I review
Effects of ethanol on lipid metabolism
Enrique Baraona and Charles S. Lieber
Alcohol Research Center, Bronx Veterans Administration Hospital
and Mount Sinai School of Medicine, New York 10468
I NTRODUCTI O N
Accumulation of fat in the liver is the most common
disturbance of lipid metabolism produced by alcohol.
Since steatosis constitutes the most striking histologic
feature of the early stages of alcoholic liver injury,
this initial phase is generally defined as alcoholic fatty
liver. It must be pointed out, however, that less con-
spicuous but not less important alterations affecting
protein metabolism and subcellular organelles occur
concomitantly. These associated changes may play a
key role in perpetuating disturbances in hepatic lipid
metabolism beyond the immediate effects of the oxi-
dation of ethanol on intermediary metabolism.
Alcoholic fatty liver is often associated with hyper-
lipemia. Both the accumulation of lipids in the liver
and in the blood are multifactorial phenomena.
Though a great deal of evidence has been gathered to
establish an etiologic role of ethanol in the pathogenesis
of these syndromes, other factors associated with
alcohol abuse also play important roles.
Accumulation of fat in the liver is also prominent
in alcoholic hepatitis (defined by necrosis and inflam-
mation) and in alcoholic cirrhosis (characterized by
fibrosis and distortion of the normal architecture of
the liver). Recently developed animal models indicate
that these varieties of alcoholic liver disease probably
represent steps of a process that should be considered
as a continuous spectrum. With progressive liver
damage, the predominant mechanism leading to
steatosis and hyperlipemia changes: some lipid altera-
tions appear to represent the initial interactions be-
tween ethanol and lipid metabolism; others appear to
represent compensatory efforts to alleviate conse-
quences of the altered lipid metabolism; and, finally,
others reflect the liver failure during progression of
alcoholic liver injury. A challenging but still unre-
solved question is to what extent the serum lipid
changes may serve as sensitive indicators of this pro-
gression. T h e alterations in hepatic and serum lipids
may also bear important consequences on other tis-
sues: possible relationships between the alcohol-
induced lipid changes and the pathogenesis of some
hemolytic anemias, pancreatitis, and, particularly,
atherosclerosis have been emphasized.
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PATHOGENESIS OF ALCOHOLIC
FATTY LIVER
Etiologic role of ethanol
Ethanol administration is associated with a variety of
secondary effects, which by themselves can alter lipid
metabolism. These include local toxic effects at the site
of administration, particularly in the gastrointestinal
tract (1,2) and the peritoneum (3), and systemic stress-
ful effects secondary to alcohol intoxication. Chronic
ethanol administration, on the other hand, is compli-
cated by interference with nutrition. Therefore, con-
siderable efforts have been spent to differentiate the
effects due to ethanol itself from those of associated
complications. This is of more than academic interest
since the treatment of the medical complications of
alcoholism directly depends upon the recognition of
the etiologic factor.
Acute effects of ethanol on liver lipid
Mallov and Bloch (4) first reported that a single large
dose of ethanol (4.2-6.2 glkg body weight) given to
rats by stomach tube or by intraperitoneal injection,
provoked significant accumulation of triglycerides in
the liver within 12-16 hr. Probably because of its
apparent simplicity, this acute alcoholic fatty liver
has been employed as a model by numerous investi-
gators and continues to be used, despite the original
recognition of the fact that most of this acute effect
may be nonspecifically due to the stress generated by
Abbreviations: FFA, fatty free acids; ADH, alcohol dehydrogenase;
MEOS, microsomal ethanol-oxidizing system; PHLA, postheparin
lipoprotein lipase activity; LCAT, 1edthin:cholesterol acyltransferase.
Journal of Lipid Research Volume 20, 1979 289
alcoholic administration. Although the changes in
liver lipids can be related in part to the oxidation of
ethanol, the degree of fat accumulation varies over a
dosage range far above that required to saturate
ethanol-oxidizing capacity (5) and the fatty liver is
markedly diminished if the ethanol dose is fraction-
ated and given at intervals in order to achieve smaller
blood ethanol concentrations (6). Like other stressful
situations, alcohol intoxication stimulates both the
hypothalamus-pituitary-adrenocortical (7- 10) and
sympatho-adrenomedullar (11, 12) systems. The re-
lease of catecholamines has been particularly implicated
because of their recognized ability to promote free
fatty acid (FFA) release from the adipose tissue and
triglyceride accumulation in the liver (13). Moreover,
the acute alcoholic fatty liver is prevented by the ad-
ministration of @adrenergic blocking agents, hypo-
physectomy, adrenalectomy, and spinal cord transec-
tion. It is likely that any stress that depletes catechol-
amine stores prior to alcohol administration will also
prevent acute alcoholic fatty liver (6). These acute
effects are not only nonspecific but they may not per-
tain to the fatty liver observed after chronic ethanol
ingestion.
