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Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:299-305

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:299-305.)
© 1995 American Heart Association, Inc.

Articles

Persistence of Low HDL-C Levels After Weight Reduction in Older Men With Small LDL Particles

Leslie I. Katzel; Patricia J. Coon; Ellen Rogus; Ronald M. Krauss; Andrew P. Goldberg

From the Department of Medicine, Division of Gerontology, University of Maryland School of Medicine and Baltimore Veterans Affairs Medical Center, Geriatrics Research, Education, and Clinical Center, Baltimore, Md, and the Life Sciences Division (R.M.K.), Department of Molecular and Nuclear Medicine, Lawrence Berkeley Laboratory, University of California, Berkeley.

Correspondence to Leslie I. Katzel, MD, PhD, Baltimore VA Medical Center, Geriatrics Service (18), 10 N Greene St, Baltimore, MD 21201.


*    Abstract
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 *Abstract
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Abstract LDL subclass pattern B is characterized by a predominance of small LDL particles (LDL peak particle size <=255 Å) and is associated with increased plasma triglyceride (TG) and reduced HDL cholesterol (HDL-C) concentrations. This study compared the effect of weight loss on lipoprotein and glucose metabolism in 15 healthy, obese (body mass index [BMI], 30.9±2.4 kg/m2), older (60±9 years) men with LDL pattern B and in 25 men of comparable age and BMI with LDL pattern A (LDL peak particle size >=260 Å). At baseline, men with LDL pattern B had higher TG and lower apolipoprotein (apo) A-I, HDL-C, and HDL2-C levels (P<.001) than men with LDL pattern A, while the total cholesterol and LDL cholesterol levels and fasting and 2-hour postprandial glucose and insulin levels did not differ between groups. With weight loss (10.1±3.6 kg) there were significant decreases in 2-hour postprandial glucose and insulin levels in men with LDL patterns B and A (P<.05). However, the change in plasma TG, HDL-C, HDL2-C, and apoA-I levels with weight loss differed between groups. In men with LDL pattern A, plasma TG levels decreased by 15% (P<.001) compared with a 34% (P<.001) decrease in LDL pattern B (two-factor ANOVA, P<.01). Plasma HDL-C concentrations increased by 0.16 mmol/L (P<.001) in the men with LDL pattern A but by only 0.07 mmol/L in the men with LDL pattern B (two-factor ANOVA, P<.05). After weight loss, only 5 of the 15 men with LDL pattern B had HDL-C levels above 0.90 mmol/L (35 mg/dL), whereas 22 of 25 men with LDL pattern A had HDL-C levels above 0.90 mmol/L ({chi}2=18, P<.0001). Furthermore, with weight loss, 11 of the 15 men with LDL pattern B increased their LDL peak particle diameter; 7 converted to intermediate LDL pattern, and 4 converted to LDL pattern A. By comparison, there were no significant changes in weight, lipoprotein, or apolipoprotein concentrations at 1-year follow-up in 12 metabolic control subjects. Thus, despite significant reductions in weight and body fat and concomitant decreases in plasma TG and insulin levels, HDL-C and HDL2 subspecies levels remain low in men with LDL pattern B.


Key Words: LDL subclasses • HDL • triglycerides • insulin resistance • abdominal obesity


*    Introduction
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 *Introduction
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LDL particles, which are the major cholesterol-carrying lipoproteins in plasma, vary in size, density, and composition. Most individuals can be classified on the basis of their LDL particle size distribution into one of two LDL subclass patterns.1 Individuals with a predominance of small LDL particles (LDL peak particle size <=255 Å) have LDL subclass pattern B; those with a predominance of larger, more buoyant LDL particles (LDL peak particle size >255 Å) have LDL subclass pattern A. Individuals with LDL pattern B often have atherogenic lipoprotein profiles, namely, reduced plasma levels of HDL cholesterol (HDL-C), increased triglyceride (TG) levels,2 3 4 and other coronary artery disease risk factors, including glucose intolerance/insulin resistance5 6 7 8 and hypertension.5 Moreover, individuals with LDL pattern B appear to be at increased risk for the development of coronary artery disease and myocardial infarction independent of these coexistent risk factors.9 10

Abdominal obesity is associated with abnormalities in glucose and lipoprotein metabolism.11 The insulin resistance and hyperinsulinemia associated with abdominal obesity are considered central in the pathogenesis of the glucose intolerance, non–insulin-dependent diabetes mellitus, hypertension, and small LDL particles found in this syndrome.5 6 7 8 12 13 14 15 The relations of TG and HDL concentrations with plasma insulin levels and body composition differ in men with LDL patterns A and B,16 resulting in higher plasma levels of TG and lower HDL-C concentrations in men with LDL pattern B than LDL pattern A for a given degree of obesity and plasma insulin levels. Based on these analyses, we hypothesized that the increment in HDL levels with weight loss would be blunted in obese men with LDL pattern B compared with LDL pattern A. This study compared the effects of weight loss on lipoprotein and glucose metabolism and LDL particle size in healthy middle-aged and older men with LDL patterns B and A.


