLiver FatHOMA-IRTGsHDL-CHDL-C/apoA-IHDL-C/apoA-IIVLDL1-TGVLDL1-apoBapoA-I PoolapoA-I FCRapoA-I PRapoA-II Pool
Age, y
BMI, kg/m20.126
Visceral fat0.0350.461a
Subcutaneous fat0.0210.813b0.310c
Liver fat−0.0530.567b0.390d0.481b
HOMA-IR0.1730.490b0.509b0.469a0.539b
TGs−0.0400.385d0.345d0.2460.353d0.357d
HDL-C−0.042−0.164−0.148−0.012−0.50−0.187−0.312c
HDL-C/apoA-I−0.122−0.453a−0.340d−0.330d−0.413a−0.414a−0.595b0.646b
HDL-C/apoA-II−0.143−0.298c−0.309c−0.283c−0.199−0.385d−0.637b0.560b0.622b
VLDL1-TG−0.0640.420a0.461a0.1880.335d0.403d0.826b−0.213−0.483b−0.575b
VLDL1-apoB0.0160.411a0.300c0.259c0.355d0.300c0.574b−0.105−0.326d−0.344d0.706b
apoA-I pool−0.340d0.486b0.338c0.474a0.284c0.1170.266c0.328d−0.056−0.1000.287c0.299c
apoA-I FCR−0.1250.410a0.1290.334d0.427a0.271c0.422a−0.340d−0.512b−0.385d0.443a0.455a−0.223
apoA-I PR−0.1540.396d0.0310.367d0.415a0.2350.434a−0.029−0.380d−0.281c0.414a0.481b0.2060.900
apoA-II pool−0.355d0.435a0.412a0.471a0.284c0.2480.380d0.247−0.087−0.460a0.433a0.326d0.824b0.1770.279c
apoA-II FCR−0.1580.310c0.1560.266c0.307c0.1290.191−0.150−0.292c0.2300.1360.244−0.1210.672b0.612b0.303c
apoA-II PR0.267c0.336d0.1710.343d0.329d0.1400.297c−0.226−0.226−0.352d0.2300.290c0.1230.606b0.652b0.580b
VLDL1-TG PR0.0490.440a0.348d0.509b0.664b0.377d0.333d−0.205−0.480b−0.305c0.307c0.287c0.1270.512b0.404d0.248
VLDL2-TG PR−0.259c0.280c0.442a0.2300.1790.1560.142−0.065−0.268c−0.291c0.336d0.0640.325d0.0830.0080.397d
VLDL1-TG direct FCR0.145−0.048−0.2130.1900.250−0.097−0.271c−0.098−0.0200.121−0.458a−0.253c−0.2470.054−0.019−0.219
VLDL1-TG indirect FCR−0.153−0.0860.0310.018−0.143−0.147−0.537b0.0830.1950.181−0.518b−0.480b0.047−0.247−0.281c0.015
VLDL1-TG total FCR0.097−0.067−0.1930.1830.200−0.128−0.390d−0.0710.0300.159−0.562b−0.359d−0.221−0.012−0.089−0.202
VLDL2-TG FCR−0.316c0.0600.1190.0540.1340.051−0.2390.058−0.051−0.021−0.085−0.1080.293c0.0530.0170.275c
VLDL1-apoB PR−0.1050.400d0.323c0.431a0.574b0.322d0.430d−0.184−0.401d−0.302c0.437a0.367d0.0810.422a0.347d0.191
VLDL2-apoB PR−0.1660.271c0.335d0.1920.348d0.1650.255c−0.242−0.307c−0.1930.360d0.307c0.0680.1900.0880.038
VLDL1-apoB direct FCR0.112−0.005−0.2320.1970.122−0.053−0.0800.066−0.0930.079−0.277c−0.288c−0.1040.0750.094−0.073
VLDL1-apoB indirect FCR0.021−0.204−0.122−0.093−0.163−0.275c−0.573b0.0020.2470.330d−0.640b−0.521b−0.211−0.224−0.292c−0.306c
VLDL1-apoB total FCR0.106−0.135−0.272c0.102−0.003−0.219−0.434a0.0560.0810.277c−0.613b−0.547b−0.222−0.082−0.109−0.256c
VLDL2-apoB FCR−0.0890.0270.257c−0.0640.1950.116−0.112−0.161−0.1290.027−0.067−0.056−0.0360.059−0.073−0.117
CETP activity0.336#−0.028−0.0910.009−0.0810.177−0.033−0.177−0.215−0.106−0.140−0.072−0.205−0.076−0.124−0.149
PLTP activity−0.007−0.018−0.121−0.027−0.177−0.1200.145−0.057−0.055−0.2160.1300.1800.048−0.0010.0850.026
