Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:598-604
(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:598-604.)
© 1999 American Heart Association, Inc.
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
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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
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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.
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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
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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 1
)
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.
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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.
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Results
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All dietary groups gained weight (Figure 2A
) and had adequate
food consumption
(Figure 2B
) 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 3
). 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 4
). 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.
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Table 1 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 2 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 2. Lipid Composition of Isolated VLDL and LDL After 2
Weeks and 6 Weeks of Experimental Liquid Diet
Treatment
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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 5, Tables 3 and 4).
Radioiodinated VLDL and LDL obtained from an animal with a
similar feeding history were injected, and parameters of
the model of Figure 1
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
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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 4). 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).
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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
3
). The lipoproteins that
accumulated were principally VLDL,
LDL, and intermediate-density
particles as judged by FPLC analysis
(Figure 4
). As
expected, cholesterol feeding resulted in
cholesterol
enrichment of VLDL and LDL at the expense of
triglyceride (Table
2
). 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 4 and Figure 5). 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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Acknowledgments
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This work was supported by NIH grants AA09988 (G.S.) and
HL50420
(R.E.O.).
Received February 25, 1998;
accepted August 17, 1998.
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Top
Abstract
Introduction