© 1997 American Heart Association, Inc.
Articles |
Alcohol Increases Plasma Levels of Cholesterol Diet–Induced Atherogenic Lipoproteins and Aortic Atherosclerosis in Rabbits
From Washington University School of Medicine, Department of Internal Medicine, Division of Atherosclerosis, Nutrition, and Lipid Research (A.S., R.A.K.S., M.A.L., G.S.), and Purina Mills Inc, St Louis, Mo; and Parke-Davis Pharmaceutical Research, Ann Arbor, Mich (M.P., T.R., D.H.).
Correspondence to Gustav Schonfeld, Washington University School of Medicine, Department of Internal Medicine, Division of Atherosclerosis, Nutrition, and Lipid Research, Campus Box 8046, 660 S Euclid Ave, St Louis, MO 63110-1093.
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Abstract |
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Abstract The purpose of the present study was to reexamine the relationship between alcohol and atherosclerosis. Two experiments were performed: The first contained three groups of New Zealand White (NZW) female rabbits. The control group was fed a cholesterol-containing liquid diet and the other two groups were fed the same diet with either 20% or 30% of the calories supplied by alcohol. The second experiment had two treatments: one control group and another group fed a 10% alcohol diet. In experiment 1, alcohol at the 20% and 30% levels increased VLDL and LDL but not HDL compared with levels in control rabbits. Hepatic mRNA levels of apolipoprotein (apo) A-I, apoB, and 7
-hydroxylase were not affected by alcohol. However, the LDL-receptor mRNA was decreased to half of control values by either 20% or 30% alcohol. Lesion areas and aortic cholesterols were significantly increased in the 20% and 30% alcohol–treated groups. Also, significant correlations were found between plasma cholesterol levels and total lesion area or lesion cholesterol contents. In experiment 2, the 10% alcohol–treated rabbits showed no differences in circulating lipoproteins, LDL-receptor mRNA, or lesion formation above that observed in controls. These experiments suggest that alcohol substituted at 20% or 30% of the dietary calories induces hypercholesterolemia and more aortic atherosclerotic lesions. The alcohol-induced accumulation of VLDL and LDL was accompanied by low hepatic LDL-receptor mRNA levels, suggesting that alcohol may affect LDL-receptor expression and rates of lipoprotein clearance, but more experiments are needed to evaluate this possibility.
Key Words: atherosclerosis • rabbit • alcohol • cholesterol • aorta
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Introduction |
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Drinking moderate amounts of alcohol is considered beneficial for the prevention of coronary heart disease in humans. The evidence supporting this position consists of autopsy and observational population studies1 2 3 4 5 6 7 and a few experimental studies in animals, primarily in cholesterol-fed rabbit models. In some studies, diminution in the sizes of atherosclerotic lesions in aortas was noted.8 9 10 In other studies, no alcohol-protective effect was seen.11 In one study, red wine produced protective effects, but alcohol itself or other alcoholic beverages did not.9 Because rabbits do not find liquid diets palatable, solid diets are fed, with alcohol provided in the drinking water. However, the relative intakes of alcohol and diet were variable and difficult to control, and animals lost varying amounts of body weight. Thus, it is difficult to know the relative importance on the experimental outcomes of the intakes of alcohol, calories, or other nutrients. Well-controlled feeding studies have been successfully performed in rats and other rodents with liquid diets in which desired amounts of alcohol were substituted for other nutrients, eg, carbohydrates.12 Therefore, one aim of this project was the development of a palatable liquid diet for rabbits to which cholesterol and/or alcohol could be added to produce hypercholesterolemia and atherosclerotic lesions. The second aim was to test the effects of alcohol added to an atherogenic liquid diet on the development of atherosclerotic lesions.
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Methods |
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In a preliminary trial, two groups of rabbits (n=5 each) were exposed to either a liquid diet containing no added cholesterol or a commercially available diet; this trial assessed whether the liquid diets alone would increase plasma cholesterol and TG over that observed in rabbits fed a commercial diet. It was determined that plasma cholesterol and TG were unaffected by diet (data not shown).
All diets were provided as a powder (Purina Test Diet) (Table 1
) and mixed weekly. The diets were based on liquid diets for rodents.13 14 Isolated soy protein was used as the protein source rather than casein, since casein causes rabbits to become hypercholesterolemic even in the absence of dietary cholesterol.15 Separate diets were prepared for the nonalcohol and alcohol groups (Table 1). The diets were isocaloric and isonitrogenous (Table 1). Results of the fatty acid analyses are summarized in Table 2. Diets were prepared weekly and kept at 4°C in sealed bottles. Feeders were filled and cleaned, and diet intakes were recorded daily and body weights weekly. The diets were fed to rabbits in a liquid feeder, which was constructed of acrylic plastic (Plexiglas).
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In experiment 1, lasting 12 weeks, 30 NZW female rabbits were divided into three equal groups. The first group was given a cholesterol-containing atherogenic diet; the second and third groups consumed the atherogenic diet in which 20% and 30% of the calories were supplied as alcohol, with a like amount of carbohydrate calories removed. To examine the effects of alcohol at equal cholesterol levels, we performed another experiment (experiment 2, lasting 10 weeks) in which alcohol was reduced to 10%. The 10% alcohol group and a parallel nonalcohol atherogenic control group each contained 10 rabbits. For both experiments, diets and water were available ad libitum. Venous plasma samples were obtained every 2 weeks between 8:00 AM and 9:00 AM for lipid analysis. Terminal venous plasmas were obtained for cholesterol, PL, and TG levels and were measured by enzymatic methods (Catalog No. 276-64909, 996-54001, and 997-69801, respectively, Wako Pure Chemical Inc). These kits allow the quantitation of PL containing choline only. The lipoprotein profiles shown in Fig 1 were performed by HPLC.16 FPLC was also used to separate the lipoproteins according to size.17 After separation by FPLC, respective elution fractions (ie, those for VLDL, LDL, and HDL) were pooled for analysis of cholesterol, PL, and TG. Aortas were removed, pinned flat, and photographed. Atherosclerotic lesion areas were assessed by planimetry of photographed vessels, and cholesterol contents of vessels were measured after homogenizing the tissues, followed by gas chromatography.18 Messenger RNA levels for liver (RNA ZOL B, Tel-Test Inc) apoA-I, apoE, LDL receptor, and cholesterol 7-hydroxylase were quantified by solution hybridization assays, as described.19
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Vitamin E Concentration in Plasma
The method of Shaish et al20 was used to determine -tocopherol levels in plasma. All extractions and preparations for HPLC analysis were carried out under dim light and on ice to prevent degradation of antioxidants. Antioxidants were quantified by reverse-phase HPLC analysis. -Tocopherol was detected by monitoring its absorbency at 195 nm and by comparison with the retention time of authentic standards.
Statistical Analysis
The two experiments were analyzed separately. Lesion areas (ie, arch, thoracic, and abdominal aorta), LDL-receptor mRNA, 7-hydroxylase, apoA-I mRNA, and apoE mRNA were analyzed by ANOVA for a randomized complete block design.21 Body weight, feed consumption, and plasma cholesterol were analyzed using ANOVA for a split-plot design, with rabbit diet as the whole-plot factor and time (weeks) sampled as the subplot factor. This procedure allowed testing for the effects of diet and week and their interaction. When significant differences were found, means were partitioned by Fisher's protected least significant difference.21 All correlations were done with Pearson's product-moment correlation. All data were analyzed using the General Linear Models Procedure of SAS (1995). Statements of significance were based on P<.05 unless otherwise noted.
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Results |
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In experiment 1, mean (±SEM) calories consumed (321±10 g, 309±10 g, and 297±10 g) and mean body weight gains (2567±85 g, 2482±89 g, and 2460±85 g) were statistically similar in control and 20% and 30% alcohol–treated groups, respectively. However, significant (P<.0001) increases in circulating cholesterol were detected with increasing levels of alcohol. At 4 weeks, the 30%-treated group displayed the highest level of cholesterol, followed by the 20% group, and then the control group (Fig 2
, EXP 1). The differences observed at week 4 remained constant over the course of the 12-week experiment. In experiment 2, the differences in total plasma cholesterol between the control group and 10%-treated group became evident at 8 and 10 weeks (Fig 2, EXP 2), resulting in a significantly (P<.002) higher overall mean level of circulating cholesterol (513 and 590 mg/dL, respectively).
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The changes observed in circulating cholesterol in experiment 1 were due to rises in all lipoproteins, ie, the nonalcohol cholesterol-containing diet caused VLDL, LDL, and HDL cholesterol concentrations to increase (Fig 1
). Substituting alcohol for carbohydrate produced significant (P<.0001) rises in VLDL and LDL cholesterol but not HDL cholesterol (Fig 1). On chemical analysis of FPLC fractions, the VLDL, LDL, and HDL particles contained a higher percentage of cholesterol than of TG or PL. However, the relative proportions of cholesterol, TG, and PL were not different between treatments (Fig 3). Therefore, the increases in VLDL and LDL cholesterol concentration were probably due to more particles being produced or a slower clearance of VLDL and LDL particles. Since specific apolipoproteins (ie, apoB) and clearance rates of particles were not evaluated, it is difficult to draw specific conclusions.
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We next investigated whether the rises in lipid levels were related to altered levels of mRNA apoA-I and apoE, cholesterol 7-hydroxylase, and LDL receptor in four rabbits per group. These rabbits were selected to reflect the mean cholesterols of the various groups in experiment 1. Also, we measured the LDL-receptor mRNA in experiment 2. In experiment 1, there were no alcohol-related differences evident in mRNA levels for apoA-I, apoE, or 7-hydroxylase. However, the LDL-receptor mRNA was suppressed equally in both alcohol-treated groups compared with controls (Table 3). In experiment 2, the LDL-receptor mRNA levels were similar in the 10% alcohol and concurrent nonalcohol groups (Table 3).
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Aortic lesion areas were affected by the addition of alcohol in experiment 1. The percent of lesion coverage increased in a stepwise fashion as the level of alcohol increased (ie, 0% alcohol<20% alcohol<30% alcohol, Fig 4); also, the TC content of the aortic arch increased (controls, 1.52; 20% alcohol, 4.32; 30% alcohol, 6.82, all in milligrams per gram tissue, P<.05). Since there appeared to be a relationship between plasma cholesterol and lesion formation, it was decided to pool all the animals together for correlation analysis in experiment 1. There was a significant correlation (r=.55, P<.05) between the two constituents. Additionally, we found a strong correlation between arch lesion area and arch cholesterol contents (r=.87, P<.05) and between arch cholesterol and total lesion area (r=.8, P<.05). In experiment 2, however, there were no alcohol-induced differences in lesion areas or cholesterol contents observed between the control and 10% alcohol groups (Fig 4).
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Next we investigated the possibility that alcohol depleted the antioxidant contents of the lipoproteins, thus rendering them more susceptible to oxidation and more atherogenetic. The mean vitamin E levels and vitamin E/HDL cholesterol ratios in the 30% alcohol rabbits were fourfold higher than in controls in experiment 1 (Table 4). Additionally, the 30% alcohol–treated group had about two times higher levels of vitamin E/TC and vitamin E/VLDL or vitamin E/LDL cholesterol ratios than controls. For all rabbits in experiment 1, significant correlations between TC and VLDL cholesterol versus vitamin E were .95 and .89, respectively (P<.003 for both) and between total lesion areas versus vitamin E, r=.78 (P<.03).
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Discussion |
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The first objective, development of a liquid diet that would be suitable for rabbits, was achieved. Since rabbits find alfalfa palatable, this fiber was added at 10% of dry mass. The resultant liquid diet with cholesterol added to it was acceptable and provided sufficient digestible fiber to prevent diarrhea and to sustain weight gains. The substitution for carbohydrates of alcohol at 10%, 20%, or 30% of calories yielded diets equal in palatability and ability to support increases in body weight to diets containing identical amounts of cholesterol but no alcohol. It is not clear why experiments 1 and 2 displayed different rates of rise in plasma cholesterol.
In response to added dietary cholesterol, humans on average exhibit increased plasma concentrations of both LDL and HDL, including the HDL1 or HDLc apoE-rich particles22 23 and apoA-I.24 Rabbits respond by raising VLDL, LDL, and HDL levels, but the rise in TC is more extreme.25 The alcohol-induced rise in HDL in humans may be due to enhanced HDL and apoA-I production26 27 28 29 and/or decreased cholesterol ester transfer protein levels.30 31 32 33 The response of cholesterol ester transfer protein to alcohol is regulated by genetic factors.32 33 Alterations in hepatic lipase can also affect HDL levels.34 In our NZW rabbits, alcohol did not significantly raise either HDL cholesterol or hepatic mRNA levels of apoA-I beyond what was achieved by added dietary cholesterol, but VLDL and LDL levels rose further on the 20% and 30% alcohol diets (Fig 1). In humans, alcohol-induced rises in VLDL are more variable than in our rabbits and are seen primarily in subjects with familial tendencies to high TG and chronic low-grade alcohol abuse.35 The high VLDL, when present, may be due to overproduction.36 The mechanism for the additional alcohol-induced rises of VLDL and LDL in our rabbits is not known. In rabbits, dietary cholesterol in the absence of alcohol increases TC levels and is due to the accumulation of grossly cholesterol-enriched, TG-poor VLDL and LDL particles.25 These changes in particles may be a consequence of downregulation of LDL receptors and corresponding mRNA levels,37 thereby decreasing the clearance of LDL from plasma.38 One investigator has reported a decreased LDL fractional catabolic rate and a downregulation of LDL receptors in such rabbits.39 It is possible that alcohol produced further accumulations of VLDL and LDL in the 20% or 30% alcohol–treated rabbits by increasing hepatic or intestinal secretion of lipoproteins. Alcohol stimulates endogenous hepatic and intestinal cholesterol synthesis and increases rates of intestinal absorption of cholesterol40 and could have further downregulated LDL receptors. The reduced hepatic LDL-receptor mRNA levels (Table 3) are compatible with the increase in LDL particles but certainly do not prove that formulation. The 10% alcohol diet neither suppressed LDL-receptor mRNA levels nor raised VLDL and LDL cholesterol levels, suggesting that there may be an alcohol threshold effect.
Lesion coverage of aortic regions was significantly increased in the 20% and 30% alcohol groups (Fig 4), and significant correlations were found between plasma cholesterol versus aortic cholesterol and total lesion area in experiment 1. These data are compatible with previous reports and suggest that elevated plasma cholesterol levels strongly contribute to lesion formation. Otto et al41 reported a significant correlation between plasma TC levels and aortic lesion area, as did others, using a variety of atherogenic diets containing cholesterol,42 coconut oil, butter,43 and beef fat.44 The correlations suggest that plasma cholesterol mediates both of these lesion parameters. Net fluxes of VLDL, IDL, and LDL into the aortas of rabbits are determined by the sizes of the particles and positively correlated with plasma concentrations of these lipoproteins.45 In experiment 2, the 10% alcohol and control groups had similar lesion burdens. This was surprising, since the 10% alcohol–treated group began to display an overall higher mean plasma cholesterol than controls (590 versus 513 mg/dL). Comparing the 10% and 20% groups, the plasma cholesterol levels were similar (590 and 592 mg/dL, respectively), yet the former had fewer lesions. This finding may be due to the shorter time exposure of the 10% group (10 versus 12 weeks).
Oxidation of lipoproteins is thought to play an important role in atherogenesis.46 Depletion of antioxidant contents of lipoproteins is thought to increase their vulnerability to oxidation and hence render them more atherogenic. The protective effect of red wine in the study by Klurfeld and Kritchevsky9 could have been mediated in part by antioxidant polyphenols,47 48 49 50 51 but this possibility was not evaluated. We wished to test whether antioxidant depletion played a role in the enhanced atherosclerosis seen in our rabbits. However, vitamin E levels were in fact higher in the alcohol group, whether expressed on a plasma volume basis or relative to plasma lipoprotein cholesterol, than in controls. If vitamin E is an accurate index of fat-soluble antioxidant contents, alcohol did not produce its proatherogenic effects by depleting lipoproteins of their lipid-soluble antioxidant defenses. Why didn't higher vitamin E contents of lipoproteins of alcohol-fed rabbits protect them against the atherosclerotic lesions? We do not know, but the results are compatible with the findings of Shaish et al,20 who demonstrated a dissociation between the vitamin E–related protection of lipoproteins from oxidative stress and the development of atherosclerotic lesions in rabbits.
The effect of alcohol on cholesterol-induced atherosclerosis in rabbits is controversial. Eberhard10 showed experimentally that rabbits fed supplemented cholesterol and alcohol (eg, as 24% solution in drinking water) exhibit about a twofold increase in plasma cholesterol compared with nonalcohol controls. In experiment 1, the net change in plasma cholesterol was similar to that observed by Eberhard10 ; that is, the average circulating level of plasma cholesterol for the 20% and 30% groups (ie, 592 and 873 mg/dL, respectively) was 
1.8 times higher in comparison with controls (399 mg/dL). In contrast to our results, the deposition of cholesterol into aortas was less in Eberhard's alcohol-treated groups. Eberhard10 suggests that alcohol may affect cholesterol metabolizing and cholesterol synthesizing mechanisms and thereby prevent elevated blood cholesterol from being deposited into certain tissues. However, this may not be the case in our rabbits, in which the cholesterol contents of aortas in the 20% and 30% groups were higher. The differences observed between the present study and that conducted by Eberhard10 may stem from the procedures used to evaluate lesion formation. In the present experiment, we traced the observed lesion and calculated it as a percentage of the total area. On the other hand, Eberhard10 assigned a score to the lesion; the variation in approach would certainly give two different answers (ie, comparing discrete and nondiscrete data). Goto et al,8 using a solid diet containing 0.5% cholesterol and 5% lard and 5% or 10% alcohol in the drinking water, found no differences in body weight and food intake; however, they showed marked increases above control values compared with the 5% or 10% alcohol–treated rabbits for TG (627 versus 1423 and 1385 mg/dL) and cholesterol (1870 versus 2866 and 2724 mg/dL). We used vegetable oils instead of lard in our rabbits, which may add to the differences reported by Goto et al.8 In experiment 2, we did not observe any differences between control and 10% alcohol–treated rabbits for TG (35 versus 45 mg/dL), but overall plasma cholesterol (513 versus 590 mg/dL) values were different. Klurfeld and Kritchevsky9 demonstrated that rabbits consuming 9.5% alcohol as red wine displayed less aortic atherosclerosis than rabbits offered alcohol-water, white wine, and whiskey, which showed only "moderate reductions" in lesion formation that in fact were not statistically different; beer had no effect. The red and white wine groups also showed significant reductions in body weight gain than control rabbits. These authors did observe an increase in HDL in response to all alcoholic treatments, while other lipoproteins stayed unchanged. The differences observed between our study and that conducted by Klurfeld and Kritchevsky9 may stem from a number of factors, including strain, gender, age, rate of gain of body weight, plasma cholesterol concentration, lipoprotein profiling methodology, or combinations of the above. Even though the dosage of alcohol in experiment 1 was similar to that in previous work,10 the route of delivery and statistical design make comparisons difficult.
In addition, alcohol affects other factors involved in atherogenesis, such as platelets,52 arterial wall components,53 and vasomotion,54 none of which were addressed in any of these studies. It is possible that alcohol may affect both proatherogenic and antiatherogenic processes that in turn are affected differently according to gender, strain, age, and other factors. Nevertheless, it is clear that under conditions in which weight gains are maintained with a cholesterol-containing diet, adding alcohol tilts the balance in favor of atherogenesis in NZW female rabbits.
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Appendix |
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The following levels of vitamins were present per kilogram of liquid diet: thiamin mononitrate, 1632 mg; riboflavin, 1.5 mg; pyridoxine HCl, 1.75 mg; niacin, 7.5 mg; calcium pantothenate, 4.0 mg; folic acid, 0.5 mg; biotin, 50 mcg; cyanocobalamin, 25 mcg; inositol, 25.0 mg; p-aminobenzoic acid, 12.5 mg; vitamin A acetate, 3000 IU; cholecalciferol, 400 IU; DL-
-tocopherol acetate, 30 IU; menadione sodium bisulfite, 0.5 mg; choline bitartrate, 0.53 g; and ascorbic acid, 10 mg. The following levels of minerals were present per kilogram of liquid diet: (NH4)6Mo7O24-4H2O, 0.2 mg; Ca(C2H3O2)2, 5.13 g; KH2PO4, 3.05 g; MgSO4, 1.28 g; NaCl, 0.82 g; MnSO4-H2O, 42 mg; FeC4H2O4, 54 mg; CuSO4-5H2O, 6 mg; ZnCl2, 16 mg; CaI2O6, 0.08 mg; CrCl3-6H2O, 3.0 mg; NaF, 0.56 mg; and Na2SeO3, 0.06 mg.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This research was supported by National Institutes of Health grant AA09988-01. We are grateful to Robert Thomas Kitchens for technical help, to Purina Mills for providing the diets, and to Mary Lou Rheinheimer for preparation of the manuscript. We thank Dr Theodore Cicero for helpful discussions and for measuring plasma alcohol levels.
Received February 29, 1996; accepted August 18, 1996.
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References |
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