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Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1070-1078

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1070-1078.)
© 1995 American Heart Association, Inc.

Articles

Body Fat Distribution Is a Determinant of the High-Density Lipoprotein Response to Dietary Fat and Cholesterol in Women

Peter M. Clifton; Mavis Abbey; Mannie Noakes; Sandra Beltrame; Nicole Rumbelow; Paul J. Nestel

From CSIRO, Division of Human Nutrition, Adelaide, South Australia.


*    Abstract
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 *Abstract
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 down arrowResults
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Abstract We have conducted a dietary trial that addressed the factors influencing the variability in plasma lipids in response to dietary fat and cholesterol with a focus on the effects of gender and body fat distribution. Sixty-seven women and 53 men were selected so that overall men and women had a similar mean age, LDL cholesterol, and body mass index. After a 2-week low-fat period subjects were given two liquid supplements for 3 weeks each, one that contained 31 to 40 g fat and 650 to 845 mg cholesterol, and one that was fat free. Measurements included plasma lipids and lipoproteins, glucose, insulin, hepatic triglyceride lipase activity, apolipoprotein E polymorphism, and three indexes of body fat (body mass index, waist girth, and waist-hip ratio). In response to dietary fat and cholesterol supplementation only the changes in HDL cholesterol, especially in HDL2, differed between the sexes. Although on univariate analysis lipoprotein changes were predicted by baseline lipoprotein levels, body mass index, waist girth, waist-hip ratio, hepatic triglyceride lipase activity, and insulin, multiple regression showed only waist-hip ratio to predict changes in HDL2 cholesterol in women and body mass index and baseline HDL2 cholesterol in men. Changes in LDL were predicted by baseline LDL cholesterol in women and apolipoprotein E phenotype and age in men. These studies explain much of the variability that individuals show in lipoprotein changes, especially in the more desirable changes in cholesterol transport in HDL2, in response to eating saturated fat and cholesterol.


Key Words: body mass index • lipoproteins • insulin • lipase • dietary response • fat distribution


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
 down arrowResults
 down arrowDiscussion
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Much is known about the lipid and lipoprotein responses to dietary fat and cholesterol in humans,1 2 3 but the characteristics of individual subjects that may influence their response to a dietary challenge are less well defined. Several reviews analyzing the variable response to dietary cholesterol concluded that the response was sufficiently reproducible to suggest the operation of some inherent characteristics.4 5 Individual variability has also been reported for changes in dietary saturated fat.6 7 Factors include the basal level of plasma lipids and DNA polymorphism of apolipoproteins such as apoE8 9 10 11 and apoB.12 13

Grundy et al14 reported that men with higher HDL cholesterol responded to a dietary challenge with a greater change in HDL than those with lower HDL cholesterol. In controlled outpatient studies Mensink and Katan15 observed that women were less responsive, with smaller changes in triglycerides and HDL than men, whereas Ehnholm et al16 and Kuusi et al17 reported that men and women showed very similar changes in lipid levels. We have previously studied 51 men and women, matched for age, BMI, and plasma cholesterol and triglyceride levels, and noted that changes in HDL, in particular HDL2, most clearly differentiated the responses of men and women to dietary fat and cholesterol.18 Changes in LDL were not different in men and women. This was confirmed in a retrospective meta-analysis of five previous metabolic ward studies involving 66 men and women by Cobb et al.19 In their analysis HDL declined by 12% in men and 18% in women with a switch from a low polyunsaturated to a high polyunsaturated fat diet, whereas the change in LDL cholesterol was similar. Obesity and body fat may also contribute to the variability, and a recent analysis suggested that lean men were more prone to excess coronary deaths on a high cholesterol diet.20

Subjects in our previous study18 were recalled 3 months after completion and had their WHR measured. Changes in HDL and HDL2 cholesterol were inversely related to WHR. In the current study we recruited a new group of volunteers and examined prospectively the influence of body fat configuration and gender as major determinants of the variable responses to dietary fat and cholesterol. Key regulators of lipoprotein levels, especially of HDL, such as HTGL activity21 22 23 24 and plasma insulin,25 26 were also measured.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
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Healthy volunteers aged 20 to 75 years were recruited by public advertisement. All were free of clinical cardiac, renal, and hepatic disease. Subjects taking lipid-lowering medication were excluded; 49 women were postmenopausal, with 26 women on hormone replacement therapy; only 1 woman was taking oral contraceptives. Sixty-seven women and 53 men were selected. Baseline characteristics are shown in Table 1Down. The study was approved by the Human Ethics Committee of the CSIRO, Division of Human Nutrition, and written consent was obtained from each subject.


