Alcohol Consumption Raises HDL Cholesterol Levels by
Increasing the Transport Rate of Apolipoproteins
A-I and A-II
Elizabeth R. De Oliveira e Silva, MD; David Foster, PhD; Monnie McGee Harper, PhD;
Cynthia E. Seidman, MS, RD; Jonathan D. Smith, PhD; Jan L. Breslow, MD; Eliot A. Brinton, MD
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
Background—Moderate alcohol intake is associated with lower atherosclerosis risk, presumably due to increased HDL
cholesterol (HDL-C) concentrations; however, the metabolic mechanisms of this increase are poorly understood.
Methods and Results—We tested the hypothesis that ethanol increases HDL-C by raising transport rates (TRs) of the major
HDL apolipoproteins apoA-I and -II. We measured the turnover of these apolipoproteins in vivo in paired studies with
and without alcohol consumption in 14 subjects. The fractional catabolic rate (FCR) and TR of radiolabeled apoA-I and
-II were determined in the last 2 weeks of a 4-week Western-type metabolic diet, without (control) or with alcohol in
isocaloric exchange for carbohydrates. Alcohol was given as vodka in fixed amounts ranging from 0.20 to 0.81 g 䡠 kg⫺1 䡠
d⫺1 (mean⫾SD 0.45⫾0.19) to reflect the usual daily intake of each subject. HDL-C concentrations increased 18% with
alcohol compared with the control (Wilcoxon matched-pairs test, P⫽0.002). The apoA-I concentrations increased by
10% (P⫽0.048) and apoA-II concentrations increased by 17% (P⫽0.005) due to higher apoA-I and -II TRs,
respectively, whereas the FCR of both apoA-I and -II did not change. The amount of alcohol consumed correlated with
the degree of increase in HDL-C (Pearson’s r⫽0.66, P⫽0.01) and apoA-I TR (r⫽0.57, P⫽0.03). The increase in
HDL-C also correlated with the increase in apoA-I TR (r⫽0.61, P⫽0.02).
Conclusions—Alcohol intake increases HDL-C in a dose-dependent fashion, associated with and possibly caused by an
increase in the TR of HDL apolipoproteins apoA-I and -II. (Circulation. 2000;102:2347-2352.)
Key Words: alcohol 䡲 lipoproteins 䡲 cholesterol 䡲 apolipoproteins 䡲 metabolism
H
DL cholesterol (HDL-C) concentrations are well established as a major protective factor against coronary heart
disease.1 Moderate alcohol intake has been associated with
protection against coronary heart disease in observational
studies, an effect that appears to be mediated in large part by
alcohol-induced increases in HDL-C concentrations.2– 8 Despite the potential importance of the association between
alcohol consumption and increased HDL-C concentrations,
the mechanism of this effect has not been established. Two
previous turnover studies in human subjects had contradictory conclusions, perhaps because study subjects were few in
number and were in a state of caloric excess while on
alcohol.9,10
The present study tested the hypothesis that the increase in
HDL-C concentrations with moderate alcohol intake results
from increased transport rate (TR) of the major HDL apolipoproteins apoA-I and -II. We measured the in vivo turnover
of apoA-I and -II in paired HDL turnover studies in healthy
men and women without and with alcohol consumption. We
found that the increase in plasma HDL-C with moderate
alcohol consumption is associated with an increase in the TR
of apoA-I and -II, without a significant change in the
fractional catabolic rate (FCR).
Methods
Study Population
Five women and nine men were recruited from the clinic of the
Laboratory of Biochemical Genetics and Metabolism and via posted
advertisements. Eligibility was confined to subjects ⱖ21 years old
who consumed alcohol on a regular basis and had no personal or
family history of alcoholism. Subjects were also excluded for
significant systemic disease by history, physical examination, and
laboratory screening and for use of tobacco or medications known to
alter lipid concentrations, including birth control pills. Although
there were no exclusions based on race or ethnic background, all
subjects were white.
