© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
A Hepatic Lipase Gene Promoter Polymorphism Attenuates the Increase in Hepatic Lipase Activity With Increasing Intra-abdominal Fat in Women
From the Department of Medicine, Divisions of Metabolism, Endocrinology, and Nutrition (M.C.C., J.E.H., J.Q.P., J.D.B.) and Medical Genetics (S.S.D.); and the Department of Family and Child Nursing (E.S.M.), University of Washington, Seattle.
Correspondence to Dr Molly C. Carr, Division of Metabolism, Endocrinology, and Nutrition, Box 356426, University of Washington, Seattle, WA 98195-6426. E-mail carr{at}u.washington.edu
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Abstract |
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Abstract—High hepatic lipase (HL) activity is associated with an atherogenic lipoprotein profile of small, dense LDL particles and lower HDL2-C. Intra-abdominal fat (IAF) is positively associated with HL activity. A hepatic lipase gene (LIPC) promoter variant (G
A-250) is associated with lower HL activity, higher
HDL2-C, and less dense LDL particles. To determine
whether the LIPC promoter polymorphism acts
independently of IAF to regulate HL, 57 healthy, premenopausal women
were studied. The LIPC promoter A allele was
associated with significantly lower HL activity (GA/AA=104±34 versus
GG=145±57 nmoles · mL-1 ·
min-1, P=0.009). IAF was positively
correlated with HL activity (r=0.431,
P<0.001). Multivariate analysis
revealed a strong relationship between both the LIPC
promoter genotype (P=0.001) and IAF
(P<0.001) with HL activity. The relationship between
IAF and HL activity for carriers and noncarriers of the A allele
was curvilinear with the carriers having a lower apparent maximum level
of plasma HL activity compared with noncarriers (138 versus 218
nmoles · mL-1 · min-1,
P<0.001). In addition, the LIPC A
allele was associated with a significantly higher
HDL2-C (GA/AA=16±7 versus GG=11±5 mg/dL,
P=0.003). We conclude that the LIPC promoter A
allele attenuates the increase in HL activity due to IAF in
premenopausal women.
Key Words: cholesterol • lipoprotein • visceral obesity • LIPC • triglyceride
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Introduction |
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Hepatic lipase (HL) is a 476 amino acid glycoprotein lipolytic enzyme that is a serine hydrolase. It appears to act not only in hydrolysis of triglyceride (TG) and phospholipid in HDL and LDL1 2 but also as a ligand directing lipoproteins to hepatic cell surface receptors.3 4 5 HL is secreted by hepatocytes and anchored to the liver sinusoidal surface by heparin sulfate proteoglycans.6 The HL gene (LIPC) spans 35 kb of DNA, maps to chromosome 15q21, and is composed of nine exons and eight introns.7 8
HL plays a role in the metabolic processing of both HDL and LDL. HL acts to convert large, buoyant HDL2 to small, dense HDL3 by modulating the phospholipid content of the particle.9 10 By functioning as a ligand between the lipoprotein and cell surface receptors, HL has been shown to play a role in increased clearance of HDL particles11 12 and remnant lipoproteins.13 HL also catalyzes the hydrolysis of triglyceride and phospholipid in large, buoyant LDL forming small, dense more atherogenic LDL particles.14
Increased risk of premature coronary artery disease (CAD) has been shown to be associated with the presence of small, dense LDL particles.15 16 17 18 19 Similarly, low HDL-C is another major risk factor for CAD.20 21 It appears that gender differences in HDL-C levels may account, in part, for the temporal separation in CAD risk between men and women.20 HDL-C metabolism is modulated by both environmental and genetic factors that combine to account for the significant interindividual variation in HDL-C levels and hence CAD risk. Sedentary lifestyle,22 tobacco usage,23 and obesity24 are all associated with lower HDL-C levels. Forty to sixty percent of the variation in HDL levels appear to be genetic,25 and Cohen et al have demonstrated genetic linkage between the hepatic lipase promoter (LIPC) locus and HDL-C levels that account for approximately 25% of the interindividual variation in plasma HDL-C levels.26
HL activity appears to be influenced by several different factors including intra-abdominal fat (IAF),27 ethnic background,28 29 sex-steroid hormones,30 31 32 and LIPC genotype.28 29 Four polymorphisms have now been identified in the 5' flanking region of the LIPC gene; a G to A substitution at position -250, C to T at -514, T to C at -710, and A to G at -763, which appear to be in complete linkage disequilibrium in white populations.33 The allele frequency of the substitution ranges from 0.1533 to 0.2129 in white populations, 0.4529 to 0.5328 in African-Americans, and 0.47 in Japanese-Americans.29 This variation in allele frequency between ethnic groups may partially explain the observed higher HDL-C levels seen in African-American and Japanese-American men. The less common haplotype of the LIPC gene promoter appears to be associated with decreased HL activity, increased HDL-C,29 33 and increased LDL buoyancy.29
Estrogen levels appear to influence HL activity significantly. Estrogen replacement in postmenopausal women has been shown to reduce HL activity by 31% back to premenopausal levels.32 The higher HL activity and the resultant decrease in HDL2-C with menopause may account for some of the increased risk for CAD in the postmenopausal state. Differences in body composition may explain the gender differences in HL activity. Despres et al have shown that IAF content is strongly correlated with HL activity and that this association is independent of the effect of total body adiposity.27 Premenopausal women have less IAF than men,34 and the modestly higher HL activity seen in postmenopausal women35 may be due to the increase in central adiposity that accompanies the menopausal transition.36 37
In the present study, we investigated whether the LIPC promoter polymorphism and intra-abdominal fat content contributed independently or interactively to the variation of HL activity and plasma lipids in premenopausal women.
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Methods |
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Subjects
Fifty-seven premenopausal white women, aged 21 to 54 years, were studied (Table 1
). Forty-seven women are
participating in a longitudinal, community-based study and had been
selected by phone contact as described previously.38 The
women were identified as premenopausal as assessed by daily menstrual
diaries. Some were oligomenorrheic as they neared the menopausal
transition but all had menstrual flows in the previous 6 months. These
are baseline data for subjects participating in a longitudinal study of
lipid metabolism in the menopausal transition. Ten
additional premenopausal women were recruited through advertisements at
the University of Washington as normal controls for a study of
weight loss.
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None of the women were taking any lipid-altering medications, including ß-blockers or estrogen. They had no lipid disorders or other medical conditions affecting lipid metabolism, including diabetes, liver disease, or pregnancy. Women were excluded from the study if they had a body mass index (BMI) of >40kg/m2, TG or LDL-C levels >95th percentile for their age,39 or were characterized as having small, dense LDL (phenotype B or I) by gradient gel electrophoresis.15 40 The Human Subjects Review Committee of the University of Washington approved the study protocol. Informed consent was obtained from all participants.
The mean age of these 57 women was 44.4±6.6 years (Table 1
)
with a mean weight of 70.9±14.5 kg and a BMI of 26.0±4.7
kg/m2. Their percent total body fat was
36.9±7.7% as measured by total body DEXA scan (see below). There was
a wide range in IAF area (10.5 to 183.5 cm2) at
the umbilicus as measured by computed tomography (CT) scan, with
a mean IAF area of 66.5±44.5 cm2. The mean
abdominal subcutaneous fat area was 239.7±134.5
cm2.
Blood Collection
Blood was collected in 0.1% ethylenediamine-tetraacetic
acid after a 12- to 16-hour overnight fast for DNA isolation,
lipoprotein measurements, lipase activity, and density gradient
ultracentrifugation (DGUC). Insulin and glucose were
collected in sodium heparin in supine subjects at 15, 20, and 25
minutes. A heparin bolus of 60 U/kg was given, and blood was collected
after 10 minutes in lithium heparin tubes (Becton Dickinson) for
the measurement of lipase activity. Blood was immediately
centrifuged at 4°C at 3000 rpm for 15 minutes. Lipid
measurements were made on fresh plasma within 2 days. Lipase activities
and DGUC were obtained on plasma that had been immediately frozen and
stored at -70°C.
Lipid and Hormone Determinations
Plasma total cholesterol, TG, HDL-C,
HDL2-C, HDL3-C, Apo B, and
Lp(a) were measured at the Northwest Lipid Research Laboratory as
previously described.41 42 Glucose was measured by the
glucose oxidase method using Trinder reagent (Sigma) with an inter- and
intra-assay coefficient of variation (CV) of <2%. Insulin was
measured by radioimmune assay, as described
previously.43 Briefly, this assay uses antisera raised to
intact insulin in rabbits and iodinated insulin as tracer
and has an inter- and intra-assay CV of 8% and 6%, respectively.
Glucose and insulin were measured 3 times serially (15 minutes after
insertion of intravenous line), with blood draw 5 minutes
apart on each subject and the mean of the 3 samples is reported.
Estradiol was measured by solid-phase chemoluminescent immunoassay and
follicle-stimulating hormone was measured by solid-phase 2-site
immunometric assay by the University of Washington Laboratory Medicine
Department.
Post Heparin Lipase Activity
The total lipolytic activity was measured in plasma after
heparin bolus as previously described.44 Glycerol
tri(1-14C) oleate (Amersham) and lecithin were incubated with
postheparin plasma for 60 minutes at 37°C, and the
liberated C14 labeled free fatty acids were then extracted and counted.
Lipoprotein lipase activity was calculated as the lipolytic activity
removed from the plasma by the incubation with a specific monoclonal
antibody against lipoprotein lipase (LPL), and HL activity was
determined as the activity remaining after incubation with the LPL
antibody. Enzyme activity is expressed as nanomoles of free fatty
acid released per minute per milliliter of plasma at 37°C. For each
assay, a bovine milk LPL standard was used to correct for interassay
variation, and a human postheparin plasma standard was
included to monitor interassay variation. Intra-assay coefficient of
variation of hepatic lipase is 6%, between assays is 14%.
DGUC
A discontinuous salt density gradient was created in an
ultracentrifuge tube using a modification45 of a
previous method.46 Samples were centrifuged at
65 000 rpm for 70 minutes (total 
t2=1.95x
1011) at 10°C in a Beckman VTi 65.1 vertical
rotor. Thirty-eight 0.45-mL fractions were then collected from the
bottom of the centrifuge tube, and cholesterol was
measured in each fraction. The relative flotation rate (Rf), which
characterizes LDL peak buoyancy, was obtained by dividing the fraction
number containing the LDL-C peak by the total number of
fractions collected. The coefficient of variation of the Rf value
obtained by replicate analysis was 3.6%, as described
previously.47
DNA Isolation and Analysis
DNA was extracted from leukocytes of 10 mL freshly drawn blood
by the method of Poncz et al.48 The polymorphism at
nucleotide position -250 was determined by polymerase
chain reaction amplification using a primer pair, as described
previously.29
Body Composition
Body composition was measured by CT scan (GE Highspeed
Advantage) and DEXA scan. A single image was obtained by CT scan on
inspiration at the level of the umbilicus. The CT image was
analyzed for cross-sectional area of fat using a density
contour program available in the standard GE computer software as
described previously.49 A single blinded observer made all
the CT measurements of intra-abdominal fat.
Total body fat (%) was measured using a dual x-ray DEXA scan (Hologic QDR 1500). The laboratory has an interassay CV of 1.6%, 1.3%, and 1.3% for fat mass, lean mass, and % body fat, respectively.
Statistical Methods
Statistical analysis was performed using Sigma Stat,
version 2.0 (Jandel Scientific). Comparisons between genotypes
were performed using unpaired t tests. Linear regression
analysis was used to determine the effects of body composition,
age, insulin, estradiol, and promoter variants on HL activity and the
relationship between HL activity and lipids. In Table 2, HL activity was adjusted
linearly for the effect of IAF (cm2). Multiple
linear regression was used to obtain correlation coefficients and
probability value in Table 3.
Multiple regression was also used to examine the relationship between
IAF, total body fat (by DEXA), and HL activity after accounting for the
variance due to the LIPC genotype, age, and estradiol. This
method computes a series of simultaneous normal linear
equations that are soluble using inverse matrix algebra. Hardy-Weinberg
equilibrium was tested using 
2
analysis. The significance level was set at 
=0.05.
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An apparent Vmax for the HL activity was calculated using the Wolff linearization of the Michealis-Menton curve for enzyme kinetics.50 51 This plot maximizes the accuracy for estimation of apparent maximum (Vmax) for plots with wide ranges of values on the x-axis.50 52 An apparent Vmax can be accurately calculated for the relationship between HL activity and the dependent variable IAF.51
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Results |
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Relationship Between HL Activity and IAF
There was a significant positive relationship between HL activity and all measures of body adiposity (Table 2
). IAF
(cm2), as measured by CT scan, was strongly
correlated with HL activity (r=0.431, P<0.001).
Other measures of central adiposity (trunk dexa, subcutaneous abdominal
fat, waist-to-hip ratio) were also highly correlated with HL
activity with correlation coefficients ranging from 0.393 to 0.452 (all
P
0.002) (Table 2). Insulin was marginally related
to HL activity (r=0.227, P=0.089); however, in
multivariate analysis, this relationship was
abolished (P=0.93) after accounting for IAF.
To determine whether the measures of body adiposity related to HL
activity were independent of IAF, HL activity was adjusted for IAF. As
seen in Table 2, none of the measures of adiposity were related
to HL activity after adjustment for IAF. Measures of body fat were
highly correlated (eg, IAF and total body fat, r=0.735), as
IAF is included in the total body fat measurement. Therefore, in an
attempt to determine which of these 2 measures, or both, relate to
hepatic lipase activity, multivariate analysis
was performed. In multiple linear analysis IAF
(P=0.031) remained significantly related to HL activity,
whereas total body fat (by DEXA) (P=0.48) was no longer
significant. In addition, the relationship between insulin and HL
activity was not independent of IAF.
Relationship Between HL Activity and LIPC Genotype
When the women are categorized based on the presence or absence of
the rare LIPC (A) allele, there was a significant
difference in HL activity (145±57 versus 104±34 nmoles ·
mL-1 · min-1 in GG
versus GA and AA combined, respectively) (Figure 1). The GG genotype was
associated with a 39% higher HL activity as compared with the GA and
AA genotypes combined (P=0.009). The frequency of
the A allele is 0.17, and the population sample studied is in
Hardy-Weinberg equilibrium (2=0.04,
P=0.98).
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As previously seen in men,29 there appears to be an
absence of women with higher levels of HL activity among carriers of
the A allele compared with those having the GG genotype
(Figure 1). The range of HL activity was much wider among the
subjects with the GG genotype (47 to 281 nmoles ·
mL-1 · min-1) as
compared with carriers of the A allele (53 to 166 nmoles ·
mL-1 · min-1). In
the univariate analysis (Table 2), the
polymorphism in the promoter region of the LIPC gene
accounted for 12% (r2=0.118) of the
variance in the HL activity in these premenopausal women.
Combined Effects of the LIPC Genotype and IAF on HL
Activity
Multivariate analysis revealed that both
IAF (P=<0.001) and the LIPC genotype
(P=0.001) were significantly associated with HL activity
(r=0.577), after accounting for each other. These 2
variables accounted for 33% of the variance in HL activity.
Within each genotype, there was a highly significant
curvilinear relationship between HL activity and IAF (GG,
r=0.779; GA/AA, r=0.873; P<0.001)
(Figure 2). With increasing IAF, HL
activity increases to a different apparent maximum depending on
genotype. Using the Wolff linearization of Michealis-Menton
kinetics (see Methods), one can calculate a maximal level for hepatic
lipase activity within each genotype. The maximal level for the
GG genotype was significantly higher than that for the carriers
of the A allele (218 versus 138 nmoles ·
mL-1 · min-1,
P<0.001). Thus, at high levels of IAF, there was a wide
divergence of the HL activity between the 2 genotypes.
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Relationship of Lipids to HL Activity, LIPC Variants, and
IAF
There were also differences between genotypes in total
cholesterol (176±29 versus 200±22 mg/dL in GG versus
GA/AA, respectively) that were confined to differences in the HDL-C
subfractions (Table 4). The significantly
lower HL activity in the carriers of the A allele was accompanied
by a statistically significant increase (23%) in HDL-C in comparison
with the noncarriers (65±16 versus 53±12, P=0.003), as
well as higher HDL2-C and
HDL3-C levels. HDL2-C and
HDL3-C levels were 45% (16±7 versus 11±5,
P=0.003) and 17% (49±10 versus 42±8, P=0.009)
higher, respectively, in the carriers of the A allele compared with
the noncarriers. Univariate analysis showed that
HDL-C was correlated with HL activity (r=0.323,
P=0.01) along with HDL2-C
(r=0.449, P<0.001) but
HDL3-C (r=0.201, P=0.13)
was not correlated (Table 3).
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LDL-Rf, a measure of LDL particle peak density, was not statistically different between genotypes. This may be due to the fact that women were excluded from the study if they had small, dense LDL, therefore truncating the sample such that there was not enough statistical power to demonstrate the effects seen in males. HL activity was related to LDL-Rf (r=0.348, P=0.016) such that the higher HL activity was associated with more dense LDL. HL activity was not related to total cholesterol, LDL-C, TG, Apo B, or Lp(a).
The relationship between IAF and lipid measures were all significant
with the exception of Lp(a) (Table 3). In
multivariate analysis, with both IAF and HL
activity in the model, the relationship between IAF and the HDL
subfractions disappeared. All other measures that were related to IAF
in univariate analysis remained significant after
accounting for HL activity. The relationship between HL and
HDL2-C remained significant in
multivariate analysis, but all other lipids
measures were no longer related to HL activity after accounting for
IAF.
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Discussion |
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In the present study, the investigation of the relationship between the -250 LIPC polymorphism, central adiposity, and HL activity in premenopausal women leads to 3 conclusions. First, central adiposity and the LIPC gene promoter polymorphism are both associated with variation in HL activity in women. Second, the relationship between central obesity and HL activity is different depending on the LIPC promoter polymorphism, such that the presence of the A allele appears to attenuate the increase in HL activity with high intra-abdominal fat levels. Third, there is a strong relationship between IAF and Apo B containing particles (TG, VLDL-C, LDL-C), but the relationship between IAF and HDL2-C appears to be mediated through their association with HL activity.
We have shown that central adiposity and the polymorphism at
position -250 of the LIPC gene are both associated with
plasma HL activity. In univariate analysis, central
obesity is positively correlated with HL activity (Table 2),
whereas the presence of the LIPC A allele is negatively
associated with HL activity. These relationships remain significant in
multivariate analysis revealing that both the
LIPC genotype and IAF may act to regulate HL activity. Another
demonstration of the relationship of the LIPC promoter
variants with HL activity is seen (Table 2) after adjusting for
the effects of IAF on HL and finding that the relationship between the
LIPC variants and HL activity remains.
Although there was a significant linear relationship between HL
activity and IAF in the GG genotype (r=0.537) and
the combined GA and AA genotypes (r=0.432), we found
that the curvilinear relationships fit the data better
(r=0.779 and 0.873, respectively) (Figure 2). A
maximal level of HL activity is approached as IAF increases in the 2
groups, and the maximum HL activity is 58% lower in the presence of
the A allele than in its absence. The lower maximal level of HL
activity in the carriers of the A allele is compatible with the
lower mean hepatic lipase activity seen in both men and
women28 29 and the truncated range of expression seen
in normal men and men with CAD29 who carry the A
allele.
It has been previously shown that HL activity is regulated by
increasing amounts of intra-abdominal fat.27 Several
groups have also shown that the LIPC promoter
polymorphisms, all in linkage disequilibrium in whites, are
associated with HL activity.28 29 53 54 Our data show
that the LIPC promoter polymorphism influences the
relationship between IAF and HL activity. The difference in HL activity
between the 2 genotypes is most evident when 2 curves diverge
at relatively high levels of IAF (Figure 2). In fact, the
maximal expression of HL activity between genotypes is highly
significant (P<0.001). Thus the potential benefit of the
LIPC promoter polymorphism to limit HL activity is most
evident in women with higher levels of intra-abdominal fat. These
results suggest that the less common promoter variant is not as
transcriptionally active as the common allele, which may place a
limit on gene expression capacity at higher IAF values.
The presence of the A allele also confers benefit to the lipid profile, which is characterized by a 23% higher HDL-C, mainly due to a 45% higher HDL2-C, the most anti-atherogenic HDL particle.55 There does not appear to be any significant effect of the LIPC promoter variants on the Apo B containing particles, including VLDL or LDL in these women.
High HL activity is associated with a more atherogenic lipid profile characterized by reduced HDL2-C and increased amounts of small, dense LDL. Tahvanainen et al have shown that carriers of the A allele have significantly higher amounts of triglyceride in IDL, LDL, and HDL particles, making them more buoyant among subjects with lower HL activities.54 In this study, we observed strong positive correlations between HL activity and HDL-C and HDL2-C levels. This is accompanied by a strong negative correlation between HL activity and LDL-Rf. All of these differences suggest that high HL activity is potentially atherogenic.
There are also strong correlations between the presence of central adiposity and lipid measures. IAF is positively correlated with TG, VLDL-C, and Apo B and negatively related to HDL2-C and LDL-Rf. To determine whether HL activity and IAF both effect these lipids, after accounting for the other, multiple regression was performed. IAF remained associated with measures of Apo B containing particles (TG, VLDL-C, LDL-C, Apo B), whereas HL remained associated with HDL2-C. The effects of IAF on HDL2-C particles were reduced, suggesting that HL activity may mediate the relationship between central obesity and HDL2-C metabolism.
We propose a model that describes the relationship between central
adiposity and hepatic lipase with a downstream effect on lipoproteins
(Figure 3). Hepatic lipase increases as a
function of IAF. The magnitude of this increase depends on the
LIPC genotype. Higher HL activity increases the
conversion of HDL2 to
HDL39 10 and the conversion of large,
buoyant LDL to small, dense LDL.14 The link between IAF
and HDL2-C metabolism appears to be
mediated, at least in part, by hepatic lipase. There is an additional
influence of IAF on LDL density beyond the effect of hepatic lipase,
perhaps by altering the synthesis of TG-rich lipoproteins.
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This cohort of healthy, premenopausal women has been rigorously characterized. They have been carefully selected as to their menopausal status, and they have a wide range of body fat content. The mean BMI of these women is 26.0 kg/m2, which closely resembles that of the American female population of the same age (26.1 kg/m2).56 Serum estradiol and follicle-stimulating hormone levels were not associated with HL activity, perhaps due to the wide fluctuations in estradiol that occur in these menstruating women who were not studied on coordinated phases of their menstrual cycle. However, estradiol was correlated with HL activity in multivariate analysis as it contributed to the relationship between HL and IAF.
Others have shown a relationship between HL activity and
insulin.53 As seen in Table 2, insulin levels are
marginally related to HL activity, but this effect is not seen after
adjustment for IAF. In multivariate analysis,
insulin added no further significance above IAF in predicting hepatic
lipase. This suggests that the relationship between insulin and hepatic
lipase is mediated through their respective relationships with IAF. The
LIPC A allele appears to be a limiting factor at higher
IAF. In subjects with the common LIPC genotype, as
IAF (and insulin) increases, hepatic lipase increases. However, in the
subjects who carry the A allele, this increase in HL activity is
attenuated at higher levels of IAF. Thus the observed increase in
hepatic lipase activity with higher insulin levels within the common
LIPC genotype53 may be due to the
relationship between insulin and IAF.
As seen in Table 2, all measures of body adiposity were
significantly related to HL activity. Nie et al57 have
shown that HL activity is related to BMI, and we confirm this. In
addition, we sought to investigate the relationship of different fat
depots with HL activity. Measures of central adiposity, trunk DEXA, and
waist-to-hip ratio were highly correlated with HL activity but measure
both IAF and subcutaneous fat. Depres et al previously demonstrated
that IAF is related to HL activity, independent of total body
adiposity.27 Our data confirm that the relationship
between HL activity and IAF is independent of total body adiposity.
These data suggest that the IAF depot may be an important regulator of
HL activity.
In conclusion, in these normal white women, the relationship between hepatic lipase and IAF is modified by the presence of promoter variants in the LIPC gene. The LIPC A allele attenuates the expression of hepatic lipase in subjects with high IAF. Thus, in subjects with large amounts of central fat deposition, the LIPC promoter variants affect hepatic lipase levels and the subsequent levels of atherogenic lipoproteins. This study indicates a potential differential genetic susceptibility to increased atherogenic risk factors in the presence of central obesity.
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Acknowledgments |
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Supported by a grant from Bristol Myers Squibb Foundation and NIH grants HL30086 and NR04141. Dr Carr was supported by a NIH training grant (DK07247). These studies were performed with the support of the University of Washington CNRU (NIH:DK35816) and GCRC (NIH:RR37). We thank Alegria Aquino-Albers, Chris Cassaza, and Lori Iwasaki for their technical expertise as well as Anne Mariella and Linda Floyd for subject recruitment.
accepted May 19, 1999.
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