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  		Table 1. Baseline Characteristics of Subjects

Study Design
The study was primarily designed to examine the predictors of response to dietary cholesterol. As increased amounts of cholesterol are accompanied by increased amounts of fat, it was felt that the cholesterol should be accompanied by fat. The fat source used, dairy fat, constituted about 30% of the normal fat intake, and the polyunsaturated-to-saturated ratio resembled that of a normal diet. Subjects were placed on a low-fat diet (25% of energy as fat, cholesterol <250 mg/d) that they followed for the duration of the study. After a 2-week baseline period a milk-based liquid supplement was added for the next 6 weeks. Two supplements were supplied, one containing 31 g fat (56% saturated fat, 17% polyunsaturated fat) and 650 mg cholesterol per 250 mL, the other containing no fat or cholesterol but being isocaloric with the first (360 kcal in total). The cholesterol supplement consisted of cream, full cream milk, and egg yolk, and the cholesterol-free drink contained skim milk powder and long-chain glucose polymers. Men received an extra 70 mL (100 kcal) of each supplement. The supplements were given in random order for 3 weeks each. Most volunteers took the drink as a single dose, although no specific instructions were given.

The study was double-blind, and only the clinic assistant was aware of the drink order. The supplements were palatable, and the volunteers could not reliably distinguish which supplement contained fat and cholesterol. A trained dietitian provided information on sources of dietary fat to enable the subjects to achieve the 25% fat baseline diet. All food was weighed with electronic scales for 3 days (1 weekend and 2 weekdays) in each experimental period. All drinks including alcoholic beverages were recorded during this period. Nutrient intake was calculated from a computer database of foods based on the composition of Australian foods27 and, in the case of the supplements, direct food analysis (DIET/1 Nutrient Calculation software, Xyris Software). The diaries showed excellent compliance. Other lifestyle factors were also controlled throughout the study; subjects were instructed not to change their exercise patterns or their drinking habits for the duration of the study, and leisure physical activity and alcohol consumption were regulated. Habitual heavy drinkers (more than 10% of energy as alcohol) were excluded. There was only one light smoker (a woman) in the study. Compliance was monitored by questionnaire at each visit. There was no difference between men and women in the amount of physical activity, and there were no changes across each experimental period. There was no difference between younger or older subjects in exercise patterns or alcohol consumption. WHR was measured by assessing the minimum waist circumference (usually just above the umbilicus) and the maximum hip circumference (usually at the level of the greater trochanter). Measurements were routinely taken at the umbilicus, 2 and 4 cm above the umbilicus, and the lowest measurement was selected. Subjects were weighed at each visit and received further instruction from the dietitian. Body weights did not change significantly (71.3 kg in the low-fat phase and 72.1 kg in the high-fat/high-cholesterol phase). There was no change in weight from screening to the end of baseline.

Laboratory Measurements
Blood samples were taken on two occasions at the end of the baseline period and on three occasions at the end of each experimental period after a 12-hour fast. On the second day of the baseline period blood was collected after an overnight fast for measurement of lipids and lipoproteins; then porcine heparin was injected intravenously (100 U/kg body wt) and a further blood sample taken 15 minutes later into an EDTA-containing tube and immediately placed on ice (in the final 58 subjects only). Plasma was separated by low-speed centrifugation and immediately frozen at -70°C. All measurements were performed in one run at the end of the trial. Plasma and lipoprotein lipids were measured on a Cobas-Bio centrifugal analyzer (Roche Diagnostica) with the use of Roche enzymatic kits and control sera. HDL2 and HDL3 subfractions were prepared by selective precipitation28 with Dextralip (Sochibo) and magnesium. LDL was calculated with the Friedewald equation.29 Plasma insulin levels were measured by radioimmunoassay (Phadaseph, Pharmacia). Plasma glucose was measured on the Cobas-Bio analyzer with the use of a glucose oxidase kit (Roche Diagnostica). ApoE phenotype was determined by polymerase chain reaction with appropriate primers as described by Hixson and Vernier.30

