© 1997 American Heart Association, Inc.
Articles |
Antiatherogenic Effects of a Novel Lipoprotein Lipase-Enhancing Agent in Cholesterol-Fed New Zealand White Rabbits
From the School of Pharmaceutical Sciences (T.C., S.M., F.S., R.U., I.T.) and Graduate School of Health Sciences (T.T.), University of Shizuoka, Shizuoka, and New Drug Research Laboratory, Naruto Research Institute, Otsuka Pharmaceutical Factory (Y.I., K.T.), Tokushima, Japan.
Correspondence to Dr Takako Tomita, Graduate School of Health Sciences, University of Shizuoka, 52-1 Yada, Shizuoka, Japan 422. Email tomitat{at}sea.u-shizuoka-ken.ac.jp
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Abstract Following our report that administration of 4-diethoxyphosphorylmethyl-N-(4-bromo-2-cyanophenyl) benzamide (NO-1886) to rats elevated postheparin lipoprotein lipase (LPL) activity through an increase in the enzyme mass, we now investigate antiatherogenic effects of NO-1886 in cholesterol-fed New Zealand White rabbits. For 20 weeks, four groups of male rabbits received regular rabbit chow (the normal control), 0.25% cholesterol-containing chow (the control), and cholesterol chow supplemented with 0.5% and 1.0% NO-1886, respectively. Postheparin LPL activity at week 10 was raised by 30% in 0.5% of the NO-1886 group and 40% in 1.0% of the NO-1886 group compared with those in the control. The area under the curve of plasma cholesterol level was not different in three cholesterol-fed groups whereas the area under the curve of HDL cholesterol was approximately twofold greater in the two NO- 1886 groups than in the control, and the area under the curve of plasma triglyceride was reduced to the level of the normal control. LPL activity was correlated with HDL cholesterol (r=.764, n=18) and triglyceride (r=-.627, n=18). Relative atheromatous area, aortic cholesterol, and triglyceride contents were reduced to approximately 25%, 60%, and 55%, respectively, of the control values by NO-1886 ingestion. Multiple regression analysis of LPL, HDL cholesterol, and triglyceride indicated that HDL cholesterol was the most powerful protector against aortic cholesterol accumulation, and triglyceride was the one to protect against the atheromatous area. We concluded that NO-1886 prevented the development of atherosclerosis through increasing LPL activity with a consequent increase in HDL cholesterol and a decrease in triglyceride without a significant influence of plasma cholesterol level.
Key Words: lipoprotein lipase • high density lipoprotein • NO-1886 • New Zealand White rabbit • antiatherogenic effects
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Introduction |
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LPL hydrolyzes chyromicrons and very low density lipoprotein to remnants and LDL, whereas cholesterol, apoproteins, and surface phospholipids released from triglyceride-rich lipoproteins fuse with smaller HDL particles. The addition of cholesterol collected from peripheral cells results in a conversion of smaller HDL3 particles to less dense HDL2.1 2 Accordingly, a negative relationship has been observed between the HDL2 cholesterol concentration and the extent of coronary artery disease in several studies.3 4 The formation of HDL2 depends on the activity of LPL, thus a positive correlation has been demonstrated between postheparin plasma LPL activity and serum HDL2 cholesterol concentration under several clinical conditions.5 6 7 8
Transgenic mice overexpressing human LPL showed resistance to diet-induced hypertriglyceridemia and hypercholesterolemia9 and diabetic hyperlipidemia in diabetic transgenic mice.10 Liu et al11 and Zsigmond et al12 recently reported alteration of plasma lipid profiles in transgenic mice expressing human LPL. In contrast, LPL knockout mice showed severe hypertriglyceridemia and reduced HDL cholesterol.13
Many mutations and polymorphisms of LPL have been described in recent years.14 There are several polymorphisms of LPL that have been associated with reduced HDL cholesterol in premature atherosclerosis. Reymer et al15 reported that in approximately one in 20 males with proven atherosclerosis, an Asn 291 Ser mutation in the human LPL gene is associated with significantly reduced HDL cholesterol levels and results in a significantly decreased LPL catalytic activity. The relative frequency of this mutation increased in those patients with lower HDL cholesterol levels.