Experimental Protocol
All subjects underwent 2 study periods each of 4 weeks’ duration;
the first 2 weeks served as an equilibration phase, and the turnover
study was carried out during the second 2 weeks. Each subject
consumed both a Western-type diet (control) and the same diet plus
ethanol (EtOH), in varied order. The subjects were studied at the
Received April 20, 2000; revision received June 13, 2000; accepted June 27, 2000.
From The Rockefeller University (E.R. De O. e S., C.E.S., J.D.S., J.L.B.), New York, NY; University of Washington (D.F.) (Seattle); Hunter College
(M.M.H.), City University of New York; and Carl T. Hayden VA Medical Center (E.A.B.), Phoenix, Ariz.
Correspondence to Jan L. Breslow, Laboratory of Biochemical Genetics and Metabolism, Box 179, The Rockefeller University, 1230 York Ave, New
York, NY 10021-6399. E-mail [email protected]
© 2000 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
2347
2348
Circulation
November 7, 2000
inpatient unit of The Rockefeller University Clinical Research
Center and were encouraged to continue their usual physical activity.
The Rockefeller University Institutional Review Board approved the
study, and informed consent was obtained from each subject.
Diets
The control diet was designed with use of the US Department of
Agriculture Nutrient Data Base11 to conform to a high-fat diet often
consumed in Western societies. The diet contained 15% protein, 43%
carbohydrate, and 42% fat at a P/S ratio of 0.1, with 215 mg
cholesterol/1000 Kcal consumed. The EtOH diet was identical to the
control diet except that alcohol (as vodka) was substituted for
carbohydrate in an isocaloric manner. The EtOH dose reflected the
subject’s reported usual intake up to 1 mL 䡠 kg⫺1 䡠 d⫺1. The EtOH was
given in a single or divided dose according to the subject’s usual
intake pattern and was consumed at the end of meals. The diets
consisted of whole foods from common ingredients of known
composition.11
Kinetic Studies
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
Both apoA-I and -II were prepared and radioiodinated as previously
described.12 After the injection of labeled apolipoprotein, blood
samples of 7 to 20 mL each were drawn at 10 minutes; 4, 12, 24, 36,
and 48 hours; and then daily through day 14. Plasma was prepared,
and 1-mL aliquots were used for the determination of the remaining
125
I-apoA-I and 131I-apoA-II radioactivity. The plasma apoA-I and -II
decay curves were normalized to the 10-minute sample and analyzed
with the Matthews model.13 The model, fitted to each decay curve
with SAAM II software,14 was used to estimate the FCR. The TR of
each apolipoprotein was calculated as the product of its plasma
concentration, its FCR, and the plasma volume (assumed to be 4.5%
of the body weight), all divided by the body weight.
Lipid and Lipoprotein Measurements
Plasma samples anticoagulated with EDTA were obtained after a
12-hour overnight fast on days 1, 3, 7, 10, and 14 after isotope
injection for the determination of lipid and lipoprotein concentrations. No temporal trends were observed, so the mean of all 5
determinations was used in the data analysis. Lipid and lipoprotein
measurements were made with fresh specimens, and apolipoprotein
determinations were made with aliquots of plasma stored at ⫺70°C.
Total cholesterol and triglyceride concentrations were determined
with enzymatic methods with reagents from Boehringer-Mannheim.
Lipoprotein cholesterol concentrations were determined after serial
ultracentrifugation.15 Total and HDL-C values were standardized by
the Lipid Standardization Program of the Centers for Disease Control
and Prevention, supported by the National Heart, Lung, and Blood
Institute.16 The apoA-I concentrations were measured with enzymelinked immunosorbent assay.12 The apoA-II concentrations were
determined in the Northwest Lipids Research Clinics laboratories
based on a radial immunodiffusion assay.17
Postheparin Lipase Activity
On day 11 of each metabolic diet and 3 days before isotope injection,
an intravenous bolus injection of heparin was administered at a dose
of 60 U/kg body wt. Blood was drawn exactly 15 minutes later, and
postheparin plasma was obtained and stored at ⫺70° until assay for
hepatic lipase (HL) and lipoprotein lipase (LPL) activity. The
activity of LPL was determined with radioactive triolein in a
glycerol-based assay.12 The activity of HL was measured in triplicate
with a commercially available fluorometric assay (Progen)18 and
adapted to a 96-well microtiter plate format. Lipase activities were
expressed as ␮mol free fatty acids released 䡠 h⫺1 䡠 mL postheparin
plasma⫺1.