HTGL activity was determined by the method of Huttunen et al31 as modified by Blades et al32 in the last 58 subjects recruited into the study. A gum arabic–stabilized [14C]triolein (7.4 Bq of glycerol tri[1-14C]oleate per tube) substrate was used with a final triolein concentration of 15 mmol/L. HTGL activity was determined with 25 µL of postheparin plasma at 28°C for 2 hours in 0.2 mol/L Tris-HCl buffer, pH 8.8, in the presence of 0.75 mol/L NaCl to inhibit lipoprotein lipase. The final concentration of fatty acid–free bovine serum albumin (fraction V) was 50 g/L. The free [14C]oleic acid released from the triolein was extracted with the use of the method of Belfrage and Vaughan.33 Extraction efficiency was determined with 3.9 Bq of [9,10-(N)-3H]oleic acid added to each tube. One quality-control postheparin sample was added to each run and used to normalize all the results. Thirty-four women and 24 men had HTGL activity measured.

Statistics
Covariate ANOVA, correlations, regression analysis, and two-tailed paired t test were performed with SPSS on a personal computer (SPSS Inc). Regression analysis was performed by both forward and backward selection plus direct entry of selected variables. ANOVA was performed using gender, quartiles of waist girth, WHR, BMI, baseline levels of HDL and HDL2 cholesterol, menopausal status, and interactions between these terms. All of the data except plasma insulin and plasma triglyceride levels were normally distributed, so these two variables were log transformed before statistical testing. There was no effect of treatment order or carryover. All correlation coefficients noted in the text were P<.01 unless stated otherwise.


*    Results
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 *Results
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Baseline Data
Baseline data are shown in Table 1Up. Men and women were well matched for age (50 and 52 years, respectively), BMI (26.5 kg/m2), total cholesterol (5.7 and 5.5 mmol/L), and LDL cholesterol (4.0 and 3.7 mmol/L). Men had slightly higher plasma triglyceride levels than women (1.60 versus 1.25 mmol/L, P<.01). As expected, the WHR in women was significantly different from that of men (0.81 versus 0.93, P<.001), as was the waist girth (84.9 versus 94.5 cm, P<.001). Total HDL cholesterol (1.15 versus 0.84 mmol/L, P<.0001), HDL2 cholesterol (0.34 versus 0.18 mmol/L, P<.0001), and HDL3 cholesterol (0.80 versus 0.66 mmol/L, P<.001) were all higher in women than men. Insulin concentrations were similar (58 pmol/L in men and 54 in women), but plasma glucose was higher in men (5.3 versus 4.9 mmol/L, P<.01). HTGL activity was significantly higher in men than women (54.6 versus 37.8 µmol/mL per hour, P<.01).

Determinants of Lipoprotein Concentrations During Baseline, Low-Fat Period
Pearson Correlations
BMI, WHR, and waist girth were related to HDL cholesterol and HDL2 cholesterol in women, but only WHR was related to HDL and HDL2 cholesterol in men (Table 2Down). HDL3 cholesterol was related to all three obesity measures in men but was related only to waist girth in women. HTGL was correlated with BMI, WHR, and waist girth in women but not in men and with HDL cholesterol and HDL3 cholesterol in both sexes and HDL2 cholesterol only in women. In women only apoE phenotype was related to baseline LDL cholesterol levels, with individuals with at least one apoE4 allele having a level 30% higher than those with the apoE2/E3 allele (P=.006 for linearity, E4>E3/3>E3/2).


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  		Table 2. Univariate Correlations of Baseline Lipids in Women and Men

Multiple Regression
Because many of the predictor variables were correlated, we performed stepwise multiple regression separately in men and women, with HDL cholesterol, HDL subfractions, LDL cholesterol, and triglycerides as dependent variables. Two models were used: one with age, WHR, waist girth, BMI, insulin, and apoE phenotype (n=67 women and n=53 men), and a second with the above plus HTGL activity, as this was measured only in a subset of 34 women and 24 men.

Women. In model 1 HDL cholesterol was related to insulin and WHR, which together accounted for 27% of the variance, whereas HDL2 was related only to WHR. In model 2 (34 subjects) HDL and HDL2 cholesterol were related to insulin, HTGL, and alcohol intake, accounting for 69% and 61% of the variance, respectively. HDL3 cholesterol and plasma triglycerides were related to insulin (r=-.47 and .54, respectively) in both models.

Men. HDL cholesterol was related only to WHR and energy from alcohol (together, 28% of variance). HDL2 cholesterol was related only to WHR, and HDL3 cholesterol was related to WHR, alcohol-derived energy, and insulin (together, 50% of the variance) in model 1. With model 2 HTGL was important only for HDL cholesterol.

