Prevention of hypercholesterolemia and atherosclerosis in Japanese quail by high intake of soy protein

This study was undertaken to determine the influence of levels of soy protein on cholesterol metabolism and the development of atherosclerosis in Japanese quail (Coturnix coturnix japonica). Quail were fed purified diets containing one of four levels (10, 20, 40 or 60%) of soy protein either with (atherogenic) or without (control) 0.5% cholesterol. Results showed that higher proportions of protein (40 and 60%) in atherogenic diets had a preventive effect on the development of atherosclerosis in adult male quail. For the atherogenic diets the higher protein levels resulted in significantly lower serum and aorta cholesterol concentrations than observed with the 10 or 20% protein levels and free of aortic atherosclerosis. A dual isotope technique was used to measure the absorption rates for cholesterol in quail fed with 20 and 40% soy protein. Absorption rates were not affected by the level of dietary protein but were influenced by the presence of dietary cholesterol. Relative rates were 40% in quail fed control diets and 30% in quail fed atherogenic diets. The excretion of neutral sterols, largely cholesterol, and bile acids increased with the high intake of soy protein. These results demonstrate that in quail the presence of higher dietary levels of soy protein has both a hypocholesterolemic action and a preventive effect on cholesterol-induced atherosclerosis and one of the possible mechanisms is through increased excretion of cholesterol.     

Effects of soy protein and casein in low cholesterol diets on plasma lipoproteins in normolipidemic subjects

Dietary plant proteins may lower plasma cholesterol and LDL concentrations in hypercholesterolemic patients when substituted for animal proteins, particularly in diets with low cholesterol and saturated fat content. Plant protein diets appear, however, to be without effect on plasma lipoprotein levels in normal subjects. In the present study, we have examined whether the origin of the dietary protein, i.e. plant (soy) or animal (casein), affects the plasma lipoproteins in normolipidemic subjects when these proteins are presented as components of diets low in cholesterol and saturated fat. The study followed a crossover design. Five men and 5 women consumed liquid formula diets containing 20% of calories as casein or soy protein, 28% as fat (mainly monounsaturated), and 52% as carbohydrate; the intake of cholesterol was less than 100 mg per day. The two dietary periods, each of 1 month duration, were separated by an interim period of 1 month on self-chosen food. Following an initial 30% reduction of cholesterol and LDL plasma levels on both diets, the concentrations of each of the major lipoprotein classes (VLDL, IDL, LDL, HDL2 and HDL3) were similar during the two experimental dietary periods. Body weights were essentially constant. Dietary soy protein and casein could not be distinguished in their effects on the plasma concentrations and chemical composition of the major lipoprotein classes in normolipidemic subjects.     

Influence of fish protein as compared to casein and soy protein on serum and liver lipids, and serum lipoprotein cholesterol levels in the rabbit

Serum and hepatic cholesterol and triglyceride levels, and serum lipoprotein cholesterol were investigated in rabbits fed fish protein as compared to casein and soy protein as part of a 20% protein, low fat, cholesterol-free, semi-purified diet. A nonpurified diet was used as a control. After a 28-day experimental period, rabbits fed casein developed hypercholesterolemia compared to those fed the soy protein diet. Serum cholesterol levels of rabbits fed fish protein was intermediate and not different from that of the casein or the soy protein group. However, serum triglycerides were higher in the fish group than in the casein group. Feeding of fish protein resulted in a reduction of hepatic cholesterol compared to casein, indicating no direct relationship between serum and hepatic cholesterol. In addition, fish protein induced a decrease of cholesterol in the low density lipoproteins (LDL) compared to casein and an increase of cholesterol in the high density lipoproteins (HDL) compared to casein and soy protein. Reduction in LDL-cholesterol (LDL-C) and elevation in HDL-cholesterol (HDL-C) caused a 10-fold decrease in the LDL-C/HDL-C ratio of fish protein fed rabbits compared to those fed casein. This ratio was similar to that observed with soy protein which was also lower than the ratio of the casein group. Thus, since the LDL-C/HDL-C ratio has been shown to be a good indicator of the atherosclerosis risk, these results suggest that fish protein, as well as soy protein, may reduce the risk of atherosclerosis in rabbits, compared to casein.     

