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© 1995 American Heart Association, Inc.
Articles |
The Lipoprotein Lipase HindIII Polymorphism Modulates Plasma Triglyceride Levels in Visceral Obesity
From the Lipid Research Center, CHUL Research Center (M.-C.V., B.L., S.M., P.-J.L., J.-P.D.), the Physical Activity Sciences Laboratory (D.P., C.B.), and the Diabetes Research Unit, CHUL Research Center (A.N.), Laval University, Ste-Foy, Québec.
Correspondence to Dr Jean-Pierre Després, Lipid Research Center CHUL, 2705 Laurier Blvd, Québec, GIV 4G2, Canada.
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Abstract |
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Abstract The aim of this study was to investigate the potential interaction between the lipoprotein lipase (LPL) HindIII polymorphism and visceral adipose tissue (AT) accumulation in the modulation of triglyceride levels in visceral obesity. The LPL-HindIII genotype was determined by polymerase chain reaction in 52 men. Twenty-three subjects were heterozygous (+/-) and 28 were homozygous (+/+) for the presence of the restriction site. One subject who was homozygous for the - allele was excluded from analysis. Body mass index (BMI), fasting insulin level, and visceral AT area as measured by computed tomography were positively correlated with triglyceride levels only in subjects homozygous for the + allele. Furthermore, whereas these variables were negatively correlated with plasma HDL2 cholesterol concentrations in the +/+ group, these associations were not found in +/- heterozygotes, with the exception of BMI. To further investigate the interaction of the LPL-HindIII polymorphism with visceral obesity and hyperinsulinemia, the two genotype groups were further subdivided on the basis of BMI (low versus high), fasting insulin level (low versus high), and visceral AT area (low versus high), and their lipoprotein profiles were compared. Elevated levels of abdominal visceral AT were significantly associated with increased triglyceride concentrations in +/+ homozygous men, suggesting that visceral obesity may lead to hypertriglyceridemia in the presence of the +/+ genotype. In the +/- group, variation in the amount of visceral AT was not associated with differences in triglyceride concentration. However, hypertriglyceridemia and an increased cholesterol-to–HDL cholesterol ratio were observed in the hyperinsulinemic state irrespective of LPL-HindIII genotype status. Finally, similar positive correlations were observed between visceral AT accumulation and plasma insulin level in the homozygous (+/+) and heterozygous (+/-) groups, suggesting that the hyperinsulinemic–insulin-resistant state that is frequently associated with visceral obesity is independent of LPL-HindIII genotype. These results suggest that the HindIII polymorphism may modulate the magnitude of the dyslipidemic state associated with visceral obesity.
Key Words: lipoprotein lipase • visceral obesity • insulin • hypertriglyceridemia • candidate genes
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Introduction |
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Abdominal obesity is an important risk factor for cardiovascular disease and has been associated with several metabolic complications, such as hypertension, dyslipidemia, insulin resistance, and non–insulin-dependent diabetes mellitus.1 2 3 4 5 6 7 8 Studies that have assessed the distribution of body fat by computed tomography (CT) have concluded that the amount of fat located in the abdominal cavity, the so-called intra-abdominal or visceral fat, is the most critical correlate of metabolic disturbances associated with abdominal obesity.9 10 11 However, severe metabolic complications are not observed in all viscerally obese subjects, thereby suggesting that genetic predisposition may be a key factor in the susceptibility of viscerally obese individuals to metabolic disorders.12 We have previously proposed that genetic variation at several loci that affect lipoprotein metabolism may alter the relation between visceral obesity and plasma lipoprotein levels.4 12 13 In this regard, we have shown that the magnitude of hypertriglyceridemia associated with visceral obesity and hyperinsulinemia is influenced by three common alleles at the apo E gene locus.14 15 We have also reported that variation at the apo B gene locus, as examined by EcoRI polymorphism, modulates the relation of visceral obesity to plasma apo B and LDL–apo B levels.16 These two examples provide evidence that the impact of visceral obesity on the plasma lipoprotein-lipid profile is partly dependent on the variation at two loci for apo B and apo E genes, both of which are involved in lipid transport as well as lipoprotein catabolism via specific cell-surface receptors.