apoA-II FCRapoA-II PRVLDL1-TG PRVLDL2-TG PRVLDL1-TG Direct FCRVLDL1-TG Indirect FCRVLDL1-TG Total FCRVLDL2-TG FCRVLDL1-apoB PRVLDL2-apoB PRVLDL1-apoB Direct FCRVLDL1-apoB Indirect FCRVLDL1-apoB Total FCRVLDL2-apoB FCRCETP ActivityPLTP Activity
Age, y
BMI, kg/m2
Visceral fat
Subcutaneous fat
Liver fat
HOMA-IR
TG
HDL-C
HDL-C/apoA-I
HDL-C/apoA-II
VLDL1-TG
VLDL1-apoB
apoA-I pool
apoA-I FCR
apoA-I PR
apoA-II pool
apoA-II FCR
apoA-II PR0.915b
VLDL1-TG PR0.361d0.331d
VLDL2-TG PR0.267c0.283c0.229
VLDL1-TG direct FCR0.077−0.0090.545b−0.272
VLDL1-TG indirect FCR0.2090.156−0.1810.491b0.107
VLDL1-TG total FCR0.1250.0310.468a−0.1320.968b0.353d
VLDL2-TG FCR0.383d0.355d0.0540.648b−0.1260.618b0.037
VLDL1-apoB PR0.2440.255c0.758b0.2160.286c−0.286c0.197−0.120
VLDL2-apoB PR0.0830.0360.282c0.497b−0.0990.003−0.1030.0210.546b
VLDL1-apoB direct FCR0.0770.0830.481b−0.1350.763b0.0200.723b−0.1130.383d−0.346d
VLDL1-apoB indirect FCR−0.010−0.122−0.275c0.0450.310c0.690b0.465a0.204−0.2230.197−0.095
VLDL1-apoB total FCR0.058−0.0100.189−0.0940.772b0.452a0.840b0.0440.176−0.1620.771b0.561b
VLDL2-apoB FCR0.259c0.149−0.0800.273c−0.1380.292−0.0560.625b−0.0650.323c−0.373d0.322d−0.104
CETP activity−0.143−0.1970.083−0.0570.2470.0390.242−0.14−0.090−0.1070.0850.1020.136−0.019
PLTP activity−0.0040.065−0.095−0.180−0.181−0.375d−0.265c−264c0.024−0.0820.030−0.308c−0.172−0.160−0.23
apoA-II FCRapoA-II PRVLDL1-TG PRVLDL2-TG PRVLDL1-TG Direct FCRVLDL1-TG Indirect FCRVLDL1-TG Total FCRVLDL2-TG FCRVLDL1-apoB PRVLDL2-apoB PRVLDL1-apoB Direct FCRVLDL1-apoB Indirect FCRVLDL1-apoB Total FCRVLDL2-apoB FCRCETP ActivityPLTP Activity
Age, y
BMI, kg/m2
Visceral fat
Subcutaneous fat
Liver fat
HOMA-IR
TG
HDL-C
HDL-C/apoA-I
HDL-C/apoA-II
VLDL1-TG
VLDL1-apoB
apoA-I pool
apoA-I FCR
apoA-I PR
apoA-II pool
apoA-II FCR
apoA-II PR0.915b
VLDL1-TG PR0.361d0.331d
VLDL2-TG PR0.267c0.283c0.229
VLDL1-TG direct FCR0.077−0.0090.545b−0.272
VLDL1-TG indirect FCR0.2090.156−0.1810.491b0.107
VLDL1-TG total FCR0.1250.0310.468a−0.1320.968b0.353d
VLDL2-TG FCR0.383d0.355d0.0540.648b−0.1260.618b0.037
VLDL1-apoB PR0.2440.255c0.758b0.2160.286c−0.286c0.197−0.120
VLDL2-apoB PR0.0830.0360.282c0.497b−0.0990.003−0.1030.0210.546b
VLDL1-apoB direct FCR0.0770.0830.481b−0.1350.763b0.0200.723b−0.1130.383d−0.346d
VLDL1-apoB indirect FCR−0.010−0.122−0.275c0.0450.310c0.690b0.465a0.204−0.2230.197−0.095
VLDL1-apoB total FCR0.058−0.0100.189−0.0940.772b0.452a0.840b0.0440.176−0.1620.771b0.561b
VLDL2-apoB FCR0.259c0.149−0.0800.273c−0.1380.292−0.0560.625b−0.0650.323c−0.373d0.322d−0.104
CETP activity−0.143−0.1970.083−0.0570.2470.0390.242−0.14−0.090−0.1070.0850.1020.136−0.019
PLTP activity−0.0040.065−0.095−0.180−0.181−0.375d−0.265c−264c0.024−0.0820.030−0.308c−0.172−0.160−0.23