Transgenic overexpression of human lecithin: cholesterol acyltransferase (LCAT) in mice does not increase aortic cholesterol deposition

Results from several atherosclerosis studies using morphometric procedures have proven controversial with regard to whether over-expression of human LCAT in transgenic (Tg) mice is atherogenic. The purpose of the present study was to determine the effect of 10-fold over-expression of human LCAT on aortic free and esterified cholesterol (EC) deposition as well as plasma lipoprotein cholesteryl ester (CE) fatty acid composition in mice fed an atherogenic diet containing cholic acid. C57Bl/6 (control) and human LCAT-Tg mice were fed chow or an atherogenic diet (15% of calories from palm oil, 1.0% cholesterol and 0.5% cholic acid) for 24 weeks before measurement of aortic cholesterol content. Compared with the chow diet, control and LCAT-Tg mice fed the atherogenic diet had a 2-fold increase in plasma total, free and EC, a 7-fold increase in plasma apoB lipoprotein cholesterol, and a 40-50-fold increase in hepatic cholesterol content. The aortic EC content was increased in control (0.7 vs. 1.2 mg/g protein) and LCAT-Tg (0.3 vs. 1.5 mg/g protein) mice fed the atherogenic diet compared with those consuming the chow diet; however, there was no difference in aortic free (14.4+/-6.8 vs. 18.5+/-7.7 mg/g protein) or esterified (1.2+/-1.0 vs. 1.5+/-1.2 mg/g protein) cholesterol content between atherogenic diet-fed control and LCAT-Tg mice, respectively. LCAT-Tg mice fed the atherogenic diet had a 2-fold increase in the ratio of saturated+monounsaturated to polyunsaturated CE species in plasma apoB lipoproteins compared with control mice (9.4+/-2.4 vs. 4.9+/-0.7). We conclude that over-expression of human LCAT in Tg mice fed an atherogenic diet containing cholic acid does not result in increased aortic cholesterol deposition compared with control mice, even though the CE fatty acid saturation index of plasma apoB lipoproteins was doubled.     

Inhibition of postmenopausal atherosclerosis progression: a comparison of the effects of conjugated equine estrogens and soy phytoestrogens

Experimental evidence was sought concerning whether soy phytoestrogens (SPEs) inhibit postmenopausal atherosclerosis progression/extent and, if so, their effectiveness relative to traditional estrogen replacement therapy. Premenopausal cynomolgus monkeys were fed a moderately atherogenic diet (26 months) to induce atherosclerosis. After ovariectomy, the moderately atherogenic diet was continued, and they were treated (36 months) with a control diet (soy protein depleted of SPEs), a diet containing SPEs in soy protein isolate, or a diet containing SPE-depleted soy protein with conjugated equine estrogens (CEE; Premarin) added. SPE effects on plasma lipids were better than those of CEE (higher high density lipoprotein cholesterol and no increase in triglyceride). Relative to the control group, CEE treatment inhibited (P = 0.0001), and SPE treatment partially inhibited (P = 0.10) the progression of atherosclerosis (common iliac artery atherosclerosis before and after treatment). CEE-treated monkeys had much less coronary artery atherosclerosis than the controls (P = 0.0002), whereas SPE-treated monkeys were intermediate in lesion extent between the controls and the CEE-treated animals (P = 0.02). Both CEE and SPE significantly reduced the extent of common carotid and internal carotid artery atherosclerosis, and the two treatment groups were not significantly different.     

Experimental atherosclerosis in rabbits fed cholesterol-free diets : Part 12. Comparison of peanut and olive soils

The atherogenicity of peanut oil is well established as is the fact that the structure of the component triglycerides of peanut oil influences its atherogenicity. This study was carried out to determine if the relative saturation of peanut oil was partly responsible for the observed effects. Rabbits were fed a semipurified, cholesterol-free diet containing 14% of North American peanut oil (iodine value, 100), South American peanut oil (iodine value, 110) or olive oil (iodine value, 83) for 8 months. Rabbits fed olive oil exhibited higher levels of serum and liver lipids than did the two peanut oil-fed groups but significantly lower levels of aortic atherosclerosis.