Tsutsumi et al16 reported that a novel compound, NO-1886, possessed a potent LPL-enhancing activity. Administration of NO-1886 increased LPL activity in the postheparin plasma, the adipose tissue, and the myocardium in rats with a concomitant reduction in plasma triglyceride level and elevation of HDL2 cholesterol levels. NO-1886 increased LPL enzyme mass in postheparin plasma and LPL mRNA expression in the epididymal adipose tissue. In addition, this compound was found to correct hypertriglyceridemia with low HDL cholesterol in streptozotocin-induced diabetic rats.17 These results are very interesting, but these experiments were carried out in rats. Metabolism of cholesterol in rats, however, differs greatly from that in humans and rabbits in the following respects: (1) Rats lack CETP, which rabbits and humans have,18 and rats thus fail to transfer CE from HDL2 to LDL and very low density lipoprotein, resulting in a relatively higher HDL cholesterol to LDL cholesterol ratio.19 (2) Rats have a much larger capacity for cholesterol absorption compared with man. When cholesterol was fed, approximately 85% of circulating cholesterol was of dietary origin in rats whereas this value was only 40% in man. (The ratio of endogenous to exogenous source of plasma cholesterol is thus much less in rats than in man.20 ) (3) Macrophages, which play important roles in atherogenesis, appear to possess higher turnover rates in cellular CE metabolism (CE cycle) in rats and mice than in humans and rabbits.21 Moreover, cholesterol feeding can easily induce atherosclerosis in the arch and thoracic aorta in rabbits; however, additional supplementation of vitamin D and thiouracil to the cholesterol diet is needed to induce atherosclerosis in rats.
The present study was therefore undertaken to investigate the antiatherogenic effect of the LPL-enhancing agent NO-1886 in cholesterol-fed New Zealand White rabbits. The degree of preventive effects on the development of atherosclerosis was examined morphologically and biochemically, and the relative contribution of the resulting changes in serum lipids to protection against atherosclerosis was analyzed. We report here that an LPL-enhancing agent, NO-1886, is a novel type of antiatherogenic compound that prevents the development of atherosclerosis without affecting plasma cholesterol level.
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Methods |
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Materials
Agent NO-1886 was synthesized in the New Drug Research Laboratory of Otsuka Pharmaceutical Factory, Inc, Naruto, Tokushima, Japan. Glycerol tri[1-14C]oleate (4.1 Gbq/mmol) was obtained from DuPont-New England Nuclear Research, Boston, Mass; triolein from Sigma Chemical Co, St Louis, MO; and heparin from Takeda Pharmaceuticals, Osaka, Japan. The Nescote HDL-C kit (heparin calcium precipitation) was from Nihon Shoji Co LTD, Osaka, Japan. The cholesterol C-test Wako and triglyceride G-test Wako were from Wako Pure Chemical Industries Co LTD, Osaka, Japan.
Animal Experiments
Male New Zealand White rabbits weighing approximately 2 kg were
divided into four groups, a normal control group and three
cholesterol-fed groups. Normal control rabbits were fed
regular laboratory chow (35 g/kg/day).
Cholesterol-fed animals received regular laboratory chow
supplemented with 0.25% cholesterol (the control),
supplemented with 0.25% cholesterol and 0.5% NO-1886
(0.5% NO-1886), or 1.0% NO-1886 (1.0% NO-1886), respectively (35
g/kg/day), for 20 weeks. The animals were fed at 9
AM and given free access to tap water. Food consumption was
measured daily (all food was consumed within 1 hour), and body weight
was recorded at the times indicated. Blood samples for the drug and
lipid measurements were withdrawn at weeks 0, 2, 4, 6, 10, and 20 from
auricular veins 4 hours after feeding time. Postheparin
plasma was prepared from blood withdrawn 5 minutes after 100-IU/kg
heparin administration (IV) at weeks 0 and 10. At the end of the
experimental period, the animals were killed by phlebotomy under light
anesthesia with sodium pentobarbital. The aorta was
dissected from the heart to the bifurcation and gently rinsed with
normal saline, and the periaortic tissue was carefully removed.
Analytical Methods
Measurement of Plasma Concentration of NO-1886
Plasma NO-1886 was analyzed by high-performance liquid
chromatography (Tosoh Co LTD, Tokyo, Japan) under the
following conditions: column-TSK gel ODS-80TM, 5 µm,
4.6 mm I.D.x150 mm; temperature-40°C; mobile
phase-acetonitrile-10 mmol/L phosphate buffer (pH 6.4) (1:1,
v/v); flow rate-1 mL/minute; detection-UV spectrophotometer, 260 nm;
retention time-6.03 minutes.
Plasma Lipids
Plasma total cholesterol, HDL
cholesterol, and triglyceride were determined
by enzymatic methods using the following kits; cholesterol
C-test Wako, Nescote HDL-C kit (heparin calcium precipitation), and
triglyceride G-test Wako.