VLDL1-apoB data were derived from 58 subjects and VLDL1 TG kinetic data from 46 subjects.

a

P ≤ .001.

b

P ≤ .0001.

c

P < .05.

d

P ≤ .01.

Open in new tab
Table 3.

Pearson Correlation Coefficients in the 62 Abdominally Obese Individuals

Age, yBMI, kg/m2Visceral FatSubcutaneous FatLiver FatHOMA-IRTGsHDL-CHDL-C/apoA-IHDL-C/apoA-IIVLDL1-TGVLDL1-apoBapoA-I PoolapoA-I FCRapoA-I PRapoA-II Pool
Age, y
BMI, kg/m20.126
Visceral fat0.0350.461a
Subcutaneous fat0.0210.813b0.310c
Liver fat−0.0530.567b0.390d0.481b
HOMA-IR0.1730.490b0.509b0.469a0.539b
TGs−0.0400.385d0.345d0.2460.353d0.357d
HDL-C−0.042−0.164−0.148−0.012−0.50−0.187−0.312c
HDL-C/apoA-I−0.122−0.453a−0.340d−0.330d−0.413a−0.414a−0.595b0.646b
HDL-C/apoA-II−0.143−0.298c−0.309c−0.283c−0.199−0.385d−0.637b0.560b0.622b
VLDL1-TG−0.0640.420a0.461a0.1880.335d0.403d0.826b−0.213−0.483b−0.575b
VLDL1-apoB0.0160.411a0.300c0.259c0.355d0.300c0.574b−0.105−0.326d−0.344d0.706b
apoA-I pool−0.340d0.486b0.338c0.474a0.284c0.1170.266c0.328d−0.056−0.1000.287c0.299c
apoA-I FCR−0.1250.410a0.1290.334d0.427a0.271c0.422a−0.340d−0.512b−0.385d0.443a0.455a−0.223
apoA-I PR−0.1540.396d0.0310.367d0.415a0.2350.434a−0.029−0.380d−0.281c0.414a0.481b0.2060.900
apoA-II pool−0.355d0.435a0.412a0.471a0.284c0.2480.380d0.247−0.087−0.460a0.433a0.326d0.824b0.1770.279c
apoA-II FCR−0.1580.310c0.1560.266c0.307c0.1290.191−0.150−0.292c0.2300.1360.244−0.1210.672b0.612b0.303c
apoA-II PR0.267c0.336d0.1710.343d0.329d0.1400.297c−0.226−0.226−0.352d0.2300.290c0.1230.606b0.652b0.580b
VLDL1-TG PR0.0490.440a0.348d0.509b0.664b0.377d0.333d−0.205−0.480b−0.305c0.307c0.287c0.1270.512b0.404d0.248
VLDL2-TG PR−0.259c0.280c0.442a0.2300.1790.1560.142−0.065−0.268c−0.291c0.336d0.0640.325d0.0830.0080.397d
VLDL1-TG direct FCR0.145−0.048−0.2130.1900.250−0.097−0.271c−0.098−0.0200.121−0.458a−0.253c−0.2470.054−0.019−0.219
VLDL1-TG indirect FCR−0.153−0.0860.0310.018−0.143−0.147−0.537b0.0830.1950.181−0.518b−0.480b0.047−0.247−0.281c0.015
VLDL1-TG total FCR0.097−0.067−0.1930.1830.200−0.128−0.390d−0.0710.0300.159−0.562b−0.359d−0.221−0.012−0.089−0.202
VLDL2-TG FCR−0.316c0.0600.1190.0540.1340.051−0.2390.058−0.051−0.021−0.085−0.1080.293c0.0530.0170.275c
VLDL1-apoB PR−0.1050.400d0.323c0.431a0.574b0.322d0.430d−0.184−0.401d−0.302c0.437a0.367d0.0810.422a0.347d0.191
VLDL2-apoB PR−0.1660.271c0.335d0.1920.348d0.1650.255c−0.242−0.307c−0.1930.360d0.307c0.0680.1900.0880.038
VLDL1-apoB direct FCR0.112−0.005−0.2320.1970.122−0.053−0.0800.066−0.0930.079−0.277c−0.288c−0.1040.0750.094−0.073
VLDL1-apoB indirect FCR0.021−0.204−0.122−0.093−0.163−0.275c−0.573b0.0020.2470.330d−0.640b−0.521b−0.211−0.224−0.292c−0.306c
VLDL1-apoB total FCR0.106−0.135−0.272c0.102−0.003−0.219−0.434a0.0560.0810.277c−0.613b−0.547b−0.222−0.082−0.109−0.256c
VLDL2-apoB FCR−0.0890.0270.257c−0.0640.1950.116−0.112−0.161−0.1290.027−0.067−0.056−0.0360.059−0.073−0.117
CETP activity0.336#−0.028−0.0910.009−0.0810.177−0.033−0.177−0.215−0.106−0.140−0.072−0.205−0.076−0.124−0.149
PLTP activity−0.007−0.018−0.121−0.027−0.177−0.1200.145−0.057−0.055−0.2160.1300.1800.048−0.0010.0850.026
Age, yBMI, kg/m2Visceral FatSubcutaneous FatLiver FatHOMA-IRTGsHDL-CHDL-C/apoA-IHDL-C/apoA-IIVLDL1-TGVLDL1-apoBapoA-I PoolapoA-I FCRapoA-I PRapoA-II Pool
Age, y
BMI, kg/m20.126
Visceral fat0.0350.461a
Subcutaneous fat0.0210.813b0.310c
Liver fat−0.0530.567b0.390d0.481b
HOMA-IR0.1730.490b0.509b0.469a0.539b
TGs−0.0400.385d0.345d0.2460.353d0.357d
HDL-C−0.042−0.164−0.148−0.012−0.50−0.187−0.312c
HDL-C/apoA-I−0.122−0.453a−0.340d−0.330d−0.413a−0.414a−0.595b0.646b
HDL-C/apoA-II−0.143−0.298c−0.309c−0.283c−0.199−0.385d−0.637b0.560b0.622b
VLDL1-TG−0.0640.420a0.461a0.1880.335d0.403d0.826b−0.213−0.483b−0.575b
VLDL1-apoB0.0160.411a0.300c0.259c0.355d0.300c0.574b−0.105−0.326d−0.344d0.706b
apoA-I pool−0.340d0.486b0.338c0.474a0.284c0.1170.266c0.328d−0.056−0.1000.287c0.299c
apoA-I FCR−0.1250.410a0.1290.334d0.427a0.271c0.422a−0.340d−0.512b−0.385d0.443a0.455a−0.223
apoA-I PR−0.1540.396d0.0310.367d0.415a0.2350.434a−0.029−0.380d−0.281c0.414a0.481b0.2060.900
apoA-II pool−0.355d0.435a0.412a0.471a0.284c0.2480.380d0.247−0.087−0.460a0.433a0.326d0.824b0.1770.279c
apoA-II FCR−0.1580.310c0.1560.266c0.307c0.1290.191−0.150−0.292c0.2300.1360.244−0.1210.672b0.612b0.303c
apoA-II PR0.267c0.336d0.1710.343d0.329d0.1400.297c−0.226−0.226−0.352d0.2300.290c0.1230.606b0.652b0.580b
