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Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:598-604

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:598-604.)
© 1999 American Heart Association, Inc.


Original Contributions

Effects of Alcohol and Cholesterol Feeding on Lipoprotein Metabolism and Cholesterol Absorption in Rabbits

Mickey A. Latour; Bruce W. Patterson; Robert Thomas Kitchens; Richard E. Ostlund, Jr; Daniel Hopkins; Gustav Schonfeld

From the Department of Animal Sciences (M.A.L.), Purdue University, West Lafayette, Ind; Divisions of Atherosclerosis, Nutrition and Lipid Research (B.W.P., R.T.K., G.S.), and Endocrinology, Diabetes and Metabolism (R.E.O.), Department of Medicine, Washington University; and Purina Mills, Inc (D.H.), St. Louis, Mo.

Correspondence to Dr Gustav Schonfeld, Department of Internal Medicine, Washington University School of Medicine, Box 8046, 660 S Euclid Ave, St. Louis, MO 63110. E-mail Gschonfeld{at}imgate.wustl.edu


*    Abstract
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Abstract—Alcohol fed to rabbits in a liquid formula at 30% of calories increased plasma cholesterol by 36% in the absence of dietary cholesterol and by 40% in the presence of a 0.5% cholesterol diet. The increase was caused almost entirely by VLDL, IDL, and LDL. Cholesterol feeding decreased the fractional catabolic rate for VLDL and LDL apoprotein by 80% and 57%, respectively, and increased the production rate of VLDL and LDL apoprotein by 75% and 15%, respectively. Alcohol feeding had no effect on VLDL apoprotein production but increased LDL production rate by 55%. The efficiency of intestinal cholesterol absorption was increased by alcohol. In the presence of dietary cholesterol, percent cholesterol absorption rose from 34.4±2.6% to 44.9±2.5% and in the absence of dietary cholesterol, from 84.3±1.4% to 88.9±1.0%. Increased cholesterol absorption and increased LDL production rate may be important mechanisms for exacerbation by alcohol of hypercholesterolemia in the cholesterol-fed rabbit model.


Key Words: cholesterol • alcohol • diet • cholesterol absorption • lipoproteins • apoproteins • atherosclerosis


*    Introduction
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The effects of alcohol on cholesterol and lipoprotein metabolism have substantial public health implications. It is generally believed that moderate alcohol consumption reduces coronary heart disease risk because observational studies show that it is associated with elevated HDL cholesterol levels and decreased cardiovascular events.1 2 3 However, alcohol has many biological actions, and adverse effects on lipid metabolism and cardiovascular disease risk are also well-known, especially in individuals with familial predisposition to hyperlipidemia.4 5 Thus, the results of alcohol consumption are likely to reflect a balance that might be positive or negative in a given individual. Clearly, a more complete understanding of the interaction between alcohol and lipid metabolism is needed.

To investigate the effects of alcohol under controlled dietary conditions, we previously reported the application of cholesterol- and alcohol-containing liquid formula diets that are palatable and allow good weight gain and gastrointestinal function in rabbits.6 7 This work showed that instead of protecting against atherosclerosis, ethanol feeding at 20% to 30% of calories in the presence of dietary cholesterol (0.5% by weight) increased both plasma lipoproteins and aortic atherosclerotic lesions. In the presence of dietary cholesterol, plasma VLDL and LDL doubled when alcohol was substituted for carbohydrates at 30% of calories, and aortic arch cholesterol content increased fourfold. The current work was performed to investigate potential mechanism(s) responsible for these adverse alcohol-induced changes. The kinetics of VLDL and LDL were determined by tracer methods after varying periods of dietary treatment, and cholesterol absorption was measured at the end of the experiment. The results suggest that alcohol induced increased cholesterol absorption. As a result fractional catabolic rates for VLDL and LDL decreased and production of LDL increased. These changes probably account for the adverse effects of alcohol on lipoprotein metabolism and atherosclerosis in the cholesterol-fed rabbit.


*    Methods
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Animals and Diet
Forty female New Zealand White rabbits were housed individually during a 6-week study. The animals were divided into 4 groups at the beginning of the trial and fed liquid diets as previously described in detail.7 All diets were isonitrogenous and isocaloric with alcohol replacing carbohydrate. The control diet (L) contained 18% fat and 56% carbohydrate and was free of cholesterol. Fats were derived from vegetable sources and were 16% saturated, 58% monounsaturated, and 26% polyunsaturated. In the other diet groups alcohol was included at 30% of calories (LA), cholesterol at 0.5% by weight (LC), or both were included (LAC). The diets were obtained as powders from Purina Test Diet. Diets and water were available ad libitum, except during determinations of kinetics as described below. Body weight was recorded weekly and feed consumption was monitored daily. Fasted venous plasma samples were obtained from a marginal ear vein every week between 8 AM and 9 AM. Lipids and lipoproteins were determined by Lipid Research Clinics methodology.8 Lipoproteins from fresh plasma obtained from 2 animals/group were analyzed by fast protein liquid chromatography (FPLC) using two 25-mL Superose 6 columns (Pharmacia Biotech) connected in series and eluted with 0.15 mol/L NaCl containing 1 mmol/L EDTA, pH 8.0, at 0.5 mL/min.

Cholesterol Absorption Experiments
4-[14C]cholesterol (51 mCi/mmol) and 5,6-[3H]sitostanol (47 Ci/mmol) were purchased from Dupont New England Nuclear. Radiolabeled sitostanol was repurified by thin-layer chromatography in 98:2 chloroform:acetone on silica gel G. Unlabeled anhydrous cholesterol (product C8503, <0.1% water) was purchased from Sigma. Percent cholesterol absorption was measured by continuous feeding of [14C]cholesterol and [3H]sitostanol for 7 days at the end of a 6-week dietary treatment. Tracers were taken up in ethanol, and 1-mL aliquots were added to 4 kg feed in a blender for L and LA diets. For the diets containing cholesterol, tracers dried from 1 mL of the ethanolic solution were dissolved in 12 mL chloroform containing 5.9 g natural cholesterol and allowed to dry overnight in a Petri dish. The solid mixture was then added to 4 kg formula and mixed thoroughly in a blender. The animals received a daily dose of 0.08 µCi [14C]cholesterol and 0.2 µCi [3H]sitostanol. Stools from day 6 and day 7 were collected for separate analyses, and each lot was vigorously mixed in 100 mL water with a Waring blender for 5 minutes. An aliquot of 4 mL stool suspension was saponified in 9.3 mL ethanol and 0.64 mL 45% KOH at 65°C for 45 minutes, and sterols were extracted 3 times with petroleum ether and counted. Percent cholesterol absorption was calculated as

Kinetic Analyses
After a 12-hour fast one rabbit from each treatment group was sacrificed and bled through cardiac puncture at 2 weeks and 6 weeks of diet treatment. VLDL (d<1.006) and LDL (1.019<d<1.063) were isolated by sequential ultracentrifugation9 and dialyzed against 0.15 mol/L NaCl containing 1 mmol/L EDTA, pH 7.4, for 24 hours. Lipoprotein composition was determined by measuring free and total cholesterol and phospholipids using enzymatic assays (WAKO Chemicals USA, Inc) and total protein.10 Lipoproteins were labeled with either 125I or 131I by the method of McFarlane,11 separated from free iodine by Sephadex G25 chromatography, and injected within 24 hours of iodination. At either baseline, 2 weeks, or 6 weeks, 2 rabbits from each treatment group were fasted for 12 hours and then injected with 2.5 µCi 131I-VLDL and 5 µCi 125I-LDL by the marginal ear vein. Blood samples were removed at times 0, 10, 20, and 40 minutes, and at 1, 2, 4, 8, 12, 24, 48, 72, 96, and 120 hours. To minimize the concentration of intestinally synthesized lipoproteins rabbits were fasted at least 12 hours before any bleeding period. VLDL and LDL were isolated by ultracentrifugation, and trichloroacetic acid precipitable radioactivity was determined using narrow gamma counter windows. ApoB12 accounted for 82% of the precipitated VLDL disintegrations per minute (dpm) and 95% of precipitated LDL dpm. The kinetics of VLDL and LDL turnover were analyzed with the SAAM II compartmental modeling program (SAAM Institute, University of Washington). The model used (Figure 1Down) represents the minimal structural complexity that was both necessary and sufficient to account for the turnover of radioiodinated lipoproteins in all 4 groups of rabbits. It is similar to those previously used in New Zealand White rabbits.13 14 VLDL was assumed to consist of both a fast (V1) and a slow (V2) compartment restricted to the plasma, and the total VLDL fractional catabolic rate (FCR) was calculated as the average of fast and slow components weighted by the fraction passing through those pathways. LDL was also modeled as a 2-compartment system including a plasma compartment and a nonplasma compartment. Production rates for VLDL and LDL (mg/dL per hour) were calculated as the product of each compartment mass (mg/dL) and the FCR. The precision for estimation of model parameters, computed as mean fractional standard deviation, was 0.043 (range, 0.015 to 0.110) for VLDL and 0.071 (range, 0.035 to 0.158) for LDL.



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Figure 1. Kinetic model for lipoprotein turnover. For VLDL V1 is a fast catabolic pathway and V2 is a slow catabolic pathway.

Statistics
The data were analyzed with the General Linear Model of the Statistical Analysis System (SAS Institute). A split-plot design was used with diet as the whole-plot factor and week of sampling as the subplot factor. For cholesterol absorption studies cholesterol and alcohol were analyzed as main effects and replications on successive days within individual rabbits as a random effect. Statements of significance were based on P<0.05 unless otherwise noted.


*    Results
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All dietary groups gained weight (Figure 2ADown) and had adequate food consumption (Figure 2BDown) on the liquid formula diets. After 6 weeks alcohol-treated animals weighed 11% less than those not receiving alcohol and consumed an average of 17% less feed during the experimental period. Despite slightly reduced intake, alcohol was associated with an increase in plasma cholesterol levels (Figure 3Down). The effect of alcohol was seen at 4 weeks and thereafter in cholesterol-fed animals, and between week 4 and week 6 plasma cholesterol on the LAC diet was 40% higher than on LC (P=0.03 by repeated measures ANOVA). During the same period plasma cholesterol was increased by 36% or 42 mg/dL (P=0.005) in animals not receiving dietary cholesterol. The lipoprotein response to the diets was determined by fast protein liquid chromatography at both 2 and 6 weeks (Figure 4Down). Most of the increase in plasma cholesterol during cholesterol feeding, both in the presence and absence of alcohol, was because of increases in VLDL, LDL, and intermediate fractions between them.



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Figure 2. Effects of diets on weight gain (A) and average food consumption for the entire study (B). Error bars depict SEM and asterisks denote times when alcohol-treated animals were significantly different in weight than nonalcohol groups. Letters denote groups with significantly different food consumption at a given time.



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Figure 3. Plasma total cholesterol. Results are mean±SEM from 6 animals/group. Letters denote diets with significantly different cholesterol levels at a given time (P<0.05).



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Figure 4. FPLC profile of plasma obtained from a rabbit in each diet group at baseline and at 2 and 6 weeks of diet treatment.

Table 1Down gives changes in total plasma lipid concentration and percentage composition over time with each of the diets. Alcohol, either in the presence or absence of dietary cholesterol, had no effect on total lipid composition. However, as expected, cholesterol feeding resulted in cholesteryl ester enrichment at the expense of triglycerides regardless of whether alcohol was present. Table 2Down shows lipid composition data for isolated VLDL and LDL. By analysis of variance using all of the data there was a strong overall effect of cholesterol feeding to increase the percentage of lipoprotein cholesterol and to decrease lipoprotein triglyceride (both P<0.0001) with no effect on phospholipid. In contrast, the effect of alcohol depended on whether cholesterol was present in the diet. In the presence of cholesterol, alcohol had no effect on lipid composition. However, in the absence of cholesterol, alcohol increased the percentage of cholesterol (P=0.01) and decreased the percentage of triglyceride in VLDL and LDL (P=0.002).


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Table 1. Plasmid Lipid Composition During Cholesterol and Alcohol Feeding


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Table 2. Lipid Composition of Isolated VLDL and LDL After 2 Weeks and 6 Weeks of Experimental Liquid Diet Treatment

The kinetics of VLDL and LDL apoB turnover were investigated in animals consuming a chow diet at baseline and after 2 or 6 weeks of treatment with liquid formulas containing cholesterol or alcohol or both (Figure 5Down, Tables 3Down and 4Down). Radioiodinated VLDL and LDL obtained from an animal with a similar feeding history were injected, and parameters of the model of Figure 1Up were determined. The independent relation of cholesterol and alcohol feeding to lipoprotein FCR or production rate (PR) was determined in a statistical model using kinetic data from 0-, 2-, and 6-week time points. As expected, cholesterol feeding had substantial effects on apolipoprotein kinetics. VLDL FCR declined 80% at 6 weeks (P<0.0001 for an independent effect of cholesterol on VLDL FCR over time) and VLDL PR increased 75% (P=0.03). Cholesterol feeding reduced LDL FCR 57% at 6 weeks (P<0.0001) and increased LDL PR 15% (P=0.03).



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Figure 5. VLDL and LDL apoprotein kinetics. Each point and error bar depicts the mean and range of duplicate rabbits.


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Table 3. Kinetic Parameters of VLDL Turnover at Baseline on Chow Diet and After 2 and 6 Weeks of Liquid Formula Diet


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Table 4. Kinetic Parameters of LDL Turnover at Baseline on Chow Diet and After 2 and 6 Weeks of Liquid Formula Diet

The independent effects of alcohol were determined similarly. Alcohol had no statistically significant effect on either VLDL FCR or VLDL PR. However, alcohol increased LDL FCR slightly by 7.3% at 6 weeks (P=0.001 for an overall effect) and increased LDL PR more substantially by 55% (P=0.01).

Percent cholesterol absorption was measured by including [14C]cholesterol and [3H]sitostanol (a nonabsorbable phytosterol) in each diet during week 6 of the feeding experiment in 4 groups of 5 rabbits each (Table 4Up). Duplicate measurements of the isotope ratio were made in stool collected on days 6 and 7 of isotope administration and compared with the administered material. Evaluating all dietary groups together in a single statistical model, both cholesterol (P<0.0001) and alcohol (P=0.0008) independently altered cholesterol absorption. The interaction between cholesterol and alcohol feeding was not statistically significant (P=0.20), showing that alcohol was effective whether or not cholesterol was also present in the diet. As expected, cholesterol feeding alone reduced the efficiency of cholesterol absorption from 84.3±1.4% to 34.4±2.6% (P<0.0001). Alcohol alone increased cholesterol absorption from 84.3±1.4% to 88.9±1.0% when no dietary cholesterol was given (P=0.029). In the presence of dietary cholesterol, cholesterol absorption was increased from 34.4±2.6% to 44.9±2.5% (P=0.018).


*    Discussion
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*Discussion
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Alcohol had substantial effects in the cholesterol-fed rabbit model. After 4 weeks total plasma cholesterol was increased in animals fed alcohol plus cholesterol and by 6 weeks the difference was 43% above the level in animals fed cholesterol alone (Figure 3Up). The lipoproteins that accumulated were principally VLDL, LDL, and intermediate-density particles as judged by FPLC analysis (Figure 4Up). As expected, cholesterol feeding resulted in cholesterol enrichment of VLDL and LDL at the expense of triglyceride (Table 2Up). Alcohol had no effect on lipoprotein composition in the presence of dietary cholesterol, but it also increased cholesterol and decreased triglyceride in the absence of dietary cholesterol.

Our previous work showed that adding dietary alcohol to the cholesterol-fed rabbit substantially increased aortic intimal lesions.3 One reason for this is that alcohol increased plasma cholesterol levels. The present work documents the mechanisms that might be important. Because absorption of dietary cholesterol is not complete,15 increased intestinal absorption caused by alcohol would exacerbate the experimental hypercholesterolemia and produce the elevated plasma levels observed. Very little previous work has been reported on the relation of alcohol to cholesterol absorption. In rats, Klurfeld and collaborators16 observed a 74% increase in the amount of cholesterol tracer found in plasma 3 days after a single oral tracer dose when the diet contained alcohol. However, cholesterol absorption was not quantitated, and a corresponding decrease in fecal sterols was not observed; thus, the difference in plasma cholesterol tracer level might have been caused by alteration in plasma cholesterol turnover or pool size as well as a change in absorption. In contrast, using human subjects, Crouse and Grundy17 found no difference in percent cholesterol absorption caused by chronic consumption of alcohol at 19% of calories in human subjects on a very low cholesterol diet. Our data establish that, in the rabbit, chronic ethanol at 30% of calories resulted in significant increases in the efficiency of intestinal cholesterol absorption. The effect was observed whether or not dietary cholesterol was present, although it was quantitatively greater in the presence of dietary cholesterol, in which cholesterol absorption efficiency was increased by 30.5% of the initial value. Because cholesterol is soluble in alcohol, the transfer of solid cholesterol to intestinal bile salt micelles might have been increased in the presence of alcohol. However, it is also possible that alcohol might have had a direct effect on enterocyte function or lymphatic flow. Previous workers found that acute, but not chronic, ethanol administration increased the rate of lymph flow and triglyceride absorption in the rat.18 Similar studies with respect to cholesterol absorption have not been performed. Future studies of the effect of alcohol on cholesterol absorption should consider the time course as well as the amount of alcohol given.

The increase in efficiency of intestinal cholesterol absorption may be a fundamental mechanism of action for alcohol in the rabbit model. The lag time of 4 weeks before an alcohol-induced increase in plasma cholesterol could be observed in the cholesterol-fed animal is consistent with an effect on cholesterol absorption, because whole body cholesterol turnover is slow and the pool of body cholesterol is large.19 The most pronounced apoprotein kinetic change observed with alcohol feeding was increased LDL PR (55% increase in the absence of cholesterol and 92% increase in the presence of dietary cholesterol, Table 4Up and Figure 5Up). Previous human studies have found a positive association between increased LDL PR and increased cholesterol absorption.20 21 It is possible, therefore, that increased LDL PR as a result of alcohol in the rabbit might be caused by increased cholesterol absorption. However, our work does not distinguish between this possibility and a direct effect of alcohol on lipoprotein metabolism. Increased cholesterol absorption would be expected to reduce hepatic expression of LDL receptors, but the LDL receptor status of our rabbits is unclear. In previous work we reported a 41% reduction in hepatic LDL receptor mRNA with the cholesterol plus alcohol diet compared with a diet containing cholesterol without alcohol,7 suggesting that alcohol decreases LDL receptor expression. However, here we find a 7% increase in LDL FCR, suggesting a slight increase in LDL receptor expression. Further work will be needed to clarify this question because mRNA changes do not necessarily reflect LDL receptor function and changes in affinity of lipoproteins for the LDL receptor may make kinetic studies of fractional catabolic rate difficult to interpret.22

Additional insights into mechanisms of hyperlipoproteinemia in the rabbit follow from the apolipoprotein kinetic studies. Cholesterol feeding alone decreased VLDL and LDL apolipoprotein FCR and increased PR. Thus, both altered degradation and production of apolipoproteins are important in the pathogenesis of dietary hypercholesterolemia in the rabbit. No overall effects of alcohol were observed on VLDL apoprotein metabolism. Despite this negative result, significant increases in LDL PR were observed both in the presence and absence of alcohol. This is consistent with the ability of alcohol to increase turnover of lipoproteins4 but suggests a more complex mechanism. Increased LDL production in the absence of increased VLDL production could be caused by reduced removal of VLDL and IDL in the lipoprotein cascade or increased direct secretion of IDL and LDL. The former possibility might be associated with concomitant activation of lipoprotein lipase. The lipoprotein kinetic studies are limited in that only overall effects over time are analyzed statistically. Potential effects at 2 weeks and 6 weeks could not be determined with statistical certainty because only 2 animals per time point were used. Likewise, kinetic testing of alcohol-induced lipoproteins in nonalcohol-treated animals were not performed.

In summary, the data indicate that alcohol added to the cholesterol-containing diet accelerates the absorption of cholesterol, leading to alteration of whole body cholesterol and lipoprotein metabolism. LDL apoB PR is prominently increased, resulting in increased hypercholesterolemia and enhanced atherosclerosis.7


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Table 5. Percent Cholesterol Absorption During Alcohol and Cholesterol Feeding


*    Acknowledgments
 
This work was supported by NIH grants AA09988 (G.S.) and HL50420 (R.E.O.).

Received February 25, 1998; accepted August 17, 1998.


*    References
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up arrowAbstract
up arrowIntroduction
up arrowMethods
up arrowResults
up arrowDiscussion
*References
 
1. Steinberg D, Pearson TA, Kuller LH. Alcohol and atherosclerosis. Ann Intern Med. 1991;114:967–976.

2. Gaziano JM, Buring JE, Breslow JL, Goldhaber SZ, Rosner B, VanDenburgh M, Willett W, Hennekens CH. Moderate alcohol intake, increased levels of high-density lipoprotein and its subfractions, and decreased risk of myocardial infarction. N Engl J Med. 1993;329:1829–1834.[Abstract/Free Full Text]

3. Camargo CA Jr, Hennekens CH, Gaziano M, Glynn RJ, Manson JE, Stampfer MJ. Prospective study of moderate alcohol consumption and mortality in US male physicians. Arch Intern Med. 1997;157:79–85.[Abstract/Free Full Text]

4. Sane T, Nikkila EA, Taskinen M-R, Valimaki M, Ylikahri R. Accelerated turnover of very low density lipoprotein triglycerides in chronic alcohol users. Atherosclerosis. 1984;53:185–193.[Medline] [Order article via Infotrieve]

5. Kudzma DJ, Schonfeld G. Alcoholic hyperlipidemia: induction by alcohol but not by carbohydrate. J Lab Clin Med. 1971;77:384–395.[Medline] [Order article via Infotrieve]

6. Latour MA, Hopkins D, Kitchens T, Chen Z, Schonfeld G. Effects of feeding a liquid diet for one year to New Zealand White Rabbits. Lab Anim Sci. 1998;48:81–84.[Medline] [Order article via Infotrieve]

7. Shaish A, Pape M, Rea T, Srivastava RA, Latour MA, Hopkins D, Schonfeld G. Alcohol increases plasma levels of cholesterol diet-induced atherogenic lipoproteins and aortic atherosclerosis in rabbits. Arterioscler Thromb Vasc Biol. 1997;17:1091–1097.[Abstract/Free Full Text]

8. Manual of Laboratory Operations. Washington, DC: Department of Health, Education, and Welfare, Lipid Research Clinics Program; 1974. DHEW publication NIH 75–628.

9. Havel RJ, Eder HA, Bragdon JH. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest. 1955;34:1345–1353.

10. Markwell MK, Haas SM, Bieber LL, Tolbert NE. A modification of the Lowry procedure to simplify protein determination in membrane and lipoprotein samples. Anal Biochem. 1978;87:206–210.[Medline] [Order article via Infotrieve]

11. McFarlane AS. Metabolism of plasma proteins. In: Munro HN, Allison JA, eds. Mammalian Protein Metabolism. New York, NY: Academic Press; 1964;297–341.

12. Klein RL, Zilversmit DB. Direct determination of human and rabbit apolipoprotein B selectively precipitated with butanol-isopropyl ether. J Lipid Res. 1984;25:1380–1386.[Abstract]

13. Yamada N, Shames DM, Stoudemire JB, Havel RJ. Metabolism of lipoproteins containing apolipoprotein B-100 in blood plasma of rabbits: heterogeneity related to the presence of apolipoprotein E. Proc Nat Acad Sci U S A. 1986;83:3479–3483.[Abstract/Free Full Text]

14. Yamada N, Shames DM, Takahashi K, Havel RJ. Metabolism of apolipoprotein B-100 in large very low density lipoproteins of blood plasma: kinetic studies in normal and Watanabe heritable hyperlipidemic rabbits. J Clin Invest. 1988;82:2106–2113.

15. Wilson MD, Rudel LL. Review of cholesterol absorption with emphasis on dietary and biliary cholesterol. J Lipid Res. 1994;35:943–955.[Medline] [Order article via Infotrieve]

16. Klurfeld DM, Tepper SA, Mueller MA, Kritchevsky D. Influences of alcohol from different sources on cholesterol metabolism in rats. In: Avogaro P, Sirtori CR, Tremoli E, ed. Metabolic Effects of Alcohol. Amsterdam: Elsevier/North-Holland Biomedical Press, 1979:187–196.

17. Crouse JR, Grundy SM. Effects of alcohol on plasma lipoproteins and cholesterol and triglyceride metabolism in man. J Lipid Res. 1984;25:486–496.[Abstract]

18. Baraona E, Lieber CS. Intestinal lymph formation and fat absorption: stimulation by acute ethanol administration and inhibition by chronic ethanol feeding. Gastroenterology. 1975;68:495–502.[Medline] [Order article via Infotrieve]

19. Goodman DS, Smith FR, Seplowitz AH, Ramakrishnan R, Dell RB. Prediction of the parameters of whole body cholesterol metabolism in humans. J Lipid Res. 1980;21:699–713.[Abstract]

20. Gylling H, Miettinen TA. Cholesterol absorption and synthesis related to low density lipoprotein metabolism during varying cholesterol intake in men with different apoE phenotypes. J Lipid Res. 1992;33:1361–1371.[Abstract]

21. Kesaniemi YA, Grundy SM. Turnover of low density lipoproteins during inhibition of cholesterol absorption by neomycin. Arteriosclerosis. 1984;4:41–48.[Abstract/Free Full Text]

22. Berglund L, Witztum JL, Galeano NF, Khouw AS, Ginsberg HN, Ramakrishnan R. Three-fold effect of lovastatin treatment on low density lipoprotein metabolism in subjects with hyperlipidemia: increase in receptor activity, decrease in apoB production, and decrease in particle affinity for the receptor: results from a novel triple-tracer approach. J Lipid Res. 1998;39:913–924.[Abstract/Free Full Text]





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