Measurement of LPL Activity in Postheparin Plasma
LPL activity in postheparin plasma was measured as
described previously using glycerol tri[1-14C]oleate as
the substrate.22 Postheparin LPL activity was
calculated by subtracting HTGL activity measured in the presence of 1
mol/L of NaCl from total postheparin lipase activity
measured in the absence of 1 mol/L of NaCl.
Measurements of Atheromatous Area
The cleaned aortae were opened longitudinally, and the extent of
gross atheromatous area was quantified by a
dot-counting method. Templates of the vessels were drawn on clear
acrylic sheets and superimposed over a dot grid with a 2x2-mm grid
size. The number of dots in the lesions areas and in the whole area
were counted.
Measurement of Aortic Lipid Contents
Immediately after the measurement of
atheromatous areas, the aortae were fixed in 10%
buffered formalin and refrigerated until used.23 They were
rinsed with 70% isopropanol and then with normal saline. The intima
and media were carefully separated from the adventitia, weighed, and
minced. The minced tissue was homogenized in 5 mL of
CHCl3:MeOH (2:1, v/v) for each 0.1 g with a
Physcotron homogenizer (Nichion Irikakikai, Chiba,
Japan). The lipid residue was dissolved in a small amount of
isopropanol and sonicated. This solution was mixed with 2% Triton
X-100 (approximately seven volumes) and incubated for 20 minutes at
70°C before lipid analysis.
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Results |
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Experimental Parameters
Body weights increased slightly in all four groups during the experimental period. There was no difference in body weights in the normal group, the control group, and the 0.5% NO-1886 group; however, the weights in the 1.0% NO-1886 group were significantly lower than in the other three groups (Fig 1
). The AUCs
of body weights (mean±SD, kgx20 weeks-1) were 2.62±0.20
(normal), 2.63±0.23 (control), 2.56±0.13 (0.5% NO-1886), and
2.27±0.23 (1.0% NO-1886). A reduction in the body weights of the
1.0% NO-1886 group was not due to the toxicity but apparently was a
result of enhanced fat oxidation (see Discussion). Serum concentration
of NO-1886 at 4 hours after the feeding time was analyzed by
high-performance liquid chromatography; the time
courses are shown in Fig 1. The AUCs of NO-1886 concentration
(mean±SD, µg/mLx20 weeks-1) were 13.4±1.18
(0.5% NO-1886) and 22.4±1.78 (1.0% NO-1886).
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, n=8),
control (
, n=10), 0.5% NO-1886 (
, n=10), 1.0% NO-1886
(
, n=10). Each point and vertical bar represent mean±SE
for the number of rabbits. Significance: **P<.01 versus
normal, control, and 0.5% NO-1886, ##P<.01, 0.5% versus
1.0% NO-1886 by analysis of variance.
Time Courses of Serum Lipids
In Fig 2, the time courses of levels
of serum lipids are shown. Total cholesterol levels of
three cholesterol-fed groups were linearly elevated with
time and reached a plateau at week 4. Ingestion of NO-1886 did not
significantly influence serum cholesterol levels regardless
of the concentration of NO-1886 in the diet. The level of the normal
control group remained less than 45 mg/dL during the
experimental period. HDL cholesterol levels in NO-1886
groups markedly increased both time and dose dependently in comparison
with that of the control. A significant increase in HDL
cholesterol by the drug was observed as early as week 2.
HDL cholesterol concentration plateaued at week 10 in all
three cholesterol-fed groups and leveled off thereafter. At
week 10, the HDL cholesterol level was 1.8-fold higher in
the 0.5% NO-1886 group and 2.4-fold higher in the 1.0% NO-1886 group
than that in the control. Triglyceride levels were rapidly
elevated by cholesterol loading and peaked at week 2 in the
control whereas NO-1886 ingestion significantly lowered the level to
less than that of the normal control. The effect of NO-1886 was more
evident in the earlier experimental period. The AUCs for total
cholesterol (mg/dLx20 weeks-1) were 33
(normal), 696 (control), 651 (0.5% NO-1886), and 684 (1.0% NO-1886).
There were no differences in the AUCs of total cholesterol
among the three cholesterol-fed groups. The AUCs
(mg/dLx20 weeks-1, **significance
P<.01 versus control) of HDL cholesterol were
23 (normal), 49 (control), 96** (0.5% NO-1886), and 110** (1.0%
NO-1886), whereas the AUCs of triglyceride were 87
(normal), 132 (control), 74** (0.5% NO-1886), and 64** (1.0%
NO-1886).