*    Methods
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 *Methods
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Subject Recruitment, Screening, and Selection
This study was approved by the University of Maryland and the Francis Scott Key Medical Center Human Studies Institutional Review Boards, and all subjects provided informed consent prior to participation. Healthy nonsmoking male volunteers 46 through 79 years of age with a wide range of body mass index (BMI) and physical conditioning status were recruited from the Baltimore-Washington metropolitan area for participation in the Fitness After Forty-Five research study.17 18 Subject exclusion criteria included history of coronary artery disease, hypertension (blood pressure >140/90 mm Hg), hyperlipidemia (defined as a plasma TG or LDL cholesterol [LDL-C] level >90th percentile for age and gender according to the Lipid Research Center criteria19 ), history of diabetes mellitus or fasting glucose >140 mg/dL,20 anemia, or abnormalities in liver, renal, or electrolyte metabolism. Cross-sectional data have been reported on 160 men.16 In this study we report data on 40 obese men (BMI >27 kg/m2) who completed a 9-month weight loss intervention program. Fifteen of the 40 men had LDL pattern B (LDL peak particle diameter <=255 Å); the other 25 had LDL pattern A (LDL peak particle diameter >=260 Å). To maximize the differences between individuals with a predominance of small LDL particles and those with a predominance of large LDL particles, individuals who had an intermediate LDL pattern at baseline (LDL peak particle diameter 255.1 to 259.9 Å) were excluded from this intervention study. Twelve individuals (7 with LDL pattern A and 5 with LDL pattern B) of comparable age and obesity who were randomized to a metabolic control group that did not lose weight were tested at baseline and after 1 year of follow-up.

Study Design
Prior to baseline metabolic testing, all test subjects and the metabolic control subjects were instructed by registered dietitians in the principles of an isocaloric American Heart Association (AHA) Step I diet.21 They were told not to lose weight or change their level of physical activity. Adherence was monitored by dietary recall and analysis of 7-day food records. After 3 months on the isocaloric AHA Step I diet, the men underwent baseline metabolic testing. To further ensure dietary stability, the men were provided weight-maintaining AHA Step I diets of comparable composition to their own AHA Step I diets from our metabolic kitchen for 4 days prior to and during metabolic testing.

After completion of the baseline metabolic testing, men in the weight loss intervention group were placed on a hypocaloric AHA Step I diet. Under the supervision of registered dietitians and the investigators, the men attended group weight loss sessions. On average, the subjects were instructed to consume 300 to 500 fewer calories per day during the weight loss intervention than they consumed on the isocaloric AHA Step I diet. The goal was for the men to decrease their body weight by >10% over a 9-month period while maintaining the diet composition of the AHA Step I diet. Upon reaching their target weight, the men were stabilized at this weight for at least 1 month prior to repeat metabolic testing. Food records were reviewed to ensure compliance with the AHA Step I diet. At the time of retesting, the men in the weight loss intervention group and the metabolic control subjects were provided weight-maintaining AHA Step I diets for 6 days from the metabolic kitchen.

Body Composition
BMI was calculated as body weight in kilograms divided by height in meters squared. Body density was determined by hydrostatic weighing at baseline and after weight loss in the weight loss intervention group and at baseline and after 1 year of longitudinal follow-up in the metabolic control subject group. Percent body fat was calculated after correction for the residual lung volume using the Siri equation.22 The waist-to-hip ratio (WHR), measured as the ratio of the minimal abdominal circumference divided by the circumference at the maximal gluteal protuberance, was the index of body fat distribution.

Noninvasive Cardiac Evaluation and Measurement of Maximal Aerobic Capacity
An exercise treadmill test to >85% of the predicted age-adjusted maximal heart rate (220-age in years) was performed according to the Bruce protocol23 to exclude subjects with symptomatic heart disease. On a subsequent visit, the maximal aerobic capacity (VO2max) was determined by using a modified Balke protocol24 as described.16 The VO2max is expressed in liters per minute.

Metabolic Testing
Blood samples for the determination of fasting lipoprotein lipid levels and apolipoprotein concentrations were drawn into chilled EDTA (1 mg/mL blood) tubes after a 12- to 14-hour overnight fast on days 4 and 6 of the controlled metabolic diet. The reported lipoprotein lipids are the means of these two determinations. On day 4 of the metabolic diet, after the lipid samples were drawn, an oral glucose tolerance test (40 g glucose/m2 body surface area) was performed.25 The glucose dose averaged 80±3 g. Plasma glucose was measured by the glucose oxidase method using a Beckman Glucose Analyzer (Beckman Instruments). Plasma insulin levels (immunoreactive insulin) were measured by radioimmunoassay.26 We have demonstrated17 that in this population there is no relation between the dose of glucose administered and the 2-hour glucose (r=.07, P=NS) and 2-hour insulin (r=.11, P=NS) concentrations. This indicates that the adjusted dose of glucose based on body surface area did not significantly affect the glucose and insulin responses during the oral glucose tolerance test.