Lipoprotein Size Determinations
The average sizes of HDL, LDL, and VLDL were determined with
proton NMR spectroscopy by Dr James Otvos (University of North
Carolina [Raleigh]).19
Statistical Analysis
The present study was a standard 2-treatment, 2-period crossover
trial. We compared mean differences between the 2 diets with a
Wilcoxon signed-rank test. The null hypothesis for this test is that
there is no difference between the 2 diets. The correlations between
the dose of EtOH and the EtOH diet–induced changes in HDL and
related parameters were examined with Pearson’s correlation, as
were the correlations between changes in HDL-C and the changes in
HDL turnover parameters. A similar analysis with Spearman’s rank
order correlations gave similar results. The statistical software
package S-Plus 3.4 for Windows was used for data analysis.
Results
Baseline characteristics, EtOH intake, and plasma lipid
and lipoprotein values during the control and EtOH diets
are shown for each subject in Table 1. The subjects varied
in age from 21 to 70 years (mean⫾SD 53.3⫾15.9 years),
in weight from 51.4 to 97.5 kg (75.7⫾14.6 kg), and in
body mass index from 18.9 to 35.0 kg/m2 (25.6⫾4.2
kg/m2), and they consumed alcohol in an amount ranging
from 0.20 to 0.81 g 䡠 kg⫺1 䡠 d⫺1 (0.45⫾0.19 g 䡠 kg⫺1 䡠 d⫺1).
There was no significant change in weight or physical
activity during and between the 2 turnover studies.
As expected, HDL-C concentrations were 18% higher on
the EtOH diet than on the control diet (P⫽0.002). HDL
particle size did not change (P⫽0.23), suggesting that all size
subspecies increased equally. There were no significant
changes in total cholesterol (P⫽0.30), triglyceride (P⫽0.93),
VLDL-C (P⫽0.14), or LDL-C (P⫽0.25) concentrations with
alcohol consumption.
The results of the paired HDL turnover studies with the
control and EtOH diets are shown in Table 2. The apoA-I
concentrations were 10% higher (P⫽0.048) with the EtOH
compared with the control diet, associated with a 21%
increase in apoA-I TR (P⫽0.041) but no significant change in
apoA-I FCR (P⫽0.12). Similarly, apoA-II concentrations
were 17% higher (P⫽0.005) with the EtOH compared with
the control diet, with a 19% increase in apoA-II TR
(P⫽0.016) but no significant change in apoA-II FCR
(P⫽0.92). Thus, alcohol intake appears to increase HDL-C
concentrations via an increase in the TR of the 2 major HDL
apolipoproteins apoA-I and -II.
Alcohol intake altered the activity of both endothelial
lipases in directions believed to lower atherosclerosis risk.
HL concentrations were 8% lower (P⫽0.01) on the EtOH
diet, whereas LPL concentrations were 23% higher
(P⫽0.001).
The variability in alcohol consumption among subjects
provided the opportunity to test for a dose-response relationship between alcohol intake and HDL changes. The dose of
EtOH correlated positively with the increase in HDL-C
(r⫽0.66, P⫽0.01), and the 2 subjects (subjects 5 and 6) with
the lowest alcohol intake (0.2 g EtOH 䡠 kg⫺1 䡠 d⫺1) had no
increase in HDL-C concentrations (Figure 1). The EtOH dose
also correlated positively with the change in apoA-I (r⫽0.74,
P⫽0.003) and apoA-II (r⫽0.58, P⫽0.03) concentrations.
EtOH dose predicted the increase in apoA-I TR (Figure 1,
r⫽0.57, P⫽0.03) but not in apoA-II TR (r⫽0.44, P⫽0.11).
In conjunction with the lack of net change in FCR with
alcohol consumption, EtOH dose failed to correlate with the
De Oliveira e Silva et al
TABLE 1.