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LPL Activities in Postheparin Plasma
Blood was withdrawn at weeks 0 and 10 for the assay of LPL
activities. Peripheral LPL activity (NaCl-inhibitable
activity) was calculated by subtracting HTGL activity (NaCl
noninhibitable activity) from total postheparin lipase
activity. In Table 1,
postheparin plasma LPL activities and HTGL activities in
the control and NO-1886 groups are shown. There was no difference in
LPL activity among the three groups before the start of the experiment.
However, LPL activity at week 10 was dose-dependently increased by 30
and 40% in the 0.5 and 1.0% NO-1886 groups, respectively, compared
with that in the control. HTGL activity was not significantly altered
by NO-1886 ingestion.
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Atheromatous Areas and Aortic Lipid
Contents
The aortic wet weights of the control group were 39% greater than
those in the normal control, and NO-1886 administration reduced the
weight to the level of the normal control (Fig 3A). Relative
atheromatous area (% of whole area) measured by a
dot-counting method was 51% in the control group, and the area was
reduced to 14% and 11% in the 0.5% and 1.0% NO-1886 groups,
respectively (Fig 3B). In Fig 4 are shown
photos of aortae in each group.
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, normal control
(n=4); 
, control (n=9); 
, 0.5% NO-1886 (n=9); 
, 1.0% NO-1886
(n=9). Each column and vertical bar represent mean±SE for the
number of rabbits. Significance: **P<.01 versus control by
Dunnett's test.
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Cholesterol-loading elevated aortic cholesterol
content to 25 mg/g of tissue in the control, but NO-1886
ingestion significantly reduced this value to less than 10 mg/g
of tissue (Fig 5A). Like aortic
cholesterol contents, triglyceride contents in
the NO-1886 groups were reduced to approximately 45% of the value in
the control (Fig 5B). There was no difference in the contents of
cholesterol and triglyceride between the 0.5%
and 1.0% NO-1886 groups.
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, 0.5% NO-1886 (n=9);
Correlations Between Postheparin Plasma LPL Activity
and HDL Cholesterol, Atheromatous Area, or
Aortic Lipids
To know how the enhancement of LPL activity by NO-1886 influences
HDL cholesterol and triglyceride levels and
aortic lipid contents, correlations between LPL activity and these
variables were examined in 18 rabbits: six rabbits each from the
control, the 0.5% NO-1886, and the 1.0% NO-1886 groups. In Fig 6A, correlations between LPL activity and
HDL cholesterol level at week 10 can be seen. HDL
cholesterol (r=.764, n=18) is highly correlated
with LPL activity. Triglyceride at week 10
(r=-.627, n=18) are also inversely correlated with LPL
activity (Fig 6B).
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Atheromatous area was inversely correlated with LPL
activity (r=-.649, n=18) and AUC-HDL
cholesterol (r=-.709, n=28) and positively
correlated with AUC-triglyceride (r=.855, n=28)
(Fig 7A, B, and C). The lower part of Fig 7 shows correlations of aortic cholesterol content with LPL
activity (r=-.673, n=18) in D, with AUC-HDL
cholesterol (r=-.782, n=18) in E, and with
AUC-triglyceride (r=.579, n=18) in F. Aortic
triglyceride content also showed significant correlations
with LPL activity (r=-.576, n=18), with AUC-HDL
cholesterol (r=-.548, n=18) and with
AUC-triglyceride (r=.558, n=18) (data not
shown).
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To further define the relative contribution of LPL, HDL cholesterol, and plasma triglyceride levels in protecting against atherosclerosis, multiple regression analysis was performed. The result showed that plasma HDL cholesterol was the most powerful protector against cholesterol accumulation in the aorta (standard regression coefficient ß=-.673, P=.037; multiple correlation coefficient R=.791). However, plasma triglyceride was the greatest contributor of protection against the atheromatous area (ß=.611, P=.008, R=.875). Therefore it is assumed that both an increase in plasma HDL cholesterol and a decrease in plasma triglyceride due to the ingestion of NO-1886 protect against atherosclerosis.