Plasma TG and cholesterol levels were measured enzymatically on an Abbott ABA 200 series bichromatic analyzer.27 28 Since none of the subjects had a plasma TG>4.52 mmol/L (400 mg/dL), HDL-C was measured in the supernatant after precipitation of the apolipoprotein (apo) B–containing lipoproteins with dextran sulfate.29 The LDL-C was calculated by using the Friedewald equation.30

Plasma samples for measurement of apoA-I and apoB concentrations were stored at -70°C until the completion of the study, when all samples from a given subject were measured in the same assay. ApoA-I and apoB were measured nephelometrically by using a Beckman Immunochemistry Analyzer II (Beckman Instruments). ApoE phenotype was determined by using immunochemical techniques.31 Known apoE phenotype standards were run in the calibration lanes.

The LDL peak particle size was measured on fresh plasma samples at the Lawrence Berkeley Laboratory using gradient gel electrophoresis (GGE) as described.32 Based on the results of the scans, subjects were classified into one of three LDL pattern phenotypes: B (peak particle diameter <=255 Å), intermediate (peak particle diameter of 255.1 to 259.9 Å), or A (peak particle diameter >=260 Å).

The HDL subclass distribution was measured at baseline and after intervention in 13 of the men with LDL pattern A and in 5 of the men with LDL pattern B by using GGE.32 33 Five HDL subclasses were separated using this method.32 The relative amount of each HDL subspecies is reported as (area in the HDL subspecies mobility interval/total HDL area)x100%.

Statistical Methods
Data were entered into an SAS34 data set for analysis. Because plasma insulin levels at 120 minutes and plasma TG levels were not normally distributed, plasma TG and postprandial immunoreactive insulin levels were log10 transformed prior to the performance of parametric analysis. Paired t tests were used to compare the within-group variables before and after intervention. Two-way ANOVA with weight loss as one main effect and LDL pattern as the second main effect with an interactive term was used to compare the metabolic response to intervention between groups. Pearson product-moment correlation coefficients (r) were calculated. All results are expressed as mean±SD. Differences at P<.05 were considered significant.


*    Results
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Baseline
The baseline physical characteristics of the 25 men with LDL pattern A and the 15 men with LDL pattern B enrolled in the weight loss intervention are summarized in Table 1Down. The men with LDL pattern A and LDL pattern B were of similar age (59±8 versus 60±9 years), BMI, WHR, and VO2max; however, the men with LDL pattern B had a higher percent body fat (P<.05) than the men with LDL pattern A. The average WHR of 0.98 indicates an abdominal distribution of body fat.


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  		Table 1. Anthropometric Characteristics in the Intervention Group by LDL Pattern

Baseline fasting and 2-hour postprandial glucose and insulin levels were similar in men with LDL patterns A and B (Table 2Down). Baseline fasting plasma TG concentrations were significantly higher (P<.001) and HDL-C (P<.001) and HDL2-C concentrations were lower in men with LDL pattern B than LDL pattern A (Table 2Down). Only 1 of the 15 men with LDL pattern B had an HDL-C level above 0.90 mmol/L (35 mg/dL), the established National Cholesterol Education Program criterion for low HDL-C concentrations in men.21 By contrast, 20 of the 25 men with LDL pattern A had HDL-C levels above 0.90 mmol/L ({chi}2=20, P<.0001). Similarly, plasma apoA-I levels were lower in men with LDL pattern B than A (P<.01; Table 2Down). Plasma levels of total cholesterol, LDL-C, and apoB were similar in both groups. Four of the men with LDL pattern A were apoE phenotype 2/3, 14 were apoE 3/3, 6 were apoE 4/3, 1 was apoE 4/2, and 1 was apoE 4/4. In the men with LDL pattern B, 4 were apoE phenotype 2/3, 10 were apoE 3/3, and 1 was apoE phenotype 4/3.


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  		Table 2. Comparison of the Effect of Weight Loss on Metabolic Characteristics by LDL Pattern

Weight Loss Intervention
The 40 men lost on average 10.1±3.6 kg (range, 4.7 to 20.7 kg) of total body weight due to the intervention. This resulted in highly significant decreases (P<.001) in fat mass, BMI, percent body fat, and WHR, with no significant change in VO2max (Table 1Up). The changes in body composition with weight loss did not differ between the two groups.

The effect of weight loss on glucose tolerance, lipoprotein and apolipoprotein levels, and the LDL peak particle diameter was examined by LDL pattern. With weight loss, there were significant decreases in fasting and postprandial glucose and insulin levels in men with both LDL patterns (Table 2Up). Two-hour postprandial insulin levels decreased by 39% (P<.001) and postprandial glucose levels by 12% (P<.001). The effect of weight loss on fasting and postprandial glucose and insulin levels was similar in both LDL patterns.

The effect of weight loss on total cholesterol, LDL-C, and apoB concentrations did not differ between the two groups (Table 2Up). Plasma TG and HDL-C levels improved with weight loss in both groups of men; however, the magnitude of the changes differed (P<.05). In men with LDL pattern A, plasma TG levels decreased by 0.22 mmol/L (15%) (P<.001), whereas the men with LDL pattern B reduced their plasma TG concentrations by 0.73 mmol/L (34%) (P<.001; Fig 1Down, top). The decrease in plasma TG levels with weight loss was significantly greater in men with LDL pattern B than LDL pattern A (two-factor ANOVA, P<.01), as was the decrease in TG levels relative to the amount of weight loss (two-factor ANOVA, P<.05). In regression analysis, the decrease in TG concentration was highly correlated with the baseline TG concentration (r=.87, P<.001) and was also related to the initial LDL peak particle diameter (r=-.56, P<.001). Therefore with weight loss, individuals with the highest TG levels and smallest LDL particles at baseline had the greatest decrease in TG levels.