Effects of Dietary Fat and Cholesterol
Dietary data are shown in Table 3Down. Apart from the expected 34% difference in energy intake, there were very few differences between men and women as indicated by dietary records. The baseline low-fat diet contained 25% of calories as fat but was probably about 300 kcal/d short of weight maintenance level because volunteers adjusted to a low-fat diet but failed to adequately compensate with carbohydrates. The cholesterol intake was low at 104 to 108 mg/1000 kcal. The addition of the low-fat/low-cholesterol supplement reduced the fat calories to 19.5% but significantly increased the energy intake by 12% (P<.001). Protein as a percentage of calories was significantly reduced in both men and women (P<.01). The addition of the high-fat/high-cholesterol supplement increased the fat calories to 35% and the cholesterol to 476 to 524 mg/1000 kcal, but the changes were very similar in men and women. Saturated fatty acids increased by 8% and monounsaturated fatty acids by 5% of calories, but overall energy intake remained constant. Alcoholic beverages were consumed by 47% of the women, with an average of 14 g/d among the drinkers, and 67% of the men, with an average of 24.5 g/d (P<.05, men versus women) during the baseline period. Alcohol intake did not change significantly between phases.


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  		Table 3. Dietary Variables As Determined From 3-Day Weighed Food Records

Plasma Lipid and Lipoprotein Changes
Lipid and lipoprotein levels during the low- and high-fat diets and the difference are shown in Table 4Down. The increase in total cholesterol was the same in men and women (0.32 to 0.34 mmol/L) and represented a change of 6% (P<.001). Plasma triglycerides decreased during the high-fat diet by 0.16 to 0.22 mmol/L or 10% to 13% (P<.001), with no difference between men and women. LDL cholesterol increased by 0.25 to 0.32 mmol/L or 7% to 9% (P<.001), again with no difference between men and women. The major difference between men and women was in the change in HDL cholesterol: women had a far greater rise in total HDL cholesterol (0.17 versus 0.10 mmol/L, P<.001 for difference between men and women) and HDL2 cholesterol (0.10 versus 0.04 mmol/L, P<.002 for difference). The change in HDL3 cholesterol was the same in men and women. If the changes are expressed as percentage changes, the difference between men and women is not significant for HDL cholesterol (15.7% versus 11.9%) but remains significant for HDL2 cholesterol (35.7% versus 23.5%, P=.02).


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  		Table 4. Lipids and Lipoproteins During Low-Fat and High-Fat Periods

Univariate Predictors of Response of Lipoproteins to Fat and Cholesterol
In both men and women there were seven major predictors of dietary response: WHR, waist girth, BMI, plasma insulin, HTGL activity, and baseline lipid levels. These were not independent, and on multiple regression (see below) usually only one factor was significant.

Diet
As all subjects followed the same standard dietary protocol, there were few significant dietary predictors of response. Men and women with a higher BMI or WHR did not have a significantly lower fat and cholesterol change with the fixed amount of supplement compared with the thinner volunteers. Although underreporting of dietary energy intake may be greater in the overweight group, this would not confound the association between waist girth and change in HDL cholesterol in the thinner group. The dietary analysis from 3-day food records is shown in Table 3Up.

Effect of WHR, Waist Girth, and BMI
WHR and waist girth as well as BMI had a very significant effect on the change in HDL and HDL2 cholesterol with dietary fat and cholesterol, with a steady fall in both as waist girth increased (Table 5Down). Women with a fat configuration similar to that in men had lipoprotein responses similar to those in men. The correlations between WHR and change in HDL and HDL2 cholesterol are -.38 and -.40, respectively, for women and -.30 and -.43 for men. Waist girth was very similar to WHR and did not improve the prediction of the response to diet compared with WHR (FigureDown). WHR was unrelated to changes in HDL3 or LDL cholesterol. In men BMI was more strongly related to changes in HDL and HDL2 cholesterol (r=-.45 and -.48, respectively) than was WHR or waist girth.


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  		Table 5. Effect of Waist Girth on Baseline Lipids and Change With Diet



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  		Figure 1. Scatterplot shows changes in HDL2 cholesterol with dietary fat and cholesterol in relation to waist girth.