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Discussion |
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LPL and CETP are determinants of HDL cholesterol concentration in plasma. Although LPL is generally viewed as an antiatherogenic enzyme, it is still controversial whether LPL is proatherogenic or antiatherogenic. Supporting the antiatherogenic view, there are recent reports on several polymorphisms of LPL associated with reduced HDL cholesterol,15 24 and experimental results have been reported with transgenic mice overexpressing human LPL9 10 11 12 and with LPL knockout mice.13 However, several atherogenic actions of LPL were postulated by extrapolations from in vitro experimental data.25 CETP transfers CE in HDL2, to apo B-containing lipoproteins.26 Although physiologic functions of CETP are not clear, there is increasing evidence that inherited deficiency of CETP results in a marked elevation of plasma HDL cholesterol concomitant with a decrease in LDL cholesterol concentration.27 28 29 Activity of CETP in lipoprotein-deficient serum varies in species18 ; rats lack the activity, humans and monkeys have moderately high activity, and rabbits have rather high activity. Tsutsumi et al reported that NO-1886 does not influence CETP activity in hamsters and rabbits.30 We undertook the present study to examine the effect of NO-1886 in rabbits with high CETP activity, and we have demonstrated that this drug elevated plasma HDL cholesterol concentration by enhancing LPL activity and preventing the development of atherosclerosis. Therefore, these data strongly support the view of the antiatherogenic effect of LPL.
LPL activity was more highly correlated with HDL cholesterol than plasma triglyceride. Multiple regression analysis showed that the most powerful protector against aortic cholesterol accumulation was HDL cholesterol followed by LPL activity and plasma triglyceride, and the greatest prevention against the atheromatous area was plasma triglyceride followed by HDL cholesterol and LPL activity. These results therefore suggest that the antiatherogenic effect of NO-1886 is based on remodeling the lipoprotein profile (an increase in HDL cholesterol and a decrease in plasma triglyceride level) though an enhancement of LPL activity without affecting plasma cholesterol level. However, it is unclear from this experiment whether changes in HDL cholesterol and plasma triglyceride level exert synergistic or additional effects against atherogenesis. Hypertriglyceridemia with low HDL cholesterol is a common concomitant condition in diabetes. Recently, there has been increasing evidence of an association between triglyceride and increased risk of cardiovascular disease.31 Repeated administration of NO-1886 to streptozotocin-induced rats increased postheparin LPL activity with a consequent reduction of plasma triglyceride and an elevation of HDL cholesterol.17
Tsutsumi et al demonstrated that NO-1886 increases expression of LPL
m-RNA in the epididymal adipose tissue and LPL enzyme mass in
postheparin plasma in rats.16 The mechanism by
which NO-1886 increases expression of LPL m-RNA is not clear at the
present time. Fibrates and long chain fatty acids induce LPL mRNA
expression in hepatocyte cell lines and
preadipocytes.32 Recently, this induction was shown to be
mediated by transcription factors designated as PPARs. A
ligand-activated PPAR interacts with a peroxisome proliferator
response element localized between -169 and 157 in the human LPL
promoter.32 Lehmann et al33 have also
demonstrated that antidiabetic thiazolidinedione derivatives are potent
and selective activators of PPAR
. It might be plausible
that the LPL-enhancing action of NO-1886 is related to the activation
of PPAR.
Body weights were significantly reduced by ingestion of 1.0% NO-1886 (approximately a 350-mg/kg daily intake), but our previous experiments with an ordinary diet regimen in rats, dogs, rabbits, and monkeys showed that daily intake of 10 mg to 1000 mg/kg of NO-1886 for 6 months did not cause any toxic effects in various organs including the liver (unpublished data). Hara et al demonstrated that NO-1886 supplementation in a high-fructose diet (a hypertriglyceridemic model) reduced plasma triglyceride level with an increase in respiratory quotient, indicating enhanced fat oxidation.34 There were no differences in food intake, and no apparent skeletal muscle reduction was observed due to the drug ingestion at the end of the experiment. Thus the weight loss in the 1.0% NO-1886 group that was fed the atherogenic diet might result at least partly from a reduction in body fat stores.
Plasma concentration of NO-1886 increased dose dependently and remained constant during the experimental period. Although the level of HDL cholesterol was significantly higher in rabbits fed with the 1.0% NO-1886 diet than rabbits fed the 0.5% NO-1886 diet, there were no significant differences in LPL activity, plasma triglyceride level, atheromatous area, and aortic cholesterol and triglyceride content between high and low NO-1886 groups. Some of them showed a tendency toward dose-dependent differences. These results indicate that this compound exerted almost the maximum effect at the concentration of 0.5% NO-1886 in the diet.
In summary, NO-1886 exerted potent antiatherogenic effects through enhancing postheparin LPL activity and remodeling the lipoprotein profile (an increase in HDL cholesterol and a decrease in plasma triglyceride) without influencing plasma cholesterol level.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by a grant from the Shizuoka Academic Foundation (1994). We thank Dr Toshio Murase of Toranomon Hospital, Department of Endocrinology and Metabolism, for his valuable discussion and critical review of the manuscript.
Received October 8, 1996; accepted March 4, 1997.
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