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  		Figure 1. Plots showing distribution of plasma triglyceride (TG; top) and HDL cholesterol (HDL-C; center) concentrations and LDL peak particle size (bottom) at baseline ({circ}) and after weight loss ({square}) in men with LDL patterns A and B.

Plasma HDL-C concentrations increased by 0.16 mmol/L (16%) (P<.001) in men with LDL pattern A but by only 0.07 mmol/L (10%) (P<.05) in men with LDL pattern B (Fig 1Up, center). The change in HDL-C levels differed by LDL pattern (two-factor ANOVA, P<.05). After weight loss, only 5 of the 15 men with LDL pattern B had HDL-C levels above 0.90 mmol/L (35 mg/dL), whereas 22 of the 25 men with LDL pattern A had HDL-C levels above 0.90 mmol/L ({chi}2=18, P<.0001). In regression analysis, the change in HDL concentrations was related to the baseline HDL concentration (r=.32, P<.05) and was also related to the initial LDL peak particle diameter (r=.31, P<.05). Therefore with weight loss, individuals with the smallest LDL particles at baseline had the smallest increase in HDL levels.

Both HDL2-C and HDL3-C increased significantly in each group, but the increase was larger in LDL pattern A than B (P<.05). Whereas apoA-I concentrations increased by 9% (P<.001) in men with LDL pattern A, there was no significant change in apoA-I in subjects with LDL pattern B (P<.51). Thus, despite the loss of comparable amounts of weight, the increase in plasma apoA-I, HDL-C, and HDL2-C concentrations with weight loss were significantly less (P<.05) in men with LDL pattern B than LDL pattern A. Even after weight loss the men with LDL pattern B had significantly lower HDL-C concentrations and higher TG levels than the obese men with LDL pattern A had at baseline (P<.05).

In the 40 men, LDL peak particle diameter increased by 4.1±7.6 Å (P<.005) (Fig 1Up, bottom). With weight loss, 11 of the 15 men with LDL pattern B increased their LDL peak particle diameter; 7 converted to an intermediate LDL pattern, and 4 converted to LDL pattern A. Twenty-three of the men with LDL pattern A remained LDL pattern A, and two men converted to an intermediate LDL pattern. There was no significant correlation between the change in LDL peak particle size and the change in TG (r=.16, P=NS) or HDL-C (r=.04, P=NS) concentrations, change in percent body fat (r=.03, P=NS), or change in fasting and postprandial glucose and insulin concentrations when data from the two groups were combined or in the two LDL groups.

To confirm the results of the HDL precipitation measurements, the distributions of HDL subfractions were measured by GGE before and after weight loss in 13 men with LDL pattern A and 6 with LDL pattern B. Overall, the proportions of HDL2b and HDL2a subfractions increased with weight loss (P<.01), while those of the HDL 3a, 3b, and 3c subfractions decreased (P<.01). The magnitude of the response was less in subjects with LDL pattern B than A. Fig 2Down shows representative baseline and post–weight loss HDL subfraction distributions in two individuals who were matched for obesity and amount of weight lost. In the subject with LDL pattern A, HDL-C increased from 0.85 to 1.03 mmol/L after a loss of 12 kg. The percent HDL2b and percent HDL2a measured by GGE increased, with reciprocal shifts also present in the HDL3 subfractions. By contrast, after the same 12-kg weight loss, the subject with LDL pattern B increased his HDL-C level from 0.67 to only 0.72 mmol/L, and there was no apparent shift in the HDL subclass distribution.



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  		Figure 2. Representative HDL subfraction distributions measured by gradient gel electrophoresis before (PRE) and after (POST) the loss of 12 kg in a subject with LDL pattern A (upper tracing) and a subject with LDL pattern B (lower tracing). In the subject with LDL pattern A, an increase in HDL cholesterol (HDL-C) from 0.85 to 1.03 mmol/L was accompanied by a shift in the HDL distribution toward the HDL2b and HDL2a subspecies. In the subject with LDL pattern B, HDL-C rose from 0.67 to only 0.72 mmol/L with no apparent shift in the HDL subclass distribution.

Metabolic Control Subjects
Data from the 12 control subjects who were studied at baseline and after 1 year are summarized in Tables 3Down and 4Down. Body weight, BMI, percent body fat, WHR, and VO2max were unchanged, as were the lipoprotein, apoA-I, and apoB concentrations and LDL peak particle diameter. Fasting glucose and insulin levels were also unchanged, but postprandial glucose and insulin levels increased significantly (P<.05). This last result contrasts with the weight loss groups, in whom indices of glucose tolerance improved.