Effect of Plasma Insulin Level
The change in HDL cholesterol (r=-.45 and -.60) and HDL2 cholesterol (r=-.46 and -.29) was inversely correlated with plasma insulin in both men and women, respectively.

HTGL Activity
The change in HDL2 cholesterol was inversely correlated with HTGL activity in women only (r=-.46, P<.01).

Baseline Lipids
Changes in HDL2 were correlated with baseline HDL2 in men and women (r=.39 and .34, respectively) and baseline HDL (r=.38 and .46, respectively).

Other Predictors
If all subjects with at least one E4 allele are pooled, the relationship between change in LDL cholesterol and apoE phenotype is significant in men (P<.001). A similar relationship is seen if the apoE alleles are summed (eg, apoE2/2=4, apoE2/3=5, etc). Adjustment for baseline LDL cholesterol did not weaken this relationship.

Multiple Regression
Two models were used for HDL and HDL2 cholesterol. Model 1 included WHR, waist girth, BMI, insulin, baseline lipids, and dietary variables (change in total fat, saturated fat, monounsaturated fat and cholesterol) (n=67 women and 53 men). Model 2 included those variables listed above plus HTGL activity (n=34 women and 24 men).

If men and women are analyzed together with gender as an independent variable, only waist girth is a significant predictor of response. WHR was not used because it was strongly correlated with gender. No interactions were observed between gender and other predictor variables. With separate regression equations for men and women, the change in HDL cholesterol was related to BMI in men (P=.003) and WHR in women (P=.008). Similar results were seen with the change in HDL2 cholesterol as the dependent variable except that in men baseline HDL2 cholesterol was significant (P=.01) in addition to BMI (P=.002).

Effect of Menopausal Status
Forty-nine women were menopausal (26 on hormones) and 18 were premenopausal. Menopausal status had no effect on the response to dietary fat and cholesterol nor did the use of postmenopausal estrogen therapy with or without progestagens influence the magnitude of the changes in plasma lipoproteins. Thus all the results in women were pooled before analysis.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
In this dietary study, one of the largest of its kind, we have been able to define several important characteristics of the test subjects that explain some of the variability among individuals in their response to dietary saturated fat and cholesterol. We have put special emphasis on factors that influence changes in HDL cholesterol. This focus has had far less attention than the better-known changes in LDL cholesterol. The results substantially extend and explain our earlier observations about the relevance of gender, fat distribution, age, and baseline plasma lipoprotein concentrations on the distribution of plasma cholesterol between HDL and LDL.18 These findings have public health value in that they refine the targeting of people most at risk from eating excess saturated fat and cholesterol.

Factors Influencing Changes in Plasma Lipids With Dietary Fat and Cholesterol
We have previously shown that men and women clearly differ in their response to a high-fat/high-cholesterol diet, with a much greater rise in HDL and particularly in HDL2 cholesterol in women, whereas the rise in LDL cholesterol is similar.18 We have confirmed these earlier studies by studying another 120 subjects. In these subjects the increase in HDL cholesterol was 70% higher and the increase in HDL2 cholesterol 150% higher in women compared with men. We have extended these observations by demonstrating for the first time that fat distribution whether assessed as waist girth or as WHR appears to explain much of the gender effect (and eliminates gender from the multiple regression equation), as women with a high waist girth (and thus an android distribution of fat) showed an HDL response to fat and cholesterol that was indistinguishable from that in men. Interestingly, men with a low waist girth (and thus a gynoid distribution of fat) showed a response that was very similar to that in women. In each quartile of waist girth men and women had equal responses and were indistinguishable from each other. On multivariate analysis the most important predictor in women of the change in HDL cholesterol was the WHR, with a small independent contribution from the baseline HDL cholesterol. In men, overall obesity as measured by BMI was important and fat distribution not so critical. All of the difference between men and women in the change in HDL cholesterol lay in the HDL2 subfraction; the change in HDL2 cholesterol in women was 150% larger than the change in men and in both sexes was strongly related to waist girth with a 5-fold and 10-fold gradient from bottom to top quartile in women and men, respectively. The changes in HDL3 were not gender specific, nor were they related to waist girth; in each quartile the change was between 0.06 and 0.08 mmol/L.

The change in LDL cholesterol was similar in men and women and unlike HDL cholesterol was not related to BMI or body fat configuration. In both men and women it was related to baseline LDL cholesterol, but only to a limited extent, whereas in men only age and apoE phenotype were important on multivariate analysis. Thus, older men with an apoE4 allele would tend to have the greatest response to dietary fat and cholesterol. Conversely, these men would have the greatest lowering of LDL cholesterol on a prudent diet.