Chronic effects of ethanol on liver lipids
The concept that malnutrition is primarily responsi-
ble for the development of chronic alcoholic fatty liver
was based on experimental evidence in growing rats,
in which deficiencies in dietary protein and lipotropic
factors (choline and methionine) produced fatty liver,
whereas ethanol was devoid of apparent toxicity (14).
Moreover, alcohol administration to patients recover-
ing from fatty liver failed to prevent the disappearance
of liver fat or to elicit any deleterious effect (15, 16).
In these studies, however, the amounts of ethanol
given were considerably less than the usual intake of
alcoholics, which not uncommonly amounts to 50% or
more of the caloric requirement. When amounts of
ethanol similar to those usually consumed by alcoholics
were given to patients with fatty liver, the clearance
of fat from the liver was indeed prevented (17). In the
rat experiments in which ethanol had no effect, the
alcohol was administered in the drinking water. This
technique of alcohol administration results in ethanol
intakes equivalent to only 10-25% of the caloric re-
quirement of the animals. A comparable amount,
when given in liquid diets, results in negligible blood
ethanol concentrations and there is no development of
fatty liver (18). By incorporating ethanol in a liquid
diet containing all required nutrients and offered as
the only source of fluid and food, the consumption
of ethanol by the rat was increased to 36% of the
caloric requirement, a proportion comparable to
290 Journal of Lipid Research Volume 20, 1979
moderate alcohol consumption in man. Isocaloric
replacement of some of the carbohydrate of the diet
by ethanol consistently produced a 5- to 10-fold
increase in hepatic triglyceride concentrations ( 18-20).
The accumulation of lipids developed gradually
during the first month of ethanol feeding and persisted
thereafter for at least 1 yr in the rat (21) and 3 yr in
the baboon (22). The nutritional adequacy of the diets
was manifested by their ability to support growth and
maintain health and normal liver function and struc-
ture in the pair-fed controls. Animals fed alcohol also
gained weight, though the growth-promoting ability
of ethanol calories was smaller than that of carbohy-
drate (23). Isocaloric replacement of carbohydrate by
fat or administration of carbohydrate-deficient diets
did not reproduce the effect of ethanol (Fig. 1). This
indicates that the fatty liver is due to ethanol and not
to the manipulation of the other sources of calories.
In man with morphologically normal liver (with and
without a history of alcoholism), fatty liver develops
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when ethanol is given as a supplement to normal diet
or in isocaloric substitution for carbohydrate (18, 24-
26). These fatty livers are evident both morphologically
and by the lipid content of liver biopsy samples which
reveal up to a 25-fold rise in triglyceride concentra-
tion. The lipid accumulation is apparent already after
a few days (26) or even after one day (27) of ethanol
administration. Though the greatest increase affects
liver triglycerides, other lipid classes such as phospho-
lipid (18) and cholesterol (19) also accumulate in the
liver of rats after chronic ethanol feeding. The in-
crease in hepatic cholesterol occurs mainly in the
esterified fraction, with little (if any) increase in free
cholesterol (19).
Though the ingestion of the alcohol-containing diets
provided all nutrients in the required amounts, the
possibility of malabsorption needed to be considered.
Indeed, the ingestion of ethanol in concentrations
commonly found in alcoholic beverages produces in-
traluminal concentrations in the upper gastrointestinal
tract (including proximal jejunum) considerably
higher than those found in blood, even during ex-
treme alcohol intoxication (28). These high concen-
trations of ethanol have been shown to produce
damage and functional impairment of the intestinal
epithelium (2). High ethanol concentrations also inter-
fere with active transport of glucose, amino acids, and
vitamins both in vitro and in vivo (29-32). Moreover,
malabsorption has been found in malnourished a h -
holics (33, 34). However, chronic administration of
ethanol along with nutritionally adequate diets to both
man and animals failed to produce abnormal fecal
losses of calories, nitrogen, or fat (23,35,36),suggest-
ing that the malabsorption observed in some alcoholics
is due in part to the associated malnutrition. Further-
more, it is unlikely that a deficiency state can develop
in the short time required for the development of
alcoholic fatty liver in volunteers (26, 2'7).