Subject
Alcohol Raises HDL-C via apoA-I and -II Transport Rate
2349
Subject Characteristics and Plasma Lipid and Lipoprotein Levels
Sex
Age,
y
Weight,
kg
BMI,
T-Chol, mg/dL
kg/
EtOh Intake,
m2 g 䡠 kg⫺1 䡠 d⫺1 Control EtOH
TG, mg/dL
Control
EtOH
VLDL, mg/dL
Control
EtOH
LDL, mg/dL
Control
EtOH
HDL, mg/dL
Control
EtOH
Average HDL
Size, nm
Control
EtOH
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
1
F
54
51.4
18.9
0.81
260
281
131
174
33
34
143
149
85†
99
9.8
9.7
2
M
70
61.0
20.5
0.59
263†
291
94
100
23
30
159
159
81†
102
10.4
10.2
3
M
41
74.8
23.9
0.32
223
250
147
249
39
64
119
112
64†
73
9.2
*
4
M
67
80.0
26.7
0.63
390†
387
227†
147
37†
35
292†
275
61
77
9.0
9.1
5
M
67
97.5
30.4
0.20
251
259
220
222
56†
62
156
159
39
38
8.9
8.9
6
F
27
61.3
23.1
0.21
250†
240
143†
170
49†
43
153†
149
48
48
9.1
8.8
7
F
67
71.1
25.7
0.54
250
238
147
108
38†
33
175
159
36‡
45
8.5
9.1
8
M
21
82.8
22.9
0.22
128
161
150†
207
45†
67
56
36
39
8.9
8.4
9
M
46
97.4
30.7
0.30
272†
282
109
80
29
31
179
171
63†
81
9.4
9.6
10
M
48
73.8
24.1
0.66
313†
276
209
292
55†
79
215†
137
43
60
8.8
8.9
11
M
64
86.0
26.6
0.60
358†
297
590†
322
146†
84
170
152
42
60
8.6
9.0
12
F
66
58.7
26.4
0.34
311†
359
382†
388
79†
127
195†
192
37‡
40
*
8.5
13
F
62
92.7
35.0
0.41
267
271
108
92
26
26
186
187
55
58
8.8
9.1
14
M
47‡
47
70.6
23.9
0.52
308†
354
281†
236
51†
68
213†
240
43
46
8.9
9.1
Mean
53.3
75.7
25.6
0.45
275
282
210
199
50
56
172
164
52
62
9.10
9.11
SD
15.9
14.6
4.2
0.19
62
57
135
93
31
28
55
52
16
21
0.52
0.49
Change
䡠䡠䡠
䡠䡠䡠
䡠䡠䡠
䡠䡠䡠
⫺5%
11%
⫺4%
18%
0.7%
P§
0.93
0.14
0.25
0.002
0.23
change in apoA-I FCR (r⫽0.26, P⫽0.38) or apoA-II FCR
(r⫽0.08, P⫽0.78).
The changes in HDL-C correlated with changes in some
of the HDL turnover parameters (Figure 2). The change in
HDL-C concentrations correlated strongly with the change
in apoA-I TR (r⫽0.61, P⫽0.02) but not with the change in
apoA-I FCR (r⫽0.43, P⫽0.12). Despite the fact that the
changes in HDL-C correlated more strongly with changes
in apoA-II concentrations (r⫽0.60, P⫽0.02) than with
changes in apoA-I concentrations (r⫽0.51, P⫽0.06), the
correlation between changes in HDL-C and changes in
apoA-II TR failed to reach statistical significance (r⫽0.43,
P⫽0.12), and there was no correlation with apoA-II FCR
(r⫽0.08, P⫽0.76). Although the changes in either of the
lipases was of a direction that might have contributed to
the increase in HDL-C with EtOH use, HDL-C changes did
not correlate with the changes in HL (r⫽0.01, P⫽0.98) or
LPL (r⫽⫺0.34, P⫽0.25).
human hepatocytes,26 –28 we hypothesized that alcohol raises
HDL-C primarily by raising the TR of apoA-I and -II. In
paired metabolic HDL apolipoprotein turnover studies, we
found that dietary alcohol increases the TR of both apoA-I
and -II, roughly to the same degree as the increase in their
concentrations and in the HDL-C concentration. We also
found that the amount of alcohol consumed predicted the
degree of increase in the TR and that both correlated with the
increase in HDL-C. These results suggest that the increase in
TR is the major mechanism by which alcohol consumption
raises HDL-C.
Our results in part confirm and in part contradict the results
of the only 2 published studies of which we are aware that
explore the effects of alcohol consumption on HDL turnover
in human subjects.9,10 Malmendier and Delcroix9 studied
apoA-I metabolism in 7 healthy nonobese men before and
during a 4-week intake of 60 to 70 g EtOH/d and found a 49%
increase in the TR and a 30% increase in the FCR of apoA-I.
Thus, we confirm their finding that a prominent effect of
alcohol on HDL turnover is an increase in apoA-I TR. The
fact that the degree of increase in apoA-I TR in their study
was more than double that seen in the present study may be
due to their use of twice as much alcohol (60 to 70 g/d versus
33 g/d mean in our study), especially given our evidence for
a dose-response effect in the range of 13 to 51 g/d. Surprisingly, they saw no increase in HDL-C (2% rise, NS), which
is inconsistent with almost all other human studies and
perhaps due to confounding from the small number of
3%
0.30
䡠䡠䡠
䡠䡠䡠
䡠䡠䡠
䡠䡠䡠
BMI indicates body mass index; T-Chol, total cholesterol; TG, triglycerides.
*Missing value.
†⬎90th percentile adjusted for age/sex.
‡⬍10th percentile adjusted for age/sex.
§Wilcoxon matched-pairs test.
Discussion
Several observational studies suggest that moderate alcohol
intake reduces the risk of atherosclerosis, and the major
mechanism appears to be the well known ability of alcohol to
raise HDL-C concentrations.5,20 –24 Despite this, the metabolic
pathway or pathways by which alcohol increases HDL-C
concentrations are not well understood. Because the liver is
reported to be the major site of apoA-I synthesis25 and
because alcohol increases apoA-I production in transformed
2350
Circulation
November 7, 2000
TABLE 2.
HDL Turnover and Related Parameters on Control vs Ethanol Diets
A-I Level,
mg/dL
Subject
A-I FCR,
pools/d
A-I TR,
mg 䡠 kg⫺1 䡠 d⫺1
A-II Level,
mg/dL
A-II FCR,
pools/d
A-II TR,
mg 䡠 kg⫺1 䡠 d⫺1
HL,
␮mol 䡠 mL⫺1 䡠 h⫺1
Control
EtOH
LPL,
␮mol 䡠 mL⫺1 䡠 h⫺1
Control
EtOH
Control
EtOH
Control
EtOH
Control
EtOH
Control
EtOH
Control
EtOH
Control
EtOH
1
203.0
261.4
0.217
0.241
19.82
28.35
49.2
64.3
0.187
0.205
4.14
5.93
*
*
*
*
2
167.1
168.4
0.128
0.243
9.62
18.41
33.8
48.0
0.134
0.242
2.04
5.23
3.4
3.6
13.5
12.2
3
167.7
156.6
0.220
0.286
16.60
20.15
44.6
54.3
0.198
0.183
3.97
4.47
10.1
9.9
9.4
14.8
4
179.4
204.4
0.265
0.256
21.39
23.55
40.4
44.6
0.217
0.188
3.95
3.77
13.8
12.1
15.7
16.9
5
169.8
161.0
0.272
0.264
20.78
19.13
17.2
16.8
0.183
0.193
1.42
1.46
7.4
7.1
8.6
10.3
6
156.6
129.8
0.204
0.212
14.38
12.38
43.6
41.4
0.156
0.173
3.06
3.22
8.9
9.7
6.5
9.6
7
114.1
143.4
0.226
0.250
11.60
16.13
28.0
34.2
0.197
0.199
2.48
3.06
8.1
6.8
8.3
7.9
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8
91.4
98.8
0.217
0.254
8.93
11.29
34.6
40.0
0.180
0.187
2.80
3.37
10.3
10.6
5.2
6.6
9
164.1
180.6
0.157
0.155
11.59
12.60
29.0
35.8
0.143
0.124
1.87
2.00
12.5
13.2
7.5
10.5
10
126.6
160.3
0.372
0.583
21.19
42.05
38.0
54.6
0.242
0.199
4.14
4.89
14.1
11.7
11.7
14.2
11
132.8
171.6
0.320
0.324
19.12