We could find no relationship between changes in plasma triglyceride levels and changes in HDL cholesterol; in fact, the fall in triglycerides during the high-fat/high-cholesterol diet was exactly the same in men and women, whereas the change in HDL cholesterol was clearly different. Cobb et al19 found that men showed a fall in plasma triglycerides when shifting from a saturated fat diet to a polyunsaturated fat diet, whereas women showed a rise; they concluded that these differences in triglyceride levels were related to the differing HDL responses. This is apparently not so when saturated fat and cholesterol are added to the diet.

Our results on the effect of dietary change agree with those of Cobb et al,19 who found that diet-induced changes in HDL cholesterol were greater in women than in men. They also observed that baseline HDL was an independent predictor of the HDL response to diet but only in women, whereas we found that baseline HDL2 cholesterol also predicted the HDL2 cholesterol rise in men.

Whereas our data have clearly distinguished the responses to dietary fat and cholesterol by men and women, this is not evident in other reported studies,14 16 17 with the exception of the meta-analysis of Cobb et al.19 However, no other study has set out with such a central hypothesis and a design that attempted to match women and men so clearly. In the studies of Mensink and Katan,15 replacement of saturated fat by monounsaturated fat or carbohydrate led to greater differences in HDL cholesterol in men than in women (0.32 versus 0.13 mmol/L), but the subjects were not matched as in our study, and weight loss occurred in some individuals. Cholesterol intake was not significantly different between dietary phases. Yet in a further study during which egg consumption ceased, Beynen and Katan34 found that only women showed a significant fall in HDL cholesterol (6.2%), and men did not. Moreover, the change in HDL cholesterol was correlated with baseline HDL cholesterol, which could account for 18% of the variance. In our study baseline HDL cholesterol accounted for 12% of the variance. A later study by Ferro-Luzzi et al,35 who reported on the effect in 25 couples of changing from the "Mediterranean diet" to one high in saturated fat, showed that HDL cholesterol increased by 19% in the women, with no change in the men. Changes in LDL cholesterol were similar.

Several groups have published on the influence of apoE, especially of apoE4, on plasma lipids (reviewed in Reference 3636 ) and changes after dietary perturbation.8 9 10 11 37 38 39 40 41 In a study examining the influence of apoE phenotype on dietary responsiveness, Savolainen et al37 found that men had a significantly greater rise than women in LDL cholesterol with a large increase in saturated fat intake (19% of energy) and a small increase in cholesterol intake (180 mg/d). There were no differences in HDL cholesterol, nor did apoE phenotype influence the results. The subjects in the Finnish trial were considerably younger than in our trial, and their LDL cholesterol was 24% higher in the men than in the women, an important consideration because our study showed that baseline LDL cholesterol predicts the change in cholesterol with dietary fat and cholesterol. Other reports have shown greater dietary responsiveness in subjects with an E4 allele,8 9 10 11 41 particularly in the homozygous form,9 42 but there have also been several negative studies.37 38 39 In our study apoE phenotype significantly predicted the change in LDL cholesterol with fat and cholesterol in men, but changes in HDL cholesterol were not influenced. By contrast, Martin et al43 reported a relationship between apoE phenotype and changes in HDL cholesterol with a dietary cholesterol load.

Although plasma insulin and HTGL activity were important, they were not independent predictors of the changes in HDL, HDL2, or HDL3 cholesterol and did not enhance the assessment of high-risk groups when BMI and WHR were known.

Baseline Lipids and Fat Distribution
In men, baseline HDL cholesterol and HDL2 cholesterol were related only to WHR, whereas in women both of these were related to BMI, WHR, and waist girth. HDL3 cholesterol in men was related to overall obesity as well as estimates of fat distribution, whereas in women it was related only to waist girth. Several studies have examined determinants of HDL cholesterol in various populations.44 45 46 47 In agreement with these authors we demonstrated that plasma triglycerides, BMI, and alcohol consumption were related to the level of HDL cholesterol and accounted for 13% of the variation in men and 30% in women. Abdominal obesity, whether assessed by WHR, skinfold thickness, or computerized tomography, is associated with higher plasma triglyceride and insulin levels and lower HDL cholesterol levels, particularly HDL2.48 49 50 51 52 However, not all studies have confirmed these findings26 or shown that WHR is a better discriminator than BMI,53 especially in very obese subjects54 and in type 2 diabetic women.55 In this group with normal body weights and low plasma triglyceride levels, WHR is an important determinant of HDL cholesterol and in particular the HDL2 subfraction in women, whereas BMI is most important in men.