VLDL1-TG PR0.0490.440a0.348d0.509b0.664b0.377d0.333d−0.205−0.480b−0.305c0.307c0.287c0.1270.512b0.404d0.248
VLDL2-TG PR−0.259c0.280c0.442a0.2300.1790.1560.142−0.065−0.268c−0.291c0.336d0.0640.325d0.0830.0080.397d
VLDL1-TG direct FCR0.145−0.048−0.2130.1900.250−0.097−0.271c−0.098−0.0200.121−0.458a−0.253c−0.2470.054−0.019−0.219
VLDL1-TG indirect FCR−0.153−0.0860.0310.018−0.143−0.147−0.537b0.0830.1950.181−0.518b−0.480b0.047−0.247−0.281c0.015
VLDL1-TG total FCR0.097−0.067−0.1930.1830.200−0.128−0.390d−0.0710.0300.159−0.562b−0.359d−0.221−0.012−0.089−0.202
VLDL2-TG FCR−0.316c0.0600.1190.0540.1340.051−0.2390.058−0.051−0.021−0.085−0.1080.293c0.0530.0170.275c
VLDL1-apoB PR−0.1050.400d0.323c0.431a0.574b0.322d0.430d−0.184−0.401d−0.302c0.437a0.367d0.0810.422a0.347d0.191
VLDL2-apoB PR−0.1660.271c0.335d0.1920.348d0.1650.255c−0.242−0.307c−0.1930.360d0.307c0.0680.1900.0880.038
VLDL1-apoB direct FCR0.112−0.005−0.2320.1970.122−0.053−0.0800.066−0.0930.079−0.277c−0.288c−0.1040.0750.094−0.073
VLDL1-apoB indirect FCR0.021−0.204−0.122−0.093−0.163−0.275c−0.573b0.0020.2470.330d−0.640b−0.521b−0.211−0.224−0.292c−0.306c
VLDL1-apoB total FCR0.106−0.135−0.272c0.102−0.003−0.219−0.434a0.0560.0810.277c−0.613b−0.547b−0.222−0.082−0.109−0.256c
VLDL2-apoB FCR−0.0890.0270.257c−0.0640.1950.116−0.112−0.161−0.1290.027−0.067−0.056−0.0360.059−0.073−0.117
CETP activity0.336#−0.028−0.0910.009−0.0810.177−0.033−0.177−0.215−0.106−0.140−0.072−0.205−0.076−0.124−0.149
PLTP activity−0.007−0.018−0.121−0.027−0.177−0.1200.145−0.057−0.055−0.2160.1300.1800.048−0.0010.0850.026
apoA-II FCRapoA-II PRVLDL1-TG PRVLDL2-TG PRVLDL1-TG Direct FCRVLDL1-TG Indirect FCRVLDL1-TG Total FCRVLDL2-TG FCRVLDL1-apoB PRVLDL2-apoB PRVLDL1-apoB Direct FCRVLDL1-apoB Indirect FCRVLDL1-apoB Total FCRVLDL2-apoB FCRCETP ActivityPLTP Activity
Age, y
BMI, kg/m2
Visceral fat
Subcutaneous fat
Liver fat
HOMA-IR
TG
HDL-C
HDL-C/apoA-I
HDL-C/apoA-II
VLDL1-TG
VLDL1-apoB
apoA-I pool
apoA-I FCR
apoA-I PR
apoA-II pool
apoA-II FCR
apoA-II PR0.915b
VLDL1-TG PR0.361d0.331d
VLDL2-TG PR0.267c0.283c0.229
VLDL1-TG direct FCR0.077−0.0090.545b−0.272
VLDL1-TG indirect FCR0.2090.156−0.1810.491b0.107
VLDL1-TG total FCR0.1250.0310.468a−0.1320.968b0.353d
VLDL2-TG FCR0.383d0.355d0.0540.648b−0.1260.618b0.037
VLDL1-apoB PR0.2440.255c0.758b0.2160.286c−0.286c0.197−0.120
VLDL2-apoB PR0.0830.0360.282c0.497b−0.0990.003−0.1030.0210.546b
VLDL1-apoB direct FCR0.0770.0830.481b−0.1350.763b0.0200.723b−0.1130.383d−0.346d
VLDL1-apoB indirect FCR−0.010−0.122−0.275c0.0450.310c0.690b0.465a0.204−0.2230.197−0.095
VLDL1-apoB total FCR0.058−0.0100.189−0.0940.772b0.452a0.840b0.0440.176−0.1620.771b0.561b
VLDL2-apoB FCR0.259c0.149−0.0800.273c−0.1380.292−0.0560.625b−0.0650.323c−0.373d0.322d−0.104
CETP activity−0.143−0.1970.083−0.0570.2470.0390.242−0.14−0.090−0.1070.0850.1020.136−0.019
PLTP activity−0.0040.065−0.095−0.180−0.181−0.375d−0.265c−264c0.024−0.0820.030−0.308c−0.172−0.160−0.23
apoA-II FCRapoA-II PRVLDL1-TG PRVLDL2-TG PRVLDL1-TG Direct FCRVLDL1-TG Indirect FCRVLDL1-TG Total FCRVLDL2-TG FCRVLDL1-apoB PRVLDL2-apoB PRVLDL1-apoB Direct FCRVLDL1-apoB Indirect FCRVLDL1-apoB Total FCRVLDL2-apoB FCRCETP ActivityPLTP Activity
Age, y
BMI, kg/m2
Visceral fat
Subcutaneous fat
Liver fat
HOMA-IR
TG
HDL-C
HDL-C/apoA-I
HDL-C/apoA-II
VLDL1-TG
VLDL1-apoB
apoA-I pool
apoA-I FCR
apoA-I PR
apoA-II pool
apoA-II FCR
apoA-II PR0.915b
VLDL1-TG PR0.361d0.331d
VLDL2-TG PR0.267c0.283c0.229
VLDL1-TG direct FCR0.077−0.0090.545b−0.272
VLDL1-TG indirect FCR0.2090.156−0.1810.491b0.107
VLDL1-TG total FCR0.1250.0310.468a−0.1320.968b0.353d
VLDL2-TG FCR0.383d0.355d0.0540.648b−0.1260.618b0.037
VLDL1-apoB PR0.2440.255c0.758b0.2160.286c−0.286c0.197−0.120
VLDL2-apoB PR0.0830.0360.282c0.497b−0.0990.003−0.1030.0210.546b
VLDL1-apoB direct FCR0.0770.0830.481b−0.1350.763b0.0200.723b−0.1130.383d−0.346d
VLDL1-apoB indirect FCR−0.010−0.122−0.275c0.0450.310c0.690b0.465a0.204−0.2230.197−0.095
VLDL1-apoB total FCR0.058−0.0100.189−0.0940.772b0.452a0.840b0.0440.176−0.1620.771b0.561b
VLDL2-apoB FCR0.259c0.149−0.0800.273c−0.1380.292−0.0560.625b−0.0650.323c−0.373d0.322d−0.104
CETP activity−0.143−0.1970.083−0.0570.2470.0390.242−0.14−0.090−0.1070.0850.1020.136−0.019
PLTP activity−0.0040.065−0.095−0.180−0.181−0.375d−0.265c−264c0.024−0.0820.030−0.308c−0.172−0.160−0.23