25.02
42.8
44.0
0.217
0.217
4.18
4.30
11.2
10.1
4.4
5.0
12
117.1
138.4
0.297
0.364
15.65
22.67
32.4
38.8
0.235
0.224
3.43
3.91
10.9
8.8
5.8
9.3
13
147.2
171.2
0.446
0.298
29.54
22.96
38.2
34.4
0.239
0.228
4.11
3.53
10.2
8.6
4.5
6.8
14
155.5
149.8
0.257
0.258
17.98
17.39
24.2
30.6
0.193
0.219
2.10
3.02
10.4
8.0
6.0
7.4
Mean
149.5
164.0
0.257
0.285
17.02
20.86
35.4
41.6
0.194
0.199
3.12
3.73
10.1
9.2
8.2
10.1
29.9
37.5
0.083
0.099
5.61
7.91
8.8
11.7
0.034
0.029
1.00
1.21
2.8
2.5
3.5
SD
3.6
Change
10%
10%
21%
17%
2%
19%
⫺8%
23%
P†*
0.048
0.12
0.04
0.005
0.92
0.016
0.01
0.001
*Missing value.
†Wilcoxon matched-pairs test.
subjects and the relative lack of dietary control. It might also
reflect a counterbalancing of the increase in apoA-I TR by a
significant 30% increase in the apoA-I FCR, although they
did report a statistically significant 12% increase in plasma
apoA-I concentrations. In a second, smaller study by Gottrand et al,10 5 normolipemic men received 50 g/d EtOH as
red wine added to a metabolic diet, apparently without any
compensating reduction in other caloric intake. Alcohol
induced a 14% increase in HDL-C accompanied by 20% and
60% increases in apoA-I and -II concentrations, respectively.
They reported no change in the TR of either apoA-I or
apoA-II; although a trend to increased TR was observed (11%
and 18%, respectively). They did not find a significant
change in apoA-I FCR, which is in agreement with our result
but not with those of Malmendier and Delcroix,9 whereas the
21% decrease in apoA-II FCR reported by Gottrand et al10
was found by neither Malmendier and Delcroix9 nor us.
These apparent discrepancies may be explained by the very
small numbers of subjects in the prior studies, their lesser
dietary control, and, in the case of the study by Gottrand et
al,10 the intake of the many nonalcoholic components of wine.
The effect of alcohol intake on HDL turnover has also been
studied in nonhuman primates.29 In squirrel monkeys, high-dose
alcohol intake increased HDL-C and apoA-I concentrations.29
However, this was associated with a decrease in apoA-I FCR
and no change in apoA-I TR. The possible reasons for the
differences between the present results and those reported in
squirrel monkeys cannot be assessed given the lack of information in this model about the effects of alcohol on lipase activities,
HDL size, apoA-II turnover, and hepatocyte metabolism.
Figure 1. Relationships between changes in HDL-C (mg/dL) and apoA-I TR (mg 䡠 kg⫺1 䡠 d⫺1) with EtOH intake (g 䡠 kg⫺1 䡠 d⫺1). Results
are plotted as change in levels (EtOH minus control diet values) versus EtOH intake, with Pearson’s correlation coefficient and
significance.
De Oliveira e Silva et al
Alcohol Raises HDL-C via apoA-I and -II Transport Rate
2351
Figure 2. Relationships between changes in HDL-C (mg/dL) with changes in apo A-I TR (mg 䡠 kg⫺1 䡠 d⫺1) and apoA-I FCR (pools/d).
Results are plotted as change versus change in levels (EtOH minus control diet values), with Pearson’s correlation coefficient and
significance.