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  		Table 3. Anthropometric Characteristics of the Control Subjects (n=12)


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  		Table 4. Metabolic Characteristics of the Control Subjects (n=12)


*    Discussion
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 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
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In this study, weight loss did not raise HDL-C levels above 0.90 mmol/L (35 mg/dL) in 11 of 15 obese men with LDL pattern B. This negative result occurred despite a mean 10-kg weight loss, a 34% reduction in plasma TG levels, a 41% decrease in 2-hour postprandial plasma insulin concentrations, and an increase in LDL peak particle size in these 11 men. Furthermore, even after weight loss, men with LDL pattern B had significantly lower HDL-C and higher TG levels than the obese men with LDL pattern A had at baseline. The well-known statistical phenomenon of regression to the mean would not account for the failure of weight loss to raise HDL levels in individuals with LDL pattern B since those with the most extreme (low) values would be expected to "normalize" their values with repeated measurements. Such normalization would result in an apparent exaggerated response to intervention, not the diminished response that was observed. The change in TG and HDL concentrations with weight loss was related to the baseline TG and HDL concentrations and also correlated with the initial LDL peak particle diameter; individuals with the highest TG levels and smallest LDL particles had the greatest absolute decrease in TG levels, whereas individuals with the smallest LDL particles and lowest HDL concentrations had the smallest increase in HDL levels. Therefore, although in cross-sectional studies there is a strong negative correlation between plasma HDL-C concentrations and obesity,35 36 weight reduction failed to raise HDL-C and apoA-I levels in individuals with LDL pattern B to the extent it did in those with LDL pattern A. Based on these results, low HDL-C and HDL2 subspecies levels appear to persist in weight-reduced subjects with LDL pattern B.

The inverse relations between plasma TG and HDL-C levels and between plasma TG and LDL peak particle size reported in cross-sectional studies3 16 37 38 suggest that abnormalities in TG metabolism may result in small dense apoB-enriched LDL particles. Longitudinal data from the Framingham Offspring study that show a negative correlation between the change in LDL size with the change in plasma TG concentrations and a positive correlation with the change in HDL-C levels support the results of these cross-sectional studies.39 Significant relations between changes in LDL flotation rates and changes in TG and HDL levels and an inverse relation between changes in the buoyant LDL-I and dense LDL-III subclasses are also seen with exercise training.40 In studies by Williams et al,41 exercise-induced and diet-induced weight loss interventions increased LDL peak flotation rate, LDL peak particle diameter, and HDL2 mass and decreased VLDL mass in overweight sedentary men. In these studies the changes in LDL peak particle diameter and HDL2 mass correlated with the change in BMI. However, in the present study, there were no significant relations between the change in LDL peak particle size and the change in either TG or HDL-C concentrations or percent body fat. Although this could reflect a type II statistical error due to the smaller sample size in our study, we believe that genetic factors may in part account for this finding.4 39 42 43 44 There was no relation between the change in TG levels and the change in LDL size in patients with familial combined hyperlipidemia (FCHL).44 Furthermore, an altered relation between HDL-C concentrations and body composition has been reported in women with the apoE4 allele.43 The blunted HDL response to weight loss in men with LDL pattern B in this study was not due to the apoE phenotype since only one of the men with LDL pattern B was apoE phenotype 4/3, and none were apoE phenotype 2/2 or 4/4. The regulation of LDL subclass distribution warrants further investigation.

Abnormalities in lipoprotein lipid concentrations and metabolism often persist following intervention in patients with genetic dyslipidemias.44 45 46 47 48 49 50 Three months of gemfibrozil therapy in 13 patients with FCHL who also had LDL subclass pattern B resulted in a 55% decline in TG and a 14% increase in HDL-C concentrations, with no change in HDL2-C concentrations or in the buoyancy of LDL.44 Eleven of the 13 patients remained LDL pattern B. Similar to our findings in men with LDL pattern B, there was no relation of the change in TG levels to the change in LDL size in FCHL patients. By contrast, in another study of 6 patients with combined hyperlipidemia, 1 month of ciprofibrate therapy reduced the concentration of the dense LDL-4 and LDL-5 subspecies (d=1.039 to 1.063 g/mL) by >40%, thereby shifting the LDL subclass distribution toward the less dense subfractions.48 In 6 patients with primary hypercholesterolemia and LDL pattern B there was no significant change in LDL peak particle diameter after 8 weeks of pravastatin therapy.49 Wilson et al50 examined the effect of weight loss on lipoprotein lipid levels and apoB-100 and apoA-I metabolism in 10 patients with primary hypertriglyceridemia. Although a weight loss of 10.6 kg resulted in a 42% reduction in plasma TG levels, there were no significant changes in plasma apoB or HDL-C levels. The apoA-I fractional catabolic rate (FCR) and input rate for LDL apoB remained abnormally high in the majority of the patients after weight loss, suggesting a latent defect in TG metabolism. The investigators speculated that these abnormalities in apoB and apoA-I metabolism may be central to the pathogenesis of LDL pattern B. This is consistent with the results of kinetic studies by Ginsberg et al51 that demonstrated that many individuals with low HDL and normal TG levels have increased apoA-I FCRs and increased apoB production rates. Ginsberg et al speculated that individuals with LDL pattern B may have similar metabolic abnormalities. Vega and Grundy52 report a bimodal distribution of LDL apoB FCRs in normotriglyceridemic patients with hypoalphalipoproteinemia. They hypothesized that individuals with LDL pattern B also may have a high apoB input rate, high LDL apoB FCR, and high apoA-I FCR. Although the metabolic defect underlying LDL pattern B is not known, collectively these reports suggest that the older obese men with LDL pattern B in the present study have both high apoB production rates and catabolic rates and an increased apoA-I FCR and that these metabolic abnormalities may persist after weight loss or pharmacologic interventions.