The findings confirm earlier observations that the structure of a fat can have an affect on its atherosclerogenic potential that is independent of its level of unsaturation.     

Comparison of effects of fish oil and corn oil supplements on hyperlipidemic diet induced atherogenesis in swine.

The addition of a fish oil supplement rich in n - 3 unsaturated fatty acids to a high cholesterol, high saturated fat (BT) diet for swine has been shown previously to result in modest lowering of plasma cholesterol levels and in marked retardation of atherogenesis. It has been suggested that the effect was due to the change in polyunsaturated (PUFA) to saturated fatty acid ratios (P/S) and that a supplement of PUFA of the n - 6 series might have the same effect as the fish oil. We have tested this hypothesis in swine fed an atherogenic diet by comparing the effect of a fish oil supplement producing a P/S ratio of 0.28 to that of corn oil in the same amount producing a ratio of 0.46. The P/S ratio of the atherogenic diet without supplements was 0.16. Thirteen young male Yorkshire swine were fed either BT alone (n = 4), BT + cod liver oil (n = 4) or BT + corn oil (n = 5) for 6 months and then killed for quantitative studies of atherosclerosis in the aortas and coronary arteries including lesion areas, number of lesion cells, and number of monocytes attached to endothelium. Plasma cholesterol levels were determined periodically and lipoproteins were separated terminally by density gradient ultracentrifugation, Pevikon block electrophoresis and immunoelectrophoresis. The fish oil supplement resulted in a 30% reduction in time-weighted average plasma cholesterol levels, and a marked shift in terminal lipoprotein patterns from predominantly apo B and E containing ones to predominantly apo B only ones. Atherogenesis was reduced by the fish oil supplement as judged by several morphometric criteria including size of lesions, number of lesion cells, and number of monocytes attached to lesion endothelium. The corn oil supplement produced no significant reductions in any of these variables from those in swine fed the atherogenic BT diet without the supplement. We conclude that the n - 3 fatty acid rich fish oil supplemented diet retarded atherogenesis, but that this effect was not shared by the corn oil supplemented diet which had an even higher P/S ratio.     

Adenoviral low density lipoprotein receptor attenuates progression of atherosclerosis and decreases tissue cholesterol levels in a murine model of familial hypercholesterolemia

Familial hypercholesterolemia is an autosomal codominant disease characterized by high concentrations of pro-atherogenic lipoproteins and premature atherosclerosis secondary to low density lipoprotein receptor (LDLr) deficiency. In the current study, the effects of gene transfer with 5 x 10(10) particles of E1E3E4-deleted adenoviral vectors expressing the LDLr (AdLDLr) or VLDLr (AdVLDLr) under control of the hepatocyte-specific human alpha(1)-antitrypsin promoter and 4 copies of the human apo E enhancer in C57BL/6 LDLr(-/-) mice were investigated. Evaluation was performed in both sexes and in mice fed either standard chow or an atherogenic diet containing 0.2% cholesterol and 10% coconut oil. Compared to control mice, AdLDLr and AdVLDLr persistently decreased plasma non-HDL cholesterol in both sexes and on both diets. Six months after LDLr gene transfer in mice fed the atherogenic diet, average intimal area was 2.5-fold (p<0.01) and 3.2-fold (p<0.001) lower in male and female mice, respectively, compared to controls. In mice fed standard chow, intimal area was reduced 22-fold (p<0.001) and 21-fold (p<0.001) after LDLr gene transfer in male and female mice, respectively. We show that non-HDL lipoproteins are more atherogenic in female mice, independent of sex differences of plasma HDL cholesterol levels, and that saturated fat does not have an effect on atherosclerosis independent of plasma cholesterol levels. Finally, quantification of tissue cholesterol levels indicates that AdLDLr does not induce cholesterol accumulation in the liver and reduces cholesterol content in the myocardium, quadriceps muscle and kidney. In conclusion, hepatocyte-specific LDLr gene transfer significantly improves cholesterol homeostasis in LDLr(-/-) mice.     

Dietary protein, fat, and minerals in nephrocalcinosis in female rats.

Young female rats fed semipurified diets containing casein or a soy protein isolate had extensive nephrocalcinosis at the junction between the outer and inner stripe of the outer medullary zone after 5 wk on the diets, whereas rats fed a diet containing a lactalbumin concentrate did not. Although the percentages of actual protein and of total ash were similar in all three diets, the concentrations of individual minerals were not, owing to methods used in isolating the proteins. Comparison of the individual mineral contents of these diets with those in other laboratories as compiled from the literature suggested that factors other than minerals, including protein, are also implicated. Dietary fat appeared to be another such factor in a series of experiments in which saturated medium-chain triglycerides and corn oil were included in diets containing soy protein isolate. Although these diets had identical mineral compositions, the rats fed medium-chain triglycerides had less severe lesions.     

Plasma HDL cholesterol concentrations are correlated to bile cholesterol saturation index in the African green monkey

In an attempt to determine if plasma lipoprotein concentrations correlate with the bile cholesterol saturation index in the African green monkey, we have studied a group of adult male animals available from a long-term study investigating the effects of dietary fat and cholesterol on cholesterol metabolism and atherosclerosis. The animals were fed diets containing 0.8 mg cholesterol/kcal or 0.03 mg cholesterol/kcal for five years. Within each dietary cholesterol group, animals received 42% of dietary calories as fat, enriched with either saturated or polyunsaturated fat. Using stepwise multiple linear regression, high density lipoprotein (HDL) cholesterol concentration was found to be the best plasma lipid predictor of the bile cholesterol saturation index. When the cholesterol saturation index of a fasting gallbladder bile specimen was compared to the plasma HDL cholesterol level for individual animals, a significant positive correlation was noted for animals fed polyunsaturated fat, (r = 0.68) and for animals fed saturated fat (r = 0.72). For any value of HDL cholesterol, however, the cholesterol saturation index was higher in animals fed polyunsaturated fat compared to saturated fat. Since plasma HDL cholesterol levels were positively correlated with the bile cholesterol saturation index in adult male African green monkeys, we conclude that a metabolic link exists between plasma HDL cholesterol concentrations and bile cholesterol saturation, perhaps due to enhanced delivery of cholesterol to the liver by HDL.     

Effects of dietary animal and soy protein on cardiovascular disease risk factors

A growing body of research offers insight into the influence of dietary protein on cardiovascular disease (CVD) risk. Early studies in rabbits indicated that animal protein was atherogenic; however, this has not been demonstrated in other animals species (pig, primate) or humans. More recent studies have found that low-fat animal protein can effectively improve some CVD risk factors. Soy protein has received much attention in recent years due to its seemingly marked effect on plasma cholesterol levels. However, further research has shown the hypocholesterolemic effect of soy protein to be most pronounced in cases of moderate to severe elevations in plasma lipids. Still, animal and soy protein sources contain a variety of bioactive components that may offer protection above and beyond cholesterol reduction. This review provides evidence that as part of a low-saturated fat diet, animal and/or soy protein intake at or above the recommended intake level of 15% of total calories lowers plasma cholesterol levels, reduces blood pressure, and potentially facilitates healthy weight management.     

Plasma lipid and lipoprotein cholesterol levels in swine. Modification of protein-induced response by added cholesterol and soy fiber