Despres et al51 have reported that deep abdominal fat was the critical determinant of the low HDL cholesterol levels found in obese women and that intra-abdominal fat deposition was correlated with increased HTGL activity, which in turn was negatively correlated with HDL2 cholesterol but not HDL3 cholesterol.56 We have confirmed that HTGL activity does increase with increasing abdominal obesity in women and that it is strongly correlated with the levels of both HDL2 and HDL3 cholesterol. However, this is the first time that HTGL has been shown to correlate with regional fat distribution in nonobese women. It should be borne in mind that WHR is a very rough estimate of fat distribution, and waist girth is probably a better estimate of abdominal fat alone,57 although in the present study the use of waist girth did not significantly improve precision. Elevated HTGL activity has been frequently associated with low HDL cholesterol,21 22 23 24 44 58 but few studies have looked at all possible determinants of HDL simultaneously. Katzel et al58 found in 41 obese men that WHR was the most important determinant of HDL cholesterol and percentage of HDL2b; HTGL activity was next in importance and fasting insulin third. HTGL activity was directly related to WHR. In our group of men HTGL was the most important single determinant of HDL and HDL3 cholesterol levels. The importance of HTGL in men and women combined (40% of the variance of HDL cholesterol) is very similar to that seen by Patsch et al44 in their group of 13 women and 25 men.

Fasting plasma insulin was strongly associated positively with measures of obesity and fat distribution and inversely with levels of HDL and HDL2 cholesterol in women but only with HDL3 cholesterol in men. However, most previous studies have found plasma insulin and HDL and HDL2 cholesterol to be related in men as well as women.26 59 60 61 62 63 64 65 66 67 Ferland et al67 in a study of 69 premenopausal women also found that mechanisms other than disturbances in glucose metabolism were responsible for the negative association between deep abdominal fat and HDL2 cholesterol. In our study HTGL activity was more important in determining baseline HDL cholesterol than WHR, waist girth, BMI, or plasma insulin in men and women.

We conclude that (1) the lipoprotein responses to diet are gender specific: the rise in HDL and HDL2 cholesterol is much greater in women than men, whereas the change in LDL cholesterol is similar, and (2) the gender difference can be partly explained by the differences in fat distribution between men and women.


*    Selected Abbreviations and Acronyms
 
apo = apolipoprotein
BMI = body mass index
HTGL = hepatic triglyceride lipase
WHR = waist-hip ratio


*    Acknowledgments
 
This work was partly supported by Hoechst (Australia) and the National Heart Foundation of Australia. We extend thanks to Rosemary MacArthur, Anne Stephens, and Julie Priest for skilled technical assistance.


*    Footnotes
 
Reprint requests to Dr P.M. Clifton, CSIRO, Division of Human Nutrition, PO Box 10041, Gouger St, Adelaide 5000, South Australia.

Received November 14, 1994; accepted May 15, 1995.


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

  1. Keys A, Anderson JT, Grande F. Prediction of serum cholesterol responses of man to changes in fats in the diet. Lancet. 1957;2:959-966.
  2. Keys A, Anderson JT, Grande F. Serum cholesterol response to changes in the diet, II: the effect of cholesterol in the diet. Metabolism. 1965;14:759-765.
  3. Mensink RP, Katan MB. Effect of dietary fatty acids on serum lipids and lipoproteins: a meta-analysis of 27 trials. Arterioscler Thromb. 1992;12:911-919. [Abstract/Free Full Text]
  4. Nestel PJ. Dietary cholesterol and plasma lipoproteins. Ann N Y Acad Sci. 1993;676:1-10.
  5. Glatz JFC, Turner PR, Katan MB, Stalenhoef AFH, Lewis B. Hyporesponse and hyperresponse of serum cholesterol level and low density lipoprotein production and degradation to dietary cholesterol in man. Ann N Y Acad Sci. 1993;676:163-179. [Abstract]
  6. Jacobs DR Jr, Anderson JT, Hannan P, Keys A, Blackburn H. Variability in individual serum cholesterol response to change in diet. Arteriosclerosis. 1983;3:349-356. [Abstract/Free Full Text]
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