Several reports demonstrate an association between abdominal obesity, insulin resistance, and small LDL particles,5 6 7 8 16 indicating that some of the adverse effects of abdominal fat on plasma lipoprotein lipids and LDL subclass distribution may be mediated by insulin resistance. In the present study there were significant reductions in total adiposity and WHR with weight loss as well as significant reductions in postprandial insulin levels and improvements in glucose tolerance in individuals with LDL patterns B and A, consistent with an increase in insulin sensitivity. Based on these changes in body composition and insulin sensitivity, one would expect that the increase in HDL and HDL2 subspecies levels in men with LDL pattern B would be similar to that of LDL pattern A. It is noteworthy that the changes in plasma HDL concentrations were dissociated from changes in body composition, glucose tolerance, and insulin levels in the men with LDL pattern B. This further supports our findings16 that the regulation of HDL metabolism by insulin is altered in men with LDL pattern B.

In conclusion, moderate weight reduction in older obese men with LDL pattern B lowered plasma TG levels, improved glucose tolerance, and lowered plasma insulin levels but had a minimal effect on HDL-C concentrations. Similarly, although the average LDL peak particle size increased with weight loss in the 40 men, only 4 of the 15 men with LDL pattern B converted to LDL pattern A. This suggests that after moderate weight loss, there are defects in TG and HDL metabolism that persist in men with LDL pattern B, just as they do in individuals with genetic forms of hypertriglyceridemia.48 Although it is possible that these metabolic defects would be corrected following greater weight loss to achieve ideal body weight, other treatment modalities may be necessary to raise HDL levels and normalize the LDL particle distribution in such patients.


*    Acknowledgments
 
This work was supported by National Institute on Aging Clinical Investigator Award 5-K08-AG00497 (L.I.K.); the Veterans Affairs Regional Advisory Group grant; the Veterans Affairs Geriatric Research, Education and Clinical Center; the Johns Hopkins Academic Teaching Nursing Home Award P01 AG04402; General Clinical Research Center grant M01 RR02719-06; National Institutes of Health (NIH) grant RO1 AG07660-05 (A.P.G.); and NIH Program Project grant HL18574 from the National Heart, Lung, and Blood Institute and was conducted in part at the Lawrence Berkeley Laboratory, US Department of Energy, under contract No. DE-AC03-76SF00098 to the University of California (R.M.K.). The authors are indebted to Marilyn Lumpkin, Laura Holl, and Howard Baldwin for technical assistance; Donald Drinkwater, PhD, and Loretta Lakatta, RN, for body composition measurements; John Sorkin, MD, for biostatistical assistance; and Loretta Hetmanski for typing the manuscript.

Received May 24, 1994; accepted November 21, 1994.