In nonhuman primates (baboons), the intake of
ethanol was increased up to 50%of the caloric require-
ment in the absence of malabsorption or malnutrition.
Under these conditions, the entire spectrum of alco-
holic liver disease (from fatty liver to cirrhosis) was
reproduced (37).
Injluence of otherfactors on ethanol-inducedfatty liver
The evidence that ethanol produces fatty liver (which
actually progresses to the stage of cirrhosis) in the ab-
sence of malnutrition does not exclude a possible sec-
ondary role of nutritional factors in the liver damage
of alcoholics.
a) Role of dietary lipids. The degree of steatosis pro-
duced by alcohol depends on the lipid content of the
diet. Reduction of dietary fat to a level of 25% or less
of total calories was accompanied by a significant
reduction of the lipid accumulation in the liver of
ethanol-fed rats (21) (Fig. 2). However, even when the
dietary fat was decreased to only the necessary supply
of linoleate (to avoid essential fatty acid deficiency),
the fatty liver was not fully prevented (21). The im-
portance of dietary fat was confirmed in volunteers:
for a given amount of alcohol intake, much more
steatosis developed with a diet of normal fat content
than with low-fat diet (38).In addition to the amount,
the chain length of the dietary fatty acids is also im-
portant in determining the degree of fat deposition.
r T
too
DIETARY
COMPOSITION
% of total calories 40
20
"01 m F A 1 AMINO-ACIDS
Fig. 1. Effect on total hepatic lipids of five types of liquid diets fed
to rats for 24 days. Substitution of part of the carbohydratecalories
for ethanol produces fatty liver, whereas substitution for fat or
hypocaloric diets does not (306).
Baruona and Lieber
T
4 7
, ...... ............ ..
............a .......... ......... ..... .... ......,....
,*
2% ~ 5% ~~ 1U% 15% 25 %
35%
JL 43%
DIETARY FAT (76 of total calories)
Fig. 2. Hepatic triglycerides in seven groups of rats given ethanol
(36% of calories) with a diet normal in protein (18% of calories)
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but varying fat content. Average hepatic triglyceride concentration
in the control animals is indicated by a dotted line (21).
Replacement of dietary fat containing triglycerides of
long chain fatty acids by triglycerides containing
medium chain fatty acids reduced the amount of lipid
accumulated in the liver of ethanol-fed rats (39).This
effect was probably due to the propensity of medium
chain fatty acids to undergo oxidation rather than
esterification (40).
b) Role of protein and lipotropicfactors. As mentioned
before, the deficiency in protein and lipotropic factors
can produce fatty liver in growing rats, but primates
are far less susceptible to these deficiencies than ro-
dents (41).The effects of protein deficiency on the
liver have not been clearly delineated in human adults.
In children, protein deficiency leads to steatosis, one of
the manifestations of kwashiorkor. In rats, ethanol-
induced fatty liver was potentiated when dietary pro-
tein was reduced to 4% of total calories and the diet
was made deficient in choline (42).However, such
potentiation failed to occur in baboons given 7% of
total calories as protein (43).Moreover, an excess of
protein (25% of total calories or twice the recom-
mended amount) and massive supplementation with
choline failed to prevent the fatty liver produced by
alcohol in volunteers (26).This is not surprising since
there is no evidence that a diet deficient in choline is
deleterious to man. Unlike rodent livers, human liver
contains very little choline oxidase activity, a fact which
may explain the species differences with regard to
choline deficiency. Hepatic injury produced by lipo-
tropic deficiency appears to be primarily an experi-
mental disease of the rat with little (if any) relevance
Effects of ethanol on lipid metabolism 291
 TABLE 1. Differences between the fatty liver induced by ethanol and by choline deficiency
Ethanol Choline Deficiency

Species susceptibility Both rodents and primates are
susceptible (18, 37)
Type of liver lipids Increase in all lipid classes, including
phospholipids (18) and carnitine (44)
Influence of dietary fat Hepatic lipid accumulation is enhanced
by high fat diets (21)
Serum lipids Associated with increased production , Associated with decreased production of
of serum lipoproteins and
hyperlipemia (48)
Ultrastructural changes Marked alterations of the mitochondria
(50)
Effect of orotic acid None (52)
Rodents are particularly susceptible,
(14) whereas primates are resistant (41)
Characteristic decrease in phospholipids
(45) and carnitine (46)
Hepatic lipid accumulation is unaffected
by dietary fat (47)
serum lipoproteins and hypolipemia
(49)
Slight alterationsof the mitochