© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Bezafibrate Increases Preß1-HDL at the Expense of HDL2b in Hypertriglyceridemia
From the Department of Laboratory Medicine (T. Miida, K.I., M.O.) and the First Department of Internal Medicine (K.S., K.O., Y.N.), Niigata University School of Medicine, Niigata; the Department of Cardiology, Kido Hospital (T.Y., T.T.), Niigata; the Institute of Medical Science, St. Marianna University School of Medicine (T.K.), Kawasaki; and the Department of Pharmaceutical Care and Clinical Pharmacy (T. Murakami), Tokushima Bunri University, Tokushima, Japan.
Correspondence to Takashi Miida, Department of Laboratory Medicine, Niigata University School of Medicine, Asahimachi 1-757, Niigata, Niigata 951-8510, Japan. E-mail miida{at}med.niigata-u.ac.jp
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Abstract—Preß1-high density lipoprotein (preß1-HDL), the initial acceptor of cell-derived cholesterol, can be generated from HDL2 by hepatic lipase. Because bezafibrate elevates lipase activity, it may increase preß1-HDL at the expense of HDL2. To answer this question, we determined the apolipoprotein A-I (apoA-I) distribution in 20 hypertriglyceridemics (triglycerides>2.26 mmol/L) and 20 sex-matched normolipidemics by native 2-dimensional gel electrophoresis. At baseline, preß1-HDL was 70% higher in hypertriglyceridemics than in normolipidemics (123.5±49.9 versus 72.5±34.1 mg/L apoA-I, P<0.01). Preß1-HDL was positively correlated with triglyceride (r=0.624, P<0.0001). A 4-week bezafibrate treatment (400 mg daily) increased preß1-HDL by 30% (160.2±64.5 mg/L apoA-I, P<0.05) but decreased HDL2b by 31% (from 188.8±94.9 to 129.3±78.7 mg/L apoA-I, P<0.05). Hepatic lipase activity increased by 24% (P<0.005). Preß1-HDL was generated either from ultracentrifugally isolated HDL2 or from plasma during incubation with triglyceride lipase. In conclusion, bezafibrate increases preß1-HDL at the expense of HDL2. We speculate that such an effect might partly contribute to the antiatherogenic action of bezafibrate.
Key Words: pre-ß-HDL • hepatic lipase • apolipoprotein A-I • LpA-I • cholesteryl ester transfer protein
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Introduction |
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Earlier studies have shown that HDL consists of several distinct subfractions with different compositions and functions.1 2 3 4 5 6 In experiments with fibroblasts or HepG2 cells, cell-derived free cholesterol rapidly moves to the minor HDL subfraction, preß1-HDL.1 2 3 4 5 This free cholesterol in preß1-HDL is subsequently transferred to pre-ß3-HDL2 4 5 and is then esterified by lecithin:cholesterol acyltransferase (LCAT).2 Although the origin of preß1-HDL has not been fully elucidated, preß1-HDL is probably generated during the conversion of
-migrating
HDL.7 8 9 10
Moreover, preß1-HDL may be secreted directly from the
liver5 or formed by
the interaction of free apoA-I with certain types of
cells.11 In in vitro
experiments, preß1-HDL was generated from triglyceride (TG)-enriched
HDL2 by hepatic
lipase.7 8 Bezafibrate is 1 of the fibric acid derivatives widely used to treat patients with hypertriglyceridemia (HTG) and combined hyperlipidemia.12 13 14 Because bezafibrate increases lipase activity,15 16 17 it is highly possible that bezafibrate promotes conversion of HDL2 to preß1-HDL. To ascertain whether bezafibrate increases preß1-HDL at the expense of HDL2 in HTG, we determined the HDL subfraction concentration before and after bezafibrate treatment in 20 patients with HTG by native 2-dimensional gel electrophoresis. We also carried out in vitro experiments with TG lipase to generate preß1-HDL from HDL2 or plasma.
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Methods |
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Patient Selection
Patients with at least 2 fasting TG concentrations
2.26 mmol/L (200 mg/dL) were recruited. None took medication for the
preceding 3 months. We excluded regular drinkers with an ethanol intake
>25 g/d and patients with severe liver disease, renal disease, thyroid
disease, diabetes mellitus, coronary artery disease, cerebrovascular
disease, or other significant systemic illness. Twenty patients with
HTG (HTG group; 18 men and 2 women) were enrolled in this study. We
also examined 20 sex-matched healthy volunteers [control group; total
cholesterol (TC) <6.47 mmol/L (250 mg/dL) and TG<2.26 mmol/L (200
mg/dL)]. After explaining the purpose of this study, we obtained
informed consent from each participant. The study protocol was approved
by the ethics committee of our institution.
Study Design
The baseline data described below were obtained in
both groups. In the HTG group, additional data were obtained after a
4-week bezafibrate treatment (400 mg/d). All of the patients maintained
their usual diet, smoking habits, and level of physical activity
throughout the study period.
For lipoprotein analysis, blood was drawn into an ice-chilled glass tube supplemented with K2-EDTA after an overnight fast.10 18 19 20 21 22 Plasma was obtained by centrifugation at 0°C, 2000g for 30 minutes. To analyze cholesteryl ester transfer protein (CETP) mass, an aliquot of plasma was stored at -80°C. To analyze lipase activity, postheparin plasma was obtained as described below.
Lipoprotein Analyses
The TC, TG, and phospholipid (PL)
concentrations were measured enzymatically on a Hitachi 7450 analyzer
(Hitachi). The HDL cholesterol (HDL-C) concentration was determined by
a homogeneous method (Determiner L HDL, Kyowa Medex) on the same
analyzer. The apolipoprotein A-I (apoA-I) concentration was measured by
turbidimetric immunoassay (Apo A-I Auto · N "Daiichi," Daiichi
Pure Chemicals) on a Hitachi 7170 analyzer. In the apoA-I measurement,
the coefficient of variation in the same assay was <1%, and that
between assays was <2%.
HDL Fractionation
In all subjects, HDL was fractionated by native
2-dimensional gel electrophoresis as described
previously.3 10 18 19 20 21 22
Fresh plasma was run on an agarose gel (0.75%) and then on a 2% to
15% polyacrylamide gel at 0°C at 100 V for 20 hours. Fractionated
HDL was electroblotted to a nitrocellulose sheet at 0°C and detected
by goat anti-human apoA-I antibodies (Daiichi Pure Chemicals) iodinated
with Na125I (NEN) by a modification of the
chloramine T
method.23 The
relative concentration was expressed as the percent apoA-I based on the
radioactivity of each
subfraction.3 10 18 19 20 21 22
The absolute concentration was calculated from the percent apoA-I and
the plasma apoA-I concentration.
The molecular size of preß1-HDL was determined by using a 4% to 30% polyacrylamide gel run to equilibrium.1 After plasma was separated on a 0.75% agarose gel, the pre-ß position was cut from the gel. The agarose gel pieces were placed on a 4% to 30% gradient polyacrylamide gel together with the molecular-weight standards (high-molecular-weight electrophoresis calibration kit, Amersham Pharmacia Biotech) supplemented with ovalbumin (Sigma). The gradient gel was electrophoresed at 0°C, 200 V for 24 hours. Fractionated preß1-HDL was electroblotted to a nitrocellulose sheet and detected as described above. The molecular-weight standards transferred to a nitrocellulose sheet were stained with amido black solution (Sigma).
In some subjects, HDL2 (1.063<d<1.125) and HDL3 (1.125<d<1.210) were separated by sequential ultracentrifugation according to the method of Havel et al.24 The lipid concentrations in the separated fractions were determined by the enzymatic method on a Hitachi 7450 analyzer.
Lipase Assay
In the HTG group, lipase activity was assayed
in postheparin plasma before and after bezafibrate treatment. Ten
minutes after heparin injection (50 U/kg), blood was obtained from a
brachial vein and mixed well with sodium citrate (final concentration,
0.38%, wt/vol) in an ice-cooled glass tube. The plasma was separated
by centrifugation at 0°C and stored at -80°C until measurement.
Triton X-100–stabilized triolein substrate was mixed with postheparin
plasma (10/1, vol/vol) and incubated at 37°C during the hydrolysis
reaction.25 The
reaction was stopped by placing the tubes in ice. The mixture was
extracted with organic solvents. The free fatty acids released during
the incubation were measured by a calorimetric method. Hepatic lipase
activity was selectively measured by inhibiting lipoprotein lipase with
1 mol/L NaCl. Lipoprotein lipase activity was determined by subtracting
hepatic lipase activity from the total lipase activity. The lipase
activity was expressed as the amount of free fatty acids released per
minute
(mmol · L–1 · min–1).
Incubation Experiment
We examined the effect of lipase on
HDL2 and plasma in vitro.
HDL2 was isolated by sequential
ultracentrifugation and dialyzed against 0.15 mol/L NaCl, 1 mmol/L EDTA
(pH 7.4) extensively. Then the HDL2 was
incubated at 37°C with TG lipase (from Pseudomonas
species, Sigma catalog No. L9518) reconstituted in PBS (pH 7.4) at 7200
U/L in the presence of 5% fatty acid–free human albumin (Sigma,
catalog No. A3782). One unit was defined as the activity that releases
1 µmol of glycerol from TG per minute at pH 7.0, 37°C. Plasma was
incubated with TG lipase (3700 U/L) in the same way. The distribution
of apoA-I was determined by 2-dimensional gel electrophoresis. In the
experiment with HDL2, the changes in its size
and composition were also determined by gel filtration chromatography
described below.
Gel Filtration Chromatography
Either the hydrolyzed or unhydrolyzed sample
was applied to a fast protein liquid chromatography system equipped
with a Superose 6 column (1x30 cm, Amersham Pharmacia Biotech). The
lipoproteins were eluted at 0.5 mL/min with PBS containing 1 mmol/L
EDTA (pH 7.4). Lipids and apoA-I concentrations in the separated
fractions were determined on a Hitachi 7450
analyzer.
Other Assays
LCAT activity was measured by the endogenous
substrate method described by Nagasaki and
Akanuma.26 The
immunoreactive CETP mass was determined by enzyme-linked immunoassay
(CETP Chugai ELISE, Chugai Pharmaceutical).
Statistical Analysis
Paired t tests were used to analyze
the changes in concentration or activity induced by bezafibrate. The
influence of bezafibrate was considered significant at
P<0.05.
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Results |
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Effect of Bezafibrate on Lipoprotein Concentration, CETP Mass, and LCAT Activity
At baseline, both TC and TG were significantly higher in the HTG group (6.62±1.29 and 4.46±2.37 mmol/L, respectively) than in the control group (5.09±0.72 mmol/L, P<0.001, and 1.37±0.45 mmol/L, P<0.01). On the contrary, HDL-C and apoA-I were lower in the HTG group (1.01±0.18 mmol/L and 1288±171 mg/L, respectively) than in the control group (1.29±0.31 mmol/L, P<0.01, and 1455±244 mg/L, P<0.05). CETP mass and LCAT activity were 31% and 19% higher in the HTG group (3.0±0.9 mg/L and 95.8±21.4 mmol · L–1 · h–1) than in the control group (2.3±0.8 mg/L, P<0.05, and 80.8±14.7 mmol · L–1 · h–1, P<0.05). The HTG and sex-matched control groups were similar in age (43.6±9.0 and 45.4±15.0 years), although the body mass index (BMI) was greater in the HTG group than in the control group (25.2±2.6 and 23.5±2.8 kg/m2, P<0.1).
After 4 weeks of bezafibrate treatment, TC and TG in the HTG group decreased by 8% (6.08±0.91 mmol/L, P<0.1 versus baseline and P<0.001 versus the control group) and 50% (2.21±1.33 mmol/L, P<0.001 versus baseline and P<0.05 versus the control group), respectively. On the other hand, HDL-C and apoA-I increased by 18% (1.19±0.23 mmol/L, P<0.001 versus baseline) and 8% (1395±197 mg/L, P<0.05 versus baseline). Although CETP mass in the HTG group had a tendency to decrease after bezafibrate treatment (2.6 mg/L, P<0.1 versus baseline), its posttreatment level was still as high as that in the control group. LCAT activity in the HTG group decreased by 8% after treatment (88.0±24.9 mmol · L–1 · h–1). The posttreatment level was as high as that in the control group. BMI did not change significantly during treatment (25.±32.5 kg/m2, P<0.05 versus the control group).
Effect of Bezafibrate on HDL
Subfractions
Native 2-dimensional gel electrophoresis revealed
that preß1-HDL spots were larger in the HTG group than in the control
group, whereas the HDL2b spot was smaller in the
HTG group than in the control group
(Figures 1A
and 1C). Quantification of the HDL subfractions
confirmed this observation
(Table 1). The baseline level of preß1-HDL in the HTG
group was 70% higher than that in the control group. When we combined
the 2 groups, the preß1-HDL concentration was positively correlated
with the TG concentration (r=0.634,
P<0.001;
Figure
I; please see http://atvb.ahajournals.org) but not
with the apoA-I (r=0.163) or HDL-C
(r=0.016) concentration or BMI
(r=0.006).
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After 4 weeks of bezafibrate treatment, the preß1-HDL
increased by 30% from baseline
(Figures 1A
and 1B and
Table 1). The posttreatment level of preß1-HDL was more
than double that in the control group. Of the 6 HDL subfractions,
HDL2b was the only subfraction that decreased
significantly after bezafibrate treatment
(Figures 1A and 1B and
Table 1).
Ultracentrifugal analysis revealed that bezafibrate markedly
reduced the TG content in HDL particles. At baseline, TG concentrations
in HDL2 and HDL3 were
much higher in the HTG group than in the control group
(Table 2). After 4 weeks of treatment, TG concentration
decreased by 46% in HDL2 and by 36% in
HDL3. On the contrary, TC concentrations
increased in both HDL2 and
HDL3. The PL-to-TC ratio decreased significantly
in HDL2.
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Molecular Weight of
Preß1-HDL
According to the mobility on the 4% to 30%
polyacrylamide gel run to equilibrium, the molecular weight of
preß1-HDL was 67 and 60 kDa in both control and HTG plasma
(Figure
II; please see http://atvb.ahajournals.org). The
molecular size of preß1-HDL did not change after bezafibrate
treatment (data not shown).
Effect of Bezafibrate on Lipase
Activity
After 4 weeks of bezafibrate treatment, the mean
lipoprotein lipase activity increased from 0.386±0.087 to 0.502±0.075
mmol · L–1 ·
min–1 (P<0.005, n=10),
and the mean hepatic lipase activity increased from 0.241±0.077 to
0.300±0.078 mmol · L–1 ·
min–1 (P<0.005, n=10).
However, the changes in lipase activity were not correlated
significantly with those in preß1-HDL (data not
shown).
Effect of TG Lipase on Isolated
HDL2
TG lipase clearly promoted the conversion of
HDL2 to preß1-HDL. When
HDL2 was incubated with TG lipase, preß1-HDL
appeared at 30 minutes, and the size of HDL2 was
significantly reduced
(Figure 2). Gel filtration chromatography revealed that
HDL2 lost not only TG but also PL and apoA-I
after incubation with TG lipase
(Figures 3A and 3B). On the contrary, the TC content in
HDL2 did not change during incubation (data not
shown). It is apparent that the second apoA-I peak appeared after
incubation with TG lipase
(Figure 3B).
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When plasma was incubated with TG lipase, preß1-HDL
increased as a function of time. On the other hand,
HDL2b and HDL2a decreased
in this order
(Figure 4). When we incubated the plasma for a longer time or
with an excess amount of TG lipase, however, preß1-HDL decreased, and
smaller preß–migrating particles increased (data not
shown).
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Discussion |
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This study indicates that bezafibrate increases preß1-HDL at the expense of HDL2 in HTG. We found that preß1-HDL increased by 30% and that HDL2b decreased by 32% after 4 weeks of bezafibrate treatment (Table 1
). The percent increase in preß1-HDL (30%) was
about 4 times greater than that in apoA-I (8%).
Bezafibrate probably promotes the conversion of
HDL2 to preß1-HDL by increasing hepatic lipase
activity. In this study, hepatic lipase activity increased by 24%.
Because the HDL2 of HTG patients is rich in TG
(Table 2),27
their HDL2 must be efficiently hydrolyzed by
hepatic lipase. Barrans et
al7 showed that
preß1-HDL was generated from human TG–enriched
HDL2 after a 120-minute incubation with rat
hepatic lipase. The remaining HDL2 lost not only
TG but also PL and
apoA-I.8 Because PL
and apoA-I are major constituents of
preß1-HDL,1
preß1-HDL is probably dissociated from the surface of
HDL2. In our experiment with
HDL2, preß1-HDL was generated after incubation
with TG lipase
(Figure 2). Gel filtration chromatography confirmed that the
hydrolyzed HDL2 lost TG, PL, and apoA-I
(Figure 3). Although the second apoA-I peak did not contain a
significant amount of PL, the sample dilution probably caused the
dissociation of PL and apoA-I of
preß1-HDL.10 28
In a similar experiment with plasma, preß1-HDL increased linearly
during incubation with TG lipase
(Figure 4). Interestingly, it was predominantly
HDL2b that decreased during the first 30
minutes, whereas HDL2a decreased thereafter.
Thus, preß1-HDL is probably generated from
HDL2b in vivo, because HDL passes through the
liver (the location of hepatic lipase) quickly. This hypothesis is
consistent with the changes in HDL subfractions induced by bezafibrate
(Figures 1A and 1B and
Table 1).
We failed to find a positive correlation between the
change in preß1-HDL and that in hepatic lipase activity in the HTG
group, probably because bezafibrate alters other factors known to
regulate HDL metabolism. First, bezafibrate binds to the peroxisome
proliferater-activated receptor- (PPAR-) and enhances apoA-I
synthesis.29
Preß1-HDL was detected in lipoproteins newly secreted from HepG2
cells.5 These data
suggest that increased apoA-I synthesis may directly contribute to the
increase in preß1-HDL concentration. Second, bezafibrate decreases
TG-rich lipoproteins
markedly.12 13 14
Thus, the net TG transfer between TG-rich lipoproteins and
HDL2 must
decrease.30 In the
HTG group, the TG content of HDL2 was lower
after bezafibrate treatment than at baseline
(Table 2). Such HDL2 is likely to be
less susceptible to hepatic lipase. In addition, bezafibrate decreased
the LDL-C and CETP mass, which was positively correlated with
thepreß1-HDL
concentration.21 22
These changes induced by bezafibrate may reduce the preß1-HDL
concentration. Therefore, it is reasonable to conclude that the overall
effect of bezafibrate on preß1-HDL concentration is not simply
dependent on changes in hepatic lipase activity.
Bezafibrate is expected to increase
cell-to-plasma cholesterol transport in the HTG group by the following
mechanisms. First, bezafibrate increases preß1-HDL
(Figure 1 and
Table 1) which is the initial acceptor of cell-derived
cholesterol.1 2 3 4 5
In cultured fibroblasts, cell-to-plasma cholesterol efflux is
proportional to preß1-HDL
concentration.31
Second, bezafibrate decreases
VLDL,27 which
impairs cell-to-plasma cholesterol
efflux.32 In
patients with non–insulin dependent diabetes mellitus, cholesterol
efflux was lower than that in normolipidemic
subjects.32 33
This tendency was prominent in the postprandial
state.33 When VLDL
was removed from plasma by an apoE immunoaffinity column, cholesterol
efflux was
normalized.32 These
results strongly suggest that impaired cholesterol efflux in diabetic
patients is related to the increased plasma-to-cell cholesterol influx
due to increased VLDL. Therefore, cell-to-plasma cholesterol transport
is probably reduced at baseline in the HTG group, although the baseline
preß1-HDL concentration was higher in the HTG group than in the
control group.
Recent clinical trials have shown that bezafibrate is equally effective in preventing coronary events in survivors of myocardial infarction as are other cholesterol-lowering drugs, although it does not have as great a cholesterol-lowering effect.13 14 This preventive effect of bezafibrate may be due to the reduction in TG-rich lipoproteins (including remnant lipoproteins), fibrinogen, or enhanced conversion of HDL. More study is needed to clarify whether the bezafibrate-induced increase in preß1-HDL is antiatherogenic. In summary, bezafibrate increases preß1-HDL at the expense of HDL2 in HTG. We speculate that such changes in the HDL subfractions may favor reverse cholesterol transport.
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Acknowledgments |
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This research was supported by a grant from Kurozumi Medical Foundation (1998) and by a grant-in-aid for Science Research from the Ministry of Education, Science, and Culture of Japan (No. 12671102, 2000 to 2002). We thank Takako Ikarashi (Kido Hospital, Niigata, Japan) and Hiroshi Matsui (Denka Seiken, Gosen, Japan) for their excellent technical assistance.
Received July 25, 2000; accepted August 11, 2000.
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