*    References
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

  1. Krauss RM, Burke DJ. Identification of multiple subclasses of plasma low density lipoproteins in normal humans. J Lipid Res. 1982;23:97-104. [Abstract]
  2. Austin MA, King M-C, Vranizan KM, Krauss RM. Atherogenic lipoprotein phenotype: a proposed genetic marker for coronary heart disease risk. Circulation. 1990;82:495-506. [Abstract/Free Full Text]
  3. McNamara JR, Campos H, Ordovas JM, Peterson J, Wilson PDF, Schaefer EF. Effect of gender, age, and lipid status on low-density lipoprotein subfraction distribution: results from the Framingham Offspring Study. Arteriosclerosis. 1987;7:483-490. [Abstract/Free Full Text]
  4. Austin MA, King MC, Vranizan KM, Newman B, Krauss RM. Inheritance of low-density lipoprotein subclass patterns: results of complex segregation analysis. Am J Hum Genet. 1988;43:838-846. [Medline] [Order article via Infotrieve]
  5. Selby JV, Austin MA, Newman B, Zhang D, Quesenberry CP, Mayer EJ, Krauss RM. LDL subclass phenotypes and the insulin resistance syndrome in women. Circulation. 1993;88:381-387. [Abstract/Free Full Text]
  6. Reaven GM, Chen Y-D I, Jeppesen J, Maheux P, Krauss RM. Insulin resistance and hyperinsulinemia in individuals with small, dense, low density lipoprotein particles. J Clin Invest. 1993;92:141-146.
  7. Haffner SM, Mykkanen L, Valdez RA, Paidi M, Stern MP, Howard BV. LDL size and subclass pattern in a biethnic population. Arterioscler Thromb. 1993;13:1623-1630. [Abstract/Free Full Text]
  8. Feingold KR, Grunfeld C, Ping M, Doerrler W, Krauss RM. LDL subclass phenotypes and triglyceride metabolism in non–insulin-dependent diabetes. Arterioscler Thromb. 1992;12:1496-1502. [Abstract/Free Full Text]
  9. Austin MA, Breslow JL, Hennekens CH, Buring JE, Willett WC, Krauss RM. Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA. 1988;13:1917-1921.
  10. Crouse JR, Parks JS, Schey HM. Studies of low density lipoprotein molecular weight in human beings with coronary artery disease. J Lipid Res. 1985;26:566-574. [Abstract]
  11. Reaven GM. Role of insulin resistance in human disease. Diabetes. 1988;37:1595-1607. [Abstract]
  12. Bierman EL. Atherogenesis in diabetes. Arterioscler Thromb. 1992;12:647-656. [Free Full Text]
  13. Peeples HO, Carpenter JW, Israel RG, Barakat HA. Alterations in low-density lipoproteins in subjects with abdominal obesity. Metabolism. 1989;38:1029-1036. [Medline] [Order article via Infotrieve]
  14. Despres JP. Obesity and lipid metabolism: relevance of body fat distribution. Curr Opin Lipidol. 1991;2:5-15.
  15. Barakat HA, Carpenter JW, McLendon VD, Khazanie P, Leggett N, Heath J, Marks R. Influence of obesity, impaired glucose tolerance, and NIDDM on LDL structure and composition: possible link between hyperinsulinemia and atherosclerosis. Diabetes. 1990;39:1527-1533. [Abstract]
  16. Katzel LI, Krauss RM, Goldberg AP. Relationships of plasma TG and HDL-C concentrations to body composition and plasma insulin levels are altered in men with small low-density lipoprotein particles. Arterioscler Thromb. 1994;14:1121-1128. [Abstract/Free Full Text]
  17. Coon PJ, Bleecker ER, Drinkwater DT, Meyers DA, Goldberg AP. Effects of body composition and exercise capacity on glucose tolerance, insulin and lipoprotein lipids in healthy older men: a cross-sectional and longitudinal intervention study. Metabolism. 1989;12:1201-1209.
  18. Katzel LI, Coon PJ, Busby MJ, Gottlieb SO, Krauss RM, Goldberg AP. Reduced HDL2 cholesterol subspecies and elevated postheparin lipase activity in older men with abdominal obesity and asymptomatic myocardial ischemia. Arterioscler Thromb. 1992;12:814-823. [Abstract/Free Full Text]
  19. Rifkind BM, Segal P. Lipid Research Clinics program reference values for hyperlipidemia and hypolipidemia. JAMA. 1983;250:1869-1972. [Abstract]
  20. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes. 1979;28:1039-1057. [Medline] [Order article via Infotrieve]
  21. National Cholesterol Education Program Expert Panel, National Heart, Lung, and Blood Institute. Report of the National Cholesterol Education Program Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults. Arch Intern Med. 1988;148:36-69. [Abstract]
  22. Siri WE. The gross composition of the body. Adv Biol Med Phys. 1956;4:239-240. [Medline] [Order article via Infotrieve]
  23. Bruce RA, Horsten TR. Exercise testing in the evaluation of patients with ischemic heart disease. Prog Cardiovasc Dis. 1969;11:371-390. [Medline] [Order article via Infotrieve]
  24. Fox SM, Naughton J, Haskell WL. Physical activity and the prevention of coronary heart disease. Ann Clin Res. 1971;3:404-432. [Medline] [Order article via Infotrieve]
  25. Klimt CR, Prout TE, Bradley RF, Dolger H, Fisher G, Gastineau CF, Marks H, Meinert CL, Schumacher OP, Cooper GR, Mather A, Hainline A, Andres R. Standardization of the oral glucose tolerance test. Diabetes. 1969;18:299-310. [Medline] [Order article via Infotrieve]
  26. Zahrako DS, Beck LV. Studies of a simplified plasma insulin immunoassay using cellulose powder. Diabetes. 1968;17:444-457. [Medline] [Order article via Infotrieve]
  27. Simpson EJ, DeMers LM, Kreig AF. Faster enzymatic procedure for serum triglyceride. Clin Chem. 1975;21:1983-1985. [Abstract]
  28. Allain CC, Poon L, Chan SG, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem. 1974;20:470-475. [Abstract]