VLDL1-apoB data were derived from 58 subjects and VLDL1 TG kinetic data from 46 subjects.

a

P ≤ .001.

b

P ≤ .0001.

c

P < .05.

d

P ≤ .01.

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Independent predictors for apoA-I catabolism

Because there was a strong correlation between apoA-I FCR and apoA-I PR (r = 0.900, P < .0001), we focused on independent factors regulating apoA-I FCR by multivariable analyses.

First, we analyzed the morphological and biological parameters that may predict apoA-I FCR. With this multivariable statistical model, liver fat and plasma TGs were found to be independent predictor variables for apoA-I FCR (Table 4, predictor variables, model 1). When plasma TGs were replaced into the model, by VLDL1-TG concentration, both liver fat and VLDL1-TG concentration were found to be independent predictor variables for apoA-I FCR (Table 4, predictor variables, model 2). When plasma TGs were replaced into the model, by VLDL1-apoB concentration, both liver fat and VLDL1-apoB concentration were found to be independent predictor variables for apoA-I FCR (Table 4, predictor variables, model 3). The introduction of both VLDL1-TG and VLDL1-apoB into the model gave identical results with those obtained with model 3.

Table 4.

Mutivariable Analysis With apoA-I FCR as Dependent Variable (With Morphological and Biological Parameters)

VariablesβtP Valuer2r2 Change
Predictor variables
    Model 1
        Liver fat0.4043.42.0010.265
        TGs0.3613.07.0040.3830.118
        BMI0.2011.49.142
        Age,−0.146−1.31.196
        Subcutaneous fat0.1571.23.223
        Visceral fat−0.130−1.02.311
        HOMA-IR−0.072−0.54.591
        Gender−0.023−0.20.840
    Model 2
        Liver fat0.4143.29.0020.265
        VLDL1-TG0.2952.35.0230.3420.077
        BMI0.2171.50.140
        Subcutaneous fat0.1821.38.175
        Visceral fat−0.165−1.20.235
        Age−0.134−1.13.262
        HOMA-IR−0.098−0.68.499
        Gender0.0090.07.941
    Model 3
        Liver fat0.4003.14.0030.265
        VLDL1-apoB0.3072.42.0200.3460.081
        BMI0.2181.51.136
        Age−0.163−1.39.171
        Subcutaneous fat0.1611.21.232
        Visceral fat−0.087−0.66.509
        HOMA-IR−0.049−0.35.726
        Gender−0.034−0.28.778
Consequential variables (age and gender in the model)
    HDL-C/apoA-I−0.593−5.49<.00010.305
    Age−0.248−2.29.0260.3650.060
    Gender0.1201.04.301
    HDL-C/apoA-II0.0350.24.810
    HDL-C0.0040.03.975
    apoA-I pool−0.002−0.02.984
VariablesβtP Valuer2r2 Change
Predictor variables
    Model 1
        Liver fat0.4043.42.0010.265
        TGs0.3613.07.0040.3830.118
        BMI0.2011.49.142
        Age,−0.146−1.31.196
        Subcutaneous fat0.1571.23.223
        Visceral fat−0.130−1.02.311
        HOMA-IR−0.072−0.54.591
        Gender−0.023−0.20.840
    Model 2
        Liver fat0.4143.29.0020.265
        VLDL1-TG0.2952.35.0230.3420.077
        BMI0.2171.50.140
        Subcutaneous fat0.1821.38.175
        Visceral fat−0.165−1.20.235
        Age−0.134−1.13.262
        HOMA-IR−0.098−0.68.499
        Gender0.0090.07.941
    Model 3
        Liver fat0.4003.14.0030.265
        VLDL1-apoB0.3072.42.0200.3460.081
        BMI0.2181.51.136
        Age−0.163−1.39.171
        Subcutaneous fat0.1611.21.232
        Visceral fat−0.087−0.66.509
        HOMA-IR−0.049−0.35.726
        Gender−0.034−0.28.778
Consequential variables (age and gender in the model)
    HDL-C/apoA-I−0.593−5.49<.00010.305
    Age−0.248−2.29.0260.3650.060
    Gender0.1201.04.301
    HDL-C/apoA-II0.0350.24.810
    HDL-C0.0040.03.975
    apoA-I pool−0.002−0.02.984