Piglets, aged 8 weeks and weighing 12-18 kg, were fed semi-purified casein or soy protein diets, with or without cholesterol and soy hull fiber, for 2 months. In addition to observing the effects of the dietary treatments on growth, the modification of the primary hypocholesterolemic action of soy protein by cholesterol and soy fiber was studied. Pigs fed the soy protein or casein diets grew normally with no difference in weight gain. Plasma triglyceride and phospholipid levels, as well as several plasma metabolic indices examined, were not significantly affected by dietary treatment. However, plasma total cholesterol was higher (but not significantly) in pigs fed casein than in those fed soy protein alone. Cholesterol feeding induced markedly significant (P less than 0.05) hypercholesterolemia with either protein source, compared to feeding the proteins without added cholesterol. Dietary soy fiber fed simultaneously with cholesterol decreased the cholesterol-induced hypercholesterolemia, but the reduction was significantly greater (P less than 0.05) with soy protein than with casein in the diet. Analyses of the lipoprotein cholesterol indicated that LDL cholesterol was much more sensitive to the changes induced by feeding cholesterol and soy fiber than either HDL or VLDL cholesterol. These findings suggest a beneficial role of dietary soy fiber in hypercholesterolemia.     

-Carnitine treatment in the hyperlipidemic rabbit

A study was designed to examine the hypolipidemic effect of -carnitine treatment (4 weeks, 170 mg/kg/d) in rabbits fed a high fat diet (5% corn oil/0.5% cholesterol, w/w). Eight weeks of exposure to the high fat diet significantly increased plasma total cholesterol and triglycerides. VLDL associated triglycerides, cholesterol, apo-B, and total protein were also significantly increased with the diet. There was no change in HDL-cholesterol levels. Plasma concentration of carnitine (free, acyl, and total) all increased significantly with the high fat diet. The content of free, short-chain, and total carnitine were decreased in the liver whereas the content of long-chain acylcarnitines was increased. The diet generated a significant steatosis within the livers of these animals. Four weeks of treatment of -carnitine reduced the extent of the liver steatosis and significantly decreased plasma total cholesterol, triglycerides, VLDL associated triglycerides, cholesterol, and total protein. HDL-cholesterol levels were unaffected by the treatment. All plasma fractions of carnitine (free, acetyl, acyl, and total) were significantly increased above those levels seen after 8 weeks of the high fat diet alone. The content of liver carnitine and its esters was normalized following treatment. The high fat diet decreased liver HMG-CoA reductase activity and increased the activities of 7-α-hydroxylase and acylcholesterol acyltransferase (ACAT). -Carnitine treatment blunted the magnitude of the diet induced increase in 7α-hydroxylase activity, yet overall the activity still remained elevated relative to controls. ACAT activity increased (1.5 times) with the high fat diet and increased further (4.5 times) following carnitine treatment. The mechanism(s) underlying the hypolipidemic effect of -carnitine treatment in this animal model remain to be elucidated.     

Effect of aging on fatty streak formation in a diet-induced mouse model of atherosclerosis

Age is considered to be a major risk factor for atherosclerosis, but it is unclear whether age has a direct effect on susceptibility to atherosclerosis. Wild-type mice develop fatty streak lesions in the aortic root only when fed a cholate-containing high fat/cholesterol diet. To investigate the influence of age on fatty streak formation, young (10 weeks) and old (53 weeks) female C57BL/6 mice were fed an atherogenic diet containing 15% fat, 1.25% cholesterol and 0.5% sodium cholate for 12 weeks. Atherosclerotic lesions at the aortic root were measured after cryosections were stained with oil red O. Results showed that old mice developed a comparable size of aortic lesions with young counterparts (5,600 +/- 2,480 vs. 6,457 +/- 1,537 microm2/section; p = 0.77), although old mice had significantly higher plasma cholesterol levels than young mice on the atherogenic diet (p < 0.05). Plasma levels of soluble vascular cell adhesion molecule 1 were significantly higher in old mice than in young mice on both chow and Western diets (p < 0.005). These data indicate that age has no direct effect on atherosclerosis susceptibility although it is accompanied by elevations in plasma cholesterol and vascular cell adhesion molecule 1 levels in C57BL/6 mice. Thus, increased cardiovascular events with age are probably related to a progressive increase in plaque size rather than to an increase in atherosclerosis susceptibility.     

Sunflower, virgin-olive and fish oils differentially affect the progression of aortic lesions in rabbits with experimental atherosclerosis

In this study we report the effects of sunflower, virgin olive and fish oils on the progression of aortic lesions. A total of 24 male New Zealand rabbits (six per each group) were fed for 50 days on a diet containing 3% lard and 1.3% cholesterol, to induce atherosclerosis. An atherogenic control group (A) was killed after this period and three groups were fed for an additional period of 30 days with a diet composed of (1.75 g of supplemented oil and 98.25 of standard chow): sunflower oil (S), virgin olive oil (O) and fish oil (F). A control group (n=6) was fed with a standard chow diet for 80 days. LDL lipid composition and histological analysis of aortic atherosclerotic lesions were assayed. The atherogenic diet caused a significant increase of cholesterol levels in LDL and aorta tissue. Cholesterol ester content rose significantly in the aortic arch of groups S, O and F. Fatty streaks were found in all aortic sections, although only group S showed a significant progression of the lesion compared with group A. We conclude that the replacement of a high cholesterol-saturated fat diet by another cholesterol free-unsaturated fat diet does not regress atherosclerosis in rabbit. However, sunflower oil provokes a significant progression in lesion development, whereas diet enrichment with extra virgin olive oil and, to a lesser extent, fish oil, stops this progression.     

动脉粥样硬化相关基因在高血脂食蟹猴中的差异表达

目的研究高血脂与动脉粥样硬化基因的相关性,从中筛选动脉粥样硬化早期诊断基因。方法采用温和的动脉粥样硬化膳食(0.22 mg胆固醇/卡路里,40%的能量来源于脂肪)单笼喂养中老年雄性食蟹猴,膳食诱导12个月后,从膳食诱导实验猴中筛选出10只高血脂猴。然后采用荧光定量PCR方法检测对照组和高血脂组食蟹猴外周血白细胞内113个动脉粥样硬化相关基因的表达差异。结果在食蟹猴外周血白细胞内共检测到66个动脉粥样硬化相关基因,其中18个基因随血脂升高表达显著上调(P<0.05),21个基因表达显著下调(P<0.05),另外还有27个基因无表达差异(P>0.05)。结论以上结果为后续大样本相关研究缩小了基因遴选范围,通过进一步研究可能从中筛选出基因表达水平上的动脉粥样硬化早期诊断指标。     

Accelerated atherosclerosis in apolipoprotein E-deficient mice fed Western diets containing palm oil compared with extra virgin olive oils: a role for small, dense high-density lipoproteins

To test the hypothesis that extra virgin olive oils from different cultivars added to Western diets might behave differently than palm oil in the development of atherosclerosis, apoE-deficient mice were fed diets containing different cultivars of olive oil for 10 weeks. Female mice were assigned randomly to one of the following five groups: (1-4) fed chow diets supplemented with 0.15% (w/w) cholesterol and 20% (w/w) extra virgin olive oil from the Arbequina, Picual, Cornicabra, or Empeltre cultivars, and (5) fed a chow diet supplemented with 0.15% cholesterol and 20% palm oil. Compared to diets containing palm oil, a Western diet supplemented with one of several varieties of extra virgin olive oil decreased atherosclerosis lesions, reduced plaque size, and decreased macrophage recruitment. Unexpectedly, total plasma paraoxonase activity, apoA-I, plasma triglycerides, and cholesterol played minor roles in the regulation of differential aortic lesion development. Extra virgin olive oil induced a cholesterol-poor, apoA-IV-enriched lipoparticle that has enhanced arylesterase and antioxidant activities, which is closely associated with reductions in atherosclerotic lesions. Given the anti-atherogenic properties of extra virgin olive oil evident in animal models fed a Western diet, clinical trials are needed to establish whether these oils are a safe and effective means of treating atherosclerosis.     

Anti-atherosclerotic activity of colestipol hydrochloride in SEA quail

Young, male, SEA (Susceptible to Experimental Atherosclerosis) Japanese quail (Coturnix coturnix japonica) were fed an atherogenic diet consisting of yellow corn meal and soybean meal supplemented with 2% cholesterol and 1% cholic acid. A control group of ten animals was fed the atherogenic diet for eight weeks, and another group was fed the same diet containing 2% colestipol hydrochloride for the same length of time. At the end of the treatment period serum and arterial total cholesterols were measured and extent of macroscopic atherosclerotic lesions assessed. Colestipol hydrochloride treatment significantly reduced both serum and arterial total cholesterol levels by 50 and 59%, respectively. Grossly visible atherosclerosis was significantly reduced by 64%. These data further demonstrate that male SEA quail are an appropriate and relevant small animal model for examining the cardiovascular effects of bile acid sequestrants.     

Effects of feeding fish oil on the properties of lipoproteins isolated from rhesus monkeys consuming an atherogenic diet

This study examined plasma lipids and lipoproteins of rhesus monkeys fed fish oil incorporated into a highly atherogenic diet containing saturated fat and cholesterol. The animals were fed diets containing 2% cholesterol and either 25% coconut oil (group I), 25% fish oil/coconut oil (1:1; group II), or 25% fish oil/coconut oil (3:1; group III) for 12 months (n = 8/group). Adding menhaden fish oil to the diet increased plasma eicosapentaenoic acid and docosahexaenoic acid and decreased plasma linoleic acid in animals fed the fish oil containing diets. Plasma concentrations of all lipoprotein fractions were decreased in the fish oil groups. VLDL isolated from group I animals exhibited beta-mobility on agarose gels but the VLDL from groups II and III animals did not. The group I VLDL was more highly enriched in cholesteryl ester than was VLDL from groups II and III. Group I LDL had a small but significant increase in cholesteryl ester content compared to group III LDL. No differences in HDL composition were observed in the 3 groups. At least 6 times less apo E was recovered in VLDL, IDL, and LDL from group III animals than from group I animals. Assuming 1 molecule of apo B per lipoprotein particle, there were 50% fewer VLDL, IDL, and LDL particles in group III than in group I animals. Group III also had significantly lower molar ratios of apo E/apo B in VLDL, IDL, and LDL than did group I animals. When VLDL from all 3 groups were incubated with J774 macrophages at equal protein concentrations, only the VLDL from the group I animals stimulated cholesterol esterification. Thus, introducing fish oil into an atherogenic diet reduced the number of VLDL, IDL and LDL particles in plasma by as much as 50%, reduced the cholesteryl ester content of the circulating lipoprotein, and reduced the ability of the VLDL to stimulate cholesterol esterification in macrophages.     

Cholesterol reduction and atherosclerosis inhibition by bezafibrate in low-density lipoprotein receptor knockout mice

Fibrates, peroxisome proliferator-activated receptor a agonists, are widely used as lipid-lowering agents with anti-atherogenic activity. However, conflicting results have been reported with regard to their pharmacological effects on plasma lipoprotein profiles as well as on atherosclerosis in animal models. Furthermore, the anti-atherogenic effects of bezafibrate, one of the most commonly used fibrates, in animal models have not been reported. In the present study, we investigated the effects of bezafibrate on lipoprotein profiles as well as on atherosclerosis in low-density lipoprotein receptor knockout (LDLR-/-) mice fed an atherogenic diet for 8 weeks. Bezafibrate decreased plasma levels of both cholesterol and triglycerides (TG), while increasing plasma levels of high-density lipoprotein-cholesterol (HDL-C). Since hepatic TG production was significantly reduced in the bezafibrate-treated mice lacking LDLR, the plasma lipid-lowering effects of bezafibrate might be primarily mediated by the suppression of hepatic production of apolipoprotein-B-containing lipoproteins. In parallel with the reduced ratio of non-HDL-C to HDL-C, bezafibrate suppressed fatty streak lesions in the aortic sinus by 51%. To determine whether or not bezafibrate directly alters the expression of genes relevant to atherosclerosis, we measured mRNA expression levels of three genes in the aorta by real-time PCR: ATP-binding cassette transporter A1, lipoprotein lipase, and monocyte chemoattractant protein-1. The results showed that there were no differences in the expression of these genes between mice treated with bezafibrate and those not. In conclusion, bezafibrate inhibits atherosclerosis in LDLR-/- mice primarily by decreasing the ratio of non-HDL-C to HDL-C.