  29. Warnick R, Benderson JM, Albers JJ. Quantitation of high density lipoprotein subclasses after separation by dextran sulfate and Mg2++ precipitation. Clin Chem. 1982;28:1379-1388. [Free Full Text]
  30. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499-502. [Abstract]
  31. Menzel HJ, Utermann G. Apolipoprotein E phenotyping from serum by Western blotting. Electrophoresis. 1986;7:492-495.
  32. Nichols AV, Krauss RM, Musliner TA. Nondenaturing polyacrylamide gradient gel electrophoresis. In: Segrest JP, Albers JJ, eds. Methods in Enzymology, Plasma Lipoproteins. Part A. Preparation, Structure and Molecular Biology. Orlando, Fla: Academic Press; 1986;128:417-431.
  33. Blanche PJ, Gong EL, Forte TM, Nichols AV. Characterization of human high-density lipoproteins by gradient gel electrophoresis. Biochim Biophys Acta. 1981;665:408-419. [Medline] [Order article via Infotrieve]
  34. SAS User's Guide. version 5. Cary, NC: SAS Institute; 1985:403-506.
  35. Ostlund RE, Staten M, Kohrt WM, Schultz J, Malley M. The ratio of waist-to-hip circumference, plasma insulin level, and glucose intolerance as independent predictors of the HDL2 cholesterol level in older adults. N Engl J Med. 1990;322:229-234. [Abstract]
  36. Despres JP, Moorjani S, Lupien PJ, Tremblay A, Nadeau A, Bouchard C. Regional distribution of body fat, plasma lipoproteins and cardiovascular disease. Arteriosclerosis. 1990;10:497-511. [Abstract/Free Full Text]
  37. Campos H, Blijlevens EE, McNamara JR, Ordovas JM, Posner BM, Wilson PWF, Castelli WP, Schaefer EJ. LDL particle size distribution: results from the Framingham Offspring Study. Arterioscler Thromb. 1992;12:1410-1419. [Abstract/Free Full Text]
  38. Terry RB, Wood PD, Haskell WL, Stefanick ML, Krauss RM. Regional adiposity pattern in relation to lipids, lipoprotein cholesterol and lipoprotein subfraction mass in men. J Clin Endocrinol Metab. 1989;68:191-199. [Abstract]
  39. McNamara JR, Jenner JL, Li Z, Wilson PWF, Schaefer EJ. Change in LDL particle size is associated with change in plasma triglyceride concentration. Arterioscler Thromb. 1992;12:1284-1290. [Abstract/Free Full Text]
  40. Krauss RM, Williams PT, Lingren FT, Wood PD. Coordinate changes in levels of human serum low- and high-density lipoprotein subclasses in healthy men. Arteriosclerosis. 1988;8:155-162. [Abstract/Free Full Text]
  41. Williams PT, Krauss RM, Vranizan KM, Wood PDS. Changes in lipoprotein subfractions during diet-induced and exercise-induced weight loss in moderately overweight men. Circulation. 1990;81:1293-1304. [Abstract/Free Full Text]
  42. Nishina PM, Johnson JP, Naggert JK, Krauss RM. Linkage of atherogenic lipoprotein phenotype to the low density receptor locus on the short arm of chromosome 19. Proc Natl Acad Sci U S A. 1992;89:708-712. [Abstract/Free Full Text]
  43. Pouliot M-C, Despres J-P, Moorjani S, Lupien PJ, Tremblay A, Bouchard C. Apolipoprotein E polymorphism alters the association between body fatness and plasma lipoproteins in women. J Lipid Res. 1990;31:1023-1029. [Abstract]
  44. Hokanson JE, Austin MA, Zamboon A, Brunzell JD. Plasma triglyceride and LDL heterogeneity in familial combined hyperlipidemia. Arterioscler Thromb. 1993;13:427-434. [Abstract/Free Full Text]
  45. Witztum JL, Dilllingham MA, Giese W, Bateman J, Diekman C, Blaufuss EK, Weidman S, Schonfeld G. Normalization of triglycerides in type IV hyperlipoproteinemia fails to correct low levels of high-density lipoprotein cholesterol. N Engl J Med. 1980;303:907-914. [Abstract]
  46. Gonen B, Patsch W, Kuisk I, Goldberg A, Phair R, Schonfeld G. Altered HDL subclasses in endogenous hypertriglyceridemia are not affected by weight reduction. Metabolism. 1985;34:494-501. [Medline] [Order article via Infotrieve]
  47. Vega GL, Grundy SM. Gemfibrozil therapy in primary hypertriglyceridemia associated with coronary heart disease: effects on metabolism of low-density lipoproteins. JAMA. 1985;253:2398-2403. [Abstract]
  48. Bruckert E, Dejager S, Chapman MJ. Ciprofibrate therapy normalises the atherogenic low-density lipoprotein subspecies profile in combined hyperlipidemia. Atherosclerosis. 1993;100:91-102. [Medline] [Order article via Infotrieve]
  49. Cheung MC, Austin MA, Moulin P, Wolf AC, Cryer D, Knopp RH. Effects of pravastatin on apolipoprotein-specific high density lipoprotein subpopulations and low density lipoprotein subclass phenotypes in patients with primary hypercholesterolemia. Atherosclerosis. 1993;102:107-119. [Medline] [Order article via Infotrieve]
  50. Wilson MA, Vega GL, Gylling H, Grundy SM. Persistence of abnormalities in metabolism of apolipoproteins B-100 and A-I after weight reduction in patients with primary hypertriglyceridemia. Arterioscler Thromb. 1992;12:976-984. [Abstract/Free Full Text]
  51. Ginsberg HN, Ngai C, Wang X-J, Ramakrishnan R. Increased production rates of LDL are common in individuals with low plasma levels of HDL cholesterol independent of plasma triglyceride concentrations. Arterioscler Thromb. 1993;13:842-851. [Abstract/Free Full Text]
  52. Vega CL, Grundy SM. Two patterns of LDL metabolism in normotriglyceridemic patients with hypoalphalipoproteinemia. Arterioscler Thromb. 1993;13:579-589.[Abstract/Free Full Text]



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