Abbreviations: β, standardized coefficient; BMI, body mass index. Significant parameter values are shown in bold and italic.

For predictor variables, model 1, total r2 = 0.383. For predictor variables, model 2, total r2 = 0.342. For predictor variables, model 3, total r2 = 0.346. For consequential variables, total r2 = 0.365. Age and gender in the model.

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Table 4.

Mutivariable Analysis With apoA-I FCR as Dependent Variable (With Morphological and Biological Parameters)

VariablesβtP Valuer2r2 Change
Predictor variables
    Model 1
        Liver fat0.4043.42.0010.265
        TGs0.3613.07.0040.3830.118
        BMI0.2011.49.142
        Age,−0.146−1.31.196
        Subcutaneous fat0.1571.23.223
        Visceral fat−0.130−1.02.311
        HOMA-IR−0.072−0.54.591
        Gender−0.023−0.20.840
    Model 2
        Liver fat0.4143.29.0020.265
        VLDL1-TG0.2952.35.0230.3420.077
        BMI0.2171.50.140
        Subcutaneous fat0.1821.38.175
        Visceral fat−0.165−1.20.235
        Age−0.134−1.13.262
        HOMA-IR−0.098−0.68.499
        Gender0.0090.07.941
    Model 3
        Liver fat0.4003.14.0030.265
        VLDL1-apoB0.3072.42.0200.3460.081
        BMI0.2181.51.136
        Age−0.163−1.39.171
        Subcutaneous fat0.1611.21.232
        Visceral fat−0.087−0.66.509
        HOMA-IR−0.049−0.35.726
        Gender−0.034−0.28.778
Consequential variables (age and gender in the model)
    HDL-C/apoA-I−0.593−5.49<.00010.305
    Age−0.248−2.29.0260.3650.060
    Gender0.1201.04.301
    HDL-C/apoA-II0.0350.24.810
    HDL-C0.0040.03.975
    apoA-I pool−0.002−0.02.984
VariablesβtP Valuer2r2 Change
Predictor variables
    Model 1
        Liver fat0.4043.42.0010.265
        TGs0.3613.07.0040.3830.118
        BMI0.2011.49.142
        Age,−0.146−1.31.196
        Subcutaneous fat0.1571.23.223
        Visceral fat−0.130−1.02.311
        HOMA-IR−0.072−0.54.591
        Gender−0.023−0.20.840
    Model 2
        Liver fat0.4143.29.0020.265
        VLDL1-TG0.2952.35.0230.3420.077
        BMI0.2171.50.140
        Subcutaneous fat0.1821.38.175
        Visceral fat−0.165−1.20.235
        Age−0.134−1.13.262
        HOMA-IR−0.098−0.68.499
        Gender0.0090.07.941
    Model 3
        Liver fat0.4003.14.0030.265
        VLDL1-apoB0.3072.42.0200.3460.081
        BMI0.2181.51.136
        Age−0.163−1.39.171
        Subcutaneous fat0.1611.21.232
        Visceral fat−0.087−0.66.509
        HOMA-IR−0.049−0.35.726
        Gender−0.034−0.28.778
Consequential variables (age and gender in the model)
    HDL-C/apoA-I−0.593−5.49<.00010.305
    Age−0.248−2.29.0260.3650.060
    Gender0.1201.04.301
    HDL-C/apoA-II0.0350.24.810
    HDL-C0.0040.03.975
    apoA-I pool−0.002−0.02.984

Abbreviations: β, standardized coefficient; BMI, body mass index. Significant parameter values are shown in bold and italic.

For predictor variables, model 1, total r2 = 0.383. For predictor variables, model 2, total r2 = 0.342. For predictor variables, model 3, total r2 = 0.346. For consequential variables, total r2 = 0.365. Age and gender in the model.

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Next, we analyzed the morphological and biological parameters that may be consequent variables of apoA-I FCR. With this multivariable statistical model, the HDL-C to apoA-I ratio and age were independently associated with apoA-I FCR (Table 4, consequential variables).

We finally analyzed the kinetic parameters that may be independently associated with apoA-I FCR. For this purpose, we performed a multivariable analysis using all kinetic parameters that were correlated in univariate analysis with apoA-I FCR with a value of P < .10, except apoA-I PR. apoA-I FCR was independently associated with apoA-II FCR (P < .0001), VLDL1-TG indirect FCR (P = .001), and VLDL1-TG PR (P = .048) (Table 5). Together all three variables explained 64.7% of the variability in apoA-I FCR.

Table 5.

Mutivariable Analysis With apoA-I FCR as Dependent Variable (With VLDL Subspecies and apoA-II Kinetic Parameters)

VariablesβtP Valuer2r2 Change
ApoA-II FCR0.6676.32<.00010.448
VLDL1-TG indirect FCR−0.357−3.58.0010.6100.162
VLDL1-TG PR0.2132.04.0480.6470.037
Study center−0.193−1.66.104
ApoA-II PR−0.366−1.41.166
Age−0.115−1.16.252
BMI0.1211.09.280
VLDL1-apoB indirect FCR0.1551.09.280
Gender0.0590.58.560
VLDL1-apoB PR0.0600.42.676
VariablesβtP Valuer2r2 Change
ApoA-II FCR0.6676.32<.00010.448
VLDL1-TG indirect FCR−0.357−3.58.0010.6100.162
VLDL1-TG PR0.2132.04.0480.6470.037
Study center−0.193−1.66.104
ApoA-II PR−0.366−1.41.166
Age−0.115−1.16.252
BMI0.1211.09.280
VLDL1-apoB indirect FCR0.1551.09.280
Gender0.0590.58.560
VLDL1-apoB PR0.0600.42.676

Abbreviations: β: standardized coefficient; BMI, body mass index. Total r2 = 0.647 (age, gender, and center in the model). Significant parameter values are shown in bold and italic.

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Table 5.

Mutivariable Analysis With apoA-I FCR as Dependent Variable (With VLDL Subspecies and apoA-II Kinetic Parameters)

VariablesβtP Valuer2r2 Change
ApoA-II FCR0.6676.32<.00010.448
VLDL1-TG indirect FCR−0.357−3.58.0010.6100.162
VLDL1-TG PR0.2132.04.0480.6470.037
Study center−0.193−1.66.104
ApoA-II PR−0.366−1.41.166
Age−0.115−1.16.252
BMI0.1211.09.280
VLDL1-apoB indirect FCR0.1551.09.280
Gender0.0590.58.560
VLDL1-apoB PR0.0600.42.676
VariablesβtP Valuer2r2 Change
ApoA-II FCR0.6676.32<.00010.448
VLDL1-TG indirect FCR−0.357−3.58.0010.6100.162
VLDL1-TG PR0.2132.04.0480.6470.037
Study center−0.193−1.66.104
ApoA-II PR−0.366−1.41.166
Age−0.115−1.16.252
BMI0.1211.09.280
VLDL1-apoB indirect FCR0.1551.09.280
Gender0.0590.58.560
VLDL1-apoB PR0.0600.42.676

Abbreviations: β: standardized coefficient; BMI, body mass index. Total r2 = 0.647 (age, gender, and center in the model). Significant parameter values are shown in bold and italic.

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Liver fat, VLDL1 production, and apoA-I catabolism

Because liver fat was associated with both apoA-I FCR and VLDL1 production (VLDL1-TG PR and VLDL1-apoB PR) and apoA-I FCR was associated with VLDL1 production (VLDL1-TG PR and VLDL1-apoB PR), we wanted to test whether the association between liver fat and apoA-I FCR was driven by VLDL1 production. After adjustment for VLDL1-TG PR, liver fat was not significantly correlated with apoA-I FCR.

Discussion

In a large multicenter in vivo kinetic study in abdominally obese individuals, we show that kinetics of VLDL1 is an important independent determinant for apoA-I FCR and more precisely that apoA-I FCR is independently associated with both catabolism and production of VLDL1-TG. In addition, we show an association between liver fat and apoA-I FCR that is mostly mediated by the hepatic secretion of VLDL1-TG.

Lipoprotein kinetic studies have shown that VLDLs are metabolically heterogeneous, with accumulating evidence demonstrating that both the production and catabolism of large VLDL1 and smaller VLDL2 are regulated independently (10). The separate evaluation of VLDL1 and VLDL2 metabolism is critical in the metabolic syndrome or type 2 diabetes in which variations in plasma TG concentrations are mainly related to differences in VLDL1, and hepatic overproduction of VLDLs is mainly due to increased hepatic secretion of VLDL1 particles (11, 12). To enhance our understanding of the pathways leading to VLDL1 and VLDL2 and of the metabolic fate of these particles, we used a multicompartmental mathematical model that allows the kinetics of TGs and apoB100 in VLDL1 and VLDL2 to be simultaneously assessed after a bolus injection of glycerol and leucine. Using this model, we have gained further insight into the relationship between the metabolism of TG-rich lipoproteins and the catabolism of HDL and to show that VLDL1 kinetics modulate HDL-apoA-I turnover.

We show that apoA-I FCR is independently associated with both catabolism and production of VLDL1-TG, indicating that kinetics of VLDL1 is an important independent determinant for apoA-I FCR. Our data indicate that VLDL1-TG indirect FCR, representing the catabolism of VLDL1 particles mediated by lipoprotein lipase, is an important factor that is negatively associated with HDL apoA-I FCR. Consistent with these data, increase in VLDL (or VLDL1) FCR induced by n-3 polyunsaturated fatty acid supplementation or by rosuvastatin have been shown to be significantly associated with reduction of HDL-apoA-I catabolism (15, 20–22). Moreover, our data indicate that VLDL1 PR is also an independent regulator of HDL-apoA-I catabolism. This is in line with data from a kinetic study performed in abdominally obese men that showed that the reduction of VLDL production by weight loss was accompanied by a significant decrease in HDL-apoA-I catabolism (23). Hence, our data strongly suggest that the hypercatabolism of HDL-apoA-I observed in abdominal obesity may be the consequence of dysregulated metabolism of VLDL1 particles including both increased VLDL1 production and reduced VLDL1 catabolism. Increased production and reduced catabolism of VLDL1 particles result in an expanded pool of VLDL1, which are large triglyceride-rich lipoproteins. This may promote CETP-mediated triglyceride enrichment of HDL particles and, as a consequence, enhance HDL catabolism (24).