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The effect of alcohol consumption on the major HDL
particle size or density subfractions, HDL2 and HDL3, is
inconsistent among studies. Haskell et al21 found an increase
in HDL-C and HDL3 mass, but not HDL2, on resumption of
moderate drinking. In contrast, Contaldo et al30 reported that
the increase in HDL-C after short-term alcohol intake was
primarily an increase in HDL2. Two other studies have
indicated that alcohol consumption is associated with increased concentrations of both HDL2 and HDL3.5,24 In agreement with these latter 2 studies and with a more detailed
assessment of HDL size than in prior published studies, we
found no significant change in HDL particle size distribution.
Although some reports suggest that larger HDL subfractions
may be more strongly related to low atherosclerosis risk,
others have found that large and small HDL particles may be
equally associated with decreased risks of myocardial infarction.5 Interestingly, the only study that simultaneously measured HDL size, alcohol intake, and atherosclerosis event
rates found that increases in both large and small HDL
particles contribute to the reduced risk of events with alcohol
consumption.5
We found that moderate alcohol consumption causes an
increase in LPL and a decrease in HL activity, both of which
would be expected to cause an increase in HDL particle size.
The fact that there was no such increase is surprising and
suggests the interesting possibility of a counterbalancing
increase of smaller particles, which may have resulted from
the increase in HDL apolipoprotein TR. Our previous work
demonstrated that LPL and HL strongly predict apolipoprotein HDL FCR (inversely and positively, respectively).31 On
this basis, we would have predicted that the alcohol-induced
changes in LPL and HL both should have caused a reduction
in HDL apolipoprotein FCR. Thus, the observed lack of
change in FCR appears paradoxical, until one considers the
lack of change in HDL particle size distribution. If HDL
apolipoprotein FCR is primarily a function of HDL particle
size rather than a direct function of LPL or HL activity, the
observed lack of change in FCR would be expected as a result
of the lack of change in HDL size.
The major mechanism of the alcohol-induced increase in
HDL apolipoprotein TR is likely an increase in hepatic
production, because the liver is estimated to be the site of
synthesis of ⬇90% of plasma apoA-I in humans.25 Although
on the basis of our studies we cannot rule out an effect of
alcohol on intestinal apoA-I production, this is unlikely,
because alcohol intake is associated with increased postprandial lipemia32 and decreased HDL2 concentrations.33 Studies
of HepG2 cells, a transformed human hepatocyte cell line,
have shown that alcohol increases the synthesis and secretion
of apoA-I, causing an increase in cholesterol efflux ability.26
Furthermore, the increase with chronic exposure to alcohol
appears to be specific for apoA-I compared with some other
apolipoproteins,27 although apoA-II data were not reported.
Interestingly, this in vitro effect is dose dependent (0.05% to
0.5%),28 reminiscent of our finding of dose-dependency of
the TR effects. The molecular mechanism of the increased
apolipoprotein synthesis is not known and cannot be readily
addressed in humans in vivo. In hepatocyte culture, this effect
appears to involve the microsomal EtOH-oxidizing system27
and is speculated to be due to intracellular increases in
phospholipid and cholesterol.28
In conclusion, we demonstrated that moderate alcohol
consumption results in dose-dependent increases in plasma
concentrations of the major HDL components (HDL-C,
apoA-I and -II) through an increase in the HDL apolipoprotein TR, without a change in FCR or HDL particle size
distribution.
Acknowledgments
This work was supported by General Clinical Research Center grant
M01-RR-00102 from the National Center for Research Resources, a
Clinical Investigator Award (HL-02034) from the National Institutes
of Health, and a Merit Review Award from the Department of
Veterans’ Affairs (to Dr Brinton). We thank the nutrition research
and nursing services of the General Clinical Research Center of the
Rockefeller University Hospital. We thank Katie Tsang for technical
assistance and all study participants for their cooperation.
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Alcohol Consumption Raises HDL Cholesterol Levels by Increasing the Transport Rate of
Apolipoproteins A-I and A-II
Elizabeth R. De Oliveira e Silva, David Foster, Monnie McGee Harper, Cynthia E. Seidman,
Jonathan D. Smith, Jan L. Breslow and Eliot A. Brinton
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Circulation. 2000;102:2347-2352
doi: 10.1161/01.CIR.102.19.2347
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