Antiatherogenic Effects of a Novel Lipoprotein Lipase-Enhancing Agent in Cholesterol-Fed New Zealand White Rabbits
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.
- Received October 8, 1996.
- Accepted March 4, 1997.
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.
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.
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.
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.×150 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 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 2×2-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.
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, kg×20 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/mL×20 weeks−1) were 13.4±1.18 (0.5% NO-1886) and 22.4±1.78 (1.0% NO-1886).
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/dL×20 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/dL×20 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).
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.
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.
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.
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⇓).
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).
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 β=−.673, P=.037; multiple correlation coefficient R=.791). However, plasma triglyceride was the greatest contributor of protection against the atheromatous area (β=.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.
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 PPARγ. It might be plausible that the LPL-enhancing action of NO-1886 is related to the activation of PPARγ.
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.
Selected Abbreviations and Acronyms
|AUC||=||area under the curve|
|CETP||=||cholesterylester transfer protein|
|HTGL||=||hepatic triglyceride lipase|
|PPAR||=||peroxisome proliferator-activated receptor|
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.
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