We also newly demonstrate that liver fat, assessed by proton magnetic resonance spectroscopy, is a positive and independent predictor of HDL apoA-I catabolism among morphological and biological variables. However, visceral fat was not found to be associated with HDL apoA-I FCR. Increased VLDL1-apoB or VLDL1-TG production rate has been shown to be positively correlated with liver fat (11). In our study, we showed that the correlation between liver fat and HDL apoA-I FCR was not significant after adjustment for VLDL1-TG PR. This suggests that the association between liver fat and apoA-I FCR is mostly mediated by the hepatic production of VLDL1-TG.

When analyzing the consequent variables associated with HDL apoA-I FCR, we found that HDL-C to apoA-I ratio was negatively associated with apoA-I catabolism. Thus, overcatabolism of HDL in abdominal obesity is associated with smaller size HDL particles with reduced cholesterol content. This is in line with the negative correlation between HDL particle size and apoA-I FCR previously reported (9). It is also consistent with increased triglyceride transfer from VLDL to HDL mediated by CETP that results in the formation of smaller triglyceride-rich HDL particles that are rapidly catabolized by hepatic lipase in insulin resistance.

In addition, we newly demonstrate an independent association between apoA-I and apoA-II catabolism. In several low HDL cholesterol states, apoA-I FCR and apoA-II FCR are modified to the same extent. For example, a parallel increase in apoA-I FCR and apoA-II FCR has been reported in patients with primary HDL deficiency (25) as well as in individuals with the metabolic syndrome (12). In addition, the link between apoA-I and apoA-II catabolism is also suggested by a study showing that apoA-I facilitates hepatic lipase-mediated hydrolysis in apoA-II containing HDL particles (26). Collectively, our data indicate a robust, direct relationship between the catabolism of apoA-I and apoA-II, consistent with the tight structural nexus of these apoproteins in biogenesis and the disposal of HDL particles.

In the present study, we observe a very strong association between apoAI FCR and apoAI PR that has previously been reported (8). Although a direct mathematical link exists between PR and FCR because PR is calculated with FCR as a variable, we cannot exclude balancing feedback mechanisms between apoAI FCR and apoAI PR. However, this hypothesis needs further investigation.

We consider that the strong association between VLDL1 kinetics and HDL-apoA-I catabolism has important implications. For instance, in conditions of abdominal obesity, the reduction of hepatic secretion of VLDL1, and/or an increase in the catabolism of VLDL1 by weight loss and physical exercise will regulate the catabolism of HDL, resulting in a long-term increase in HDL cholesterol. In addition, an increase in HDL-apoA-I catabolism can result in dysfunctional, proatherogenic HDL particles, with an impaired capacity to effect cellular cholesterol efflux and a reduced antioxidative and anti-inflammatory properties (27). Hence, lifestyle interventions, such as weight regulation and aerobic exercise, may correct HDL overcatabolism and dysfunctionality by decreasing the hepatic secretion of the VLDL1 subspecies.

Our investigation has the limitations of a cross-sectional design. We studied more men than women and might have missed gender differences in the relationship between the kinetics of VLDL subspecies and HDL apoA-I. We did not study the kinetics of HDL subspecies or the turnover of LpA-I and LpA-I:A-II particles. This requires further investigation but would expect that an expanded VLDL1 pool size would result in accelerate catabolism in all HDL particles, with a preferential reduction in smaller size particles (12).

In conclusion, we demonstrated that VLDL1 is an important independent determinant for apoA-I FCR and more precisely that apoA-I FCR is independently associated with both catabolism and production of VLDL1-TG. In addition, we show an association between liver fat and apoA-I FCR that is mostly mediated by VLDL1-TG production. These data indicate that, in abdominal obesity, dysfunctional VLDL1 metabolism is an important modulator of HDL apoA-I catabolism.

Acknowledgments

We are indebted to Thomas Gautier and Valérie Deckert for the measurement of CETP and PLTP activities.

This study had a trial registration number of NCT00408148.

This work was supported by grants from Helsinki University Central Hospital EVO (Finnish State Grant) funds, Finnish Diabetes Research Foundation, Sigrid Juselius Foundation, Swedish Research Council, Swedish Heart-Lung Foundation, Diabetes Research Wellness Foundation, Novo Nordisk Foundation, Swedish Diabetes Foundation, Sahlgrenska University Hospital ALF (Avtalet om Läkarutbildning och medicinsk Forskning) funds, Sanofi and by the National Health and Medical Research Council.

Disclosure Summary: The authors have nothing to declare.

Abbreviations

     
  • apo

    apolipoprotein

    •  
  • AU

    arbitrary unit

    •  
  • CETP

    cholesteryl ester transfer protein

    •  
  • FCR

    fractional catabolic rate

    •  
  • HDL

    high-density lipoprotein

    •  
  • HDL-C

    HDL cholesterol

    •  
  • HOMA-IR

    homeostasis model assessment index of insulin resistance

    •  
  • LpA

    lipoprotein A

    •  
  • PLTP

    plasma phospholipd transfer protein

    •  
  • PR

    production rate

    •  
  • TG

    triglyceride

    •  
  • VLDL

    very low-density lipoprotein.

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Issue Section:
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