Lipoprotein lipase (LPL) is an important enzyme for hydrolysis of triglyceride-rich lipoproteins, and its activity is positively correlated with the plasma HDL cholesterol level. An LPL gene HindIII polymorphism has been found in association with hypertriglyceridemia,17 18 19 decreased HDL cholesterol levels,20 increased apo B levels,19 coronary heart disease (CHD),19 21 and some features of the insulin resistance syndrome.22 Because these metabolic complications are also characteristic features of visceral obesity, we have investigated the possibility that the LPL-HindIII polymorphism may be involved in the relation of visceral obesity to plasma insulin and lipoprotein concentrations.
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Methods |
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Subjects
A cohort of white men were recruited to participate in studies that were designed to investigate associations between obesity, regional adipose tissue (AT) distribution measured by CT, and plasma lipoprotein levels.11 Fifty-two subjects of this cohort agreed to participate in this study involving DNA analysis. They were all nonsmokers and free from metabolic disorders that required pharmacological treatment. All subjects were sedentary, and their body weight was stable at the time of investigation. The study was approved by the Ethics Committee on Human Research of Laval University.
DNA Analysis
Approximately 30 mL of peripheral venous blood was collected in
tubes containing EDTA and kept frozen at -20°C until processing. DNA
was extracted from leukocytes by standard methods after digestion with
proteinase K and extraction with phenol/chloroform. Polymerase chain
reaction (PCR) amplification was performed by using primers for the
HindIII restriction site located in intron 8 of the LPL
gene.18 Reactions were performed in a Perkin-Elmer Cetus
thermal cycler (model TC) under the following conditions: initial
denaturation at 95°C for 3 minutes; followed by 30 cycles at 95°C
for 1 minute, 60°C for 30 seconds, and 72°C for 1 minute; and a
final extension of 10 minutes at 72°C. The reaction volume of 50 µL
contained 1.0 U Taq polymerase (Perkin-Elmer Cetus), 150 ng
genomic DNA, 50 pmol of each oligonucleotide, and 3 µmol dNTP in the
buffer recommended by the manufacturer. After amplification, 12 U
HindIII was added to the PCR products and digested for 3
hours at 37°C. The resulting fragments were separated by size on an
8% nondenaturing polyacrylamide gel. The gels were run for 2 hours at
200 V, stained with ethidium bromide, and then photographed under UV
transmitted light. The size of DNA fragments was estimated using PUC
19–digested Sau3A as molecular-weight standards. The
amplified fragment had a size of 1.3 kb, and after digestion with
HindIII, the + allele cut by HindIII resulted in
fragments of 600 and 700 bp, whereas the - allele not cut by
HindIII retained the size of 1.3 kb.
Measurements of Total Body Fat
Body density was measured by the hydrostatic weighing
technique.23 Percent body fat was estimated from density
by using the Siri equation.24 Fat mass was obtained by
multiplying percent body fat by body weight. Pulmonary residual volume
was measured with the helium-dilution method of Meneely and
Kaltreider.25 Waist and hip circumferences were measured
by standardized procedures recommended by the Airlie
conference.26
CT
Cross-sectional abdominal subcutaneous and visceral AT areas
were determined by CT with a Siemens Somatom DRH scanner as previously
described.27 Briefly, the subjects were examined in the
supine position with both arms stretched above the head. CT scans were
performed at the abdominal level between the fourth and fifth lumbar
vertebrae by using a radiograph of the skeleton as a reference to
establish the position of the scan to the nearest millimeter. Total and
visceral AT areas were calculated by delineating these areas with a
graph pen and then computing the AT surfaces by using an attenuation
range of -190 to -30 Hounsfield units.28 29 Abdominal
visceral AT area was measured by drawing a line within the muscle wall
surrounding the abdominal cavity.
Oral Glucose Tolerance Test
A 75-g oral glucose tolerance test (OGTT) was performed in the
morning after an overnight fast. Blood samples were collected through a
venous catheter from an antecubital vein at 15 minutes before and at 0,
15, 30, 45, 60, 90, 120, 150, and 180 minutes after glucose ingestion
for determination of plasma glucose and insulin concentrations. Plasma
glucose was measured enzymatically,30 whereas plasma
insulin was measured by radioimmunoassay with polyethylene glycol
separation.31 Plasma glucose and insulin areas under the
curve during the OGTT were determined by the trapezoid method.
Plasma Lipoprotein Measurements
Blood samples were obtained in the morning after a 12-hour fast
from an antecubital vein into Vacutainers (Becton Dickinson) containing
EDTA. Cholesterol and triglyceride levels in plasma and lipoprotein
fractions were measured enzymatically on an RA-1000 analyzer (Technicon
Instruments Corp). VLDLs (d<1.006 g/mL) were isolated by
ultracentrifugation,32 and the HDL fraction was obtained
after precipitation of apo B–containing lipoproteins in the
infranatant (d>1.006 g/mL) with heparin and
MnCl2.33 The cholesterol content of
HDL2 and HDL3 subfractions was
determined after precipitation of HDL2 with dextran
sulfate.34 Apo B and LDL–apo B concentrations were
measured in the plasma and infranatant, (d>1.006 g/mL)
respectively, by using the rocket immunoelectrophoretic method of
Laurell35 as previously described.36
AT Biopsies and AT LPL Activity
A subsample of twenty-five subjects gave their informed consent
for AT biopsies. Approximately 500 mg of AT was surgically removed
under local anesthesia from the abdominal (lateral to the umbilicus)
and femoral (anterior mid-thigh) adipose depots. AT samples were kept
frozen at -80°C for later measurements of heparin-releasable
activity37 as previously described.38 Another
sample of AT was digested with collagenase,39
and isolated adipocytes were measured to determine mean fat cell
size.40 The density of triolein was used to transform AT
cell volume into fat cell weight. AT LPL activity was expressed in
micromoles of free fatty acid per hour per 106
cells.
Plasma Postheparin LPL Activity
After a 12-hour fast, blood was collected from subjects 10
minutes after they had received an injection of heparin (10 IU/kg body
wt IV). Assays for enzyme activity were performed with a modification
of the method of Nilsson-Ehle and Ekman,41 as previously
described.42 Briefly, plasma LPL activity was measured by
using glycerol tri[14C]oleate as the substrate in an
artificial emulsion prepared in 0.1 mol/L Tris-HCl buffer (pH 8.0)
containing Triton X-100, and the delipidated human serum samples were
incubated at 30°C for 20 minutes in the presence or absence of 1.0
mol/L NaCl. Free fatty acids released during incubation were
selectively extracted, and an aliquot was counted for 14C
radioactivity. LPL activity was calculated as the lipase activity
sensitive to 1.0 mol/L NaCl from the total lipase activity (without
NaCl). LPL activity is expressed as nanomoles of oleic acid released
per milliliter of plasma per minute.
Statistical Analysis
Comparisons between the two genotype groups were
performed with Student's t test. Associations between
variables were analyzed within each group by using Pearson's
correlation coefficient. Subjects were subdivided into groups of low
versus high body mass index (BMI), low versus high visceral AT areas,
and low versus high fasting insulin levels, with a BMI of <25
kg/m2 as the low value and a BMI of >27 kg/m2
as the high value.43 For visceral AT areas, the
100-cm2 value proposed by Després and
Lamarche44 was used as the cutoff point, as it
represents the lower limit value associated with significant
but moderate disturbances in the CHD risk profile. The median value
(71.5 pmol/L) of the fasting plasma insulin distribution in the overall
group was selected as an arbitrary cutpoint to define subjects with low
or high insulin levels. Subjects were also further subdivided on the
basis of LPL-HindIII genotype. A 2x2 ANOVA was then
performed to assess BMI, visceral AT, or insulin effects versus the
effect of the LPL-HindIII genotype. Comparisons
among subgroups were performed by using multiple-comparison ANOVA
analyses and the Duncan post hoc test in situations where a significant
group effect was observed. All statistical analyses were performed with
the SAS statistical package (SAS Institute).
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Fifty-two subjects were analyzed for the LPL-HindIII polymorphism. The relative allele frequencies were .24 and .76 for the - allele (noncarrier of the restriction site) and the + allele, respectively. Subjects were classified into two groups: (1) those who were heterozygous for the HindIII polymorphism (+/- group, n=23) and (2) those who were homozygous for the + allele (+/+ group, n=28). One subject who was homozygous for the - allele was excluded from analysis. The subjects' characteristics according to LPL genotype are presented in Table 1
. The
two genotype groups were comparable for age, BMI, fat mass,
waist-to-hip ratio, visceral AT areas, fasting insulin, and glucose and
insulin areas during OGTT. Results of Table 2 show no
difference in plasma lipoprotein levels between the two groups.
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Associations between BMI, visceral AT area, and triglyceride
concentration in the two genotype groups are shown in Fig 1. Whereas plasma triglyceride concentrations were
positively associated with BMI, visceral AT area, and fasting insulin
levels in the +/+ genotype group, no significant associations
were found in men with the +/- genotype. Significant negative
correlations were also observed between BMI, visceral AT area, fasting
insulin, and plasma HDL2 cholesterol concentration
in the +/+ genotype group (Fig 2). These
associations were not found in the +/- group, with the exception of
BMI. We then tested the hypothesis that this polymorphism could
modify the relationship between visceral obesity and fasting plasma
insulin level and the insulin response during the OGTT. Essentially
similar associations among these variables were found in both
genotypes (.60 
r.75, P<.001; data
not shown). No significant correlation was observed between visceral AT
area and plasma LDL cholesterol, LDL–apo B, and total apo B in both
genotypes (data not shown).
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To further examine the potential interaction between BMI, fasting
insulin level, visceral AT area, and LPL HindIII
genotype with plasma lipoprotein levels, subjects in both
genotypes were then subdivided according to BMI (low BMI<25
kg/m2; high BMI>27 kg/m2). No significant
differences were observed in plasma triglyceride levels among the four
subgroups, although a trend was noted for higher triglyceride
concentrations among overweight men with the +/+ genotype (Fig 3). When subjects were subdivided on the basis of
visceral AT areas, men with elevated levels of visceral AT (area 
100
cm2) and with the +/+ genotype had higher plasma
triglyceride levels compared with +/+ subjects with low levels of
visceral AT (Fig 3). In the +/- group, variation in the amount of
visceral AT was not associated with differences in triglyceride
concentration. Thus, the hypertriglyceridemic effect associated with
visceral obesity appeared to be restricted to the +/+ genotype.
Subgroups were also formed on the basis of fasting insulin levels (low
versus high) by using the median value (71.5 pmol/L) of the fasting
insulin distribution of the whole sample as the cutoff point. Elevated
triglyceride levels were observed in the hyperinsulinemic state,
irrespective of LPL genotype.
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Similar analyses were also performed for the cholesterol-to–HDL cholesterol ratio (not shown). No significant differences were observed among the four subgroups on the basis of low or high BMI. Visceral obesity had a tendency to be associated with a higher cholesterol- to–HDL cholesterol ratio in the presence of the +/+ genotype, whereas in +/- subjects, high or low visceral AT areas could not discriminate between a high and low cholesterol-to–HDL cholesterol ratio. Finally, a higher cholesterol-to–HDL cholesterol ratio was observed in the two groups with high insulin levels, suggesting that this relation may be independent of the HindIII genotype.
Although the LPL polymorphism identified with HindIII is
found in a noncoding DNA sequence (intron 8) of the gene, we tested
whether it would influence AT and postheparin LPL activities (Table 3). No significant differences were found between the
two genotypes, suggesting that the presence or absence of the
HindIII restriction site does not alter plasma and AT LPL
activities. When subgroups were formed on the basis of low and high
BMI, visceral AT areas, and fasting insulin, no significant differences
were observed between subgroups for AT and postheparin LPL activities
(data not shown).
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Discussion |
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Abdominal obesity combined with an increased accumulation of visceral AT is associated with alterations in indices of plasma glucose-insulin homeostasis and in the plasma lipoprotein profile.10 11 45 However, because substantial heterogeneity remains among abdominally obese subjects, we have proposed that visceral obesity represents a condition that may exacerbate the genetic susceptibility to non–insulin-dependent diabetes mellitus, dyslipoproteinemia, and CHD.4 13 In this regard, we have previously shown that genetic variation at two major genes involved in lipoprotein metabolism has divergent effects on dyslipidemia in visceral obesity. An EcoRI variant in the apo B gene appeared to be associated with elevated apo B and LDL–apo B concentrations in visceral obesity,16 whereas the apo E polymorphism seemed to influence plasma triglyceride levels in abdominally obese, hyperinsulinemic subjects,14 15 in contrast to its usual effect on LDL cholesterol in the general population.46 Because LPL activity is an important correlate of plasma triglyceride47 48 and HDL cholesterol49 levels, the main objective of this study was to verify whether the LPL-HindIII polymorphism could influence the magnitude of dyslipidemia (hypertriglyceridemia and low HDL cholesterol concentrations) generally observed in visceral obesity. Results of the present study suggest that visceral obesity may be associated with hypertriglyceridemia and low HDL cholesterol concentrations in subjects who are homozygous for the + allele of the HindIII restriction site in intron 8 of the LPL gene. The + allele of LPL-HindIII has been previously associated with hypertriglyceridemia and premature CHD17 18 19 21 and with low HDL concentrations.20 To the best of our knowledge, this is the first time that an interaction with visceral obesity, a common correlate of the high triglyceride–low HDL cholesterol dyslipidemic phenotype, has been reported.
In a sample of 370 normoglycemic Hispanic and 520 normoglycemic non-Hispanic white subjects, Ahn et al22 have recently reported that individuals with the +/+ genotype at the LPL-HindIII restriction site had higher fasting plasma insulin and triglyceride concentrations and reduced HDL concentrations compared with subjects with the +/- genotype. In the present study, the +/+ genotype was associated with hypertriglyceridemia and low HDL concentrations in the presence of visceral obesity. However, essentially similar correlations were noted between visceral AT accumulation and plasma insulin levels in the two genotype groups, suggesting that the hyperinsulinemic effect associated with visceral obesity was not altered by the HindIII polymorphism at the LPL locus. Thus, the magnitude of the hyperinsulinemic/insulin-resistant state associated with visceral obesity appears to be independent of HindIII genotype. In contrast to the study of Ahn et al,22 the present results do not support the notion that the LPL-HindIII genotype may be a marker for susceptibility to develop an insulin-resistant/hyperinsulinemic state. With regard to hypertriglyceridemia and a decreased HDL cholesterol level, the polymorphism may exacerbate the dyslipidemic state that is associated with excess visceral AT. At this time, we cannot rule out the possibility that the difference between the two studies is caused by low power level resulting from the small sample size on which the present report is based.
The +/+ HindIII genotype altered the association between BMI, insulinemia, and visceral obesity with fasting triglyceride levels because significant correlations were found only in the +/+ group. Essentially similar results were observed when plasma HDL2 cholesterol was used as the dependent variable. These effects on triglyceride and HDL2 cholesterol levels are consistent with a hypothesis of a physiological role for LPL, which not only hydrolyzes triglyceride-rich lipoproteins but also modulates plasma HDL levels. Several metabolic and experimental studies have shown that a high LPL activity is generally associated with high plasma HDL levels, especially the HDL2 subfraction.49 For these reasons, it is not surprising that triglycerides and HDL2 cholesterol were altered in a reciprocal manner, but our results emphasize that the magnitude of this effect is much greater in the homozygous +/+ genotype.
The LPL-HindIII polymorphism is located in intron 8 of the LPL gene and therefore should not be associated with differences in enzyme activity and theoretically, should not be the cause of the observed effects. Accordingly, femoral and abdominal AT LPL activities were not different between the two genotypes; postheparin plasma LPL activity was also similar in the two groups. Thus, it is likely that the LPL-HindIII polymorphism is in linkage disequilibrium with a functional mutation in the LPL gene or in another gene that could predispose individuals to dyslipidemia. In addition, the observed effect may also be due to differences in regulation of the LPL gene between the two genotypes. Insulin is an important regulator of the LPL enzyme, and this hormone may regulate LPL at the mRNA50 and/or posttranscriptional51 level. For example, the + allele could be associated with a functional LPL enzyme that is less sensitive to insulin and may result in a reduced response of LPL to insulin in visceral obesity. Other regulators could also be involved in mediating the effects described here.
In conclusion, these results indicate that the dyslipidemia associated with abdominal visceral obesity, particularly plasma triglycerides and HDL2 cholesterol, may be modulated to a significant extent by variation in the LPL gene, despite its lack of effect on measurable LPL activity. Thus, this LPL polymorphism may be considered as another genetic marker that influences plasma lipoprotein levels and presumably CHD risk in relation to the level of visceral fat. Obviously, it will be necessary to examine interactions among several candidate genes for a proper assessment of CHD risk. However, studies based on large cohorts will be needed to examine even simple interactions among apo E, apo B, and LPL genes.
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Acknowledgments |
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This study was supported by the Medical Research Council of Canada (MRC), the Heart and Stroke Foundation of Canada, and the Canadian Diabetes Association. M.-C. Vohl and B. Lamarche received MRC fellowships during the course of this study. The authors wish to express their gratitude to the research personnel involved in collection of the data. The contribution of the staff of the Lipid Research Center, Diabetes Research Unit, and Physical Activity Sciences Laboratory is acknowledged.
Received December 10, 1994; accepted March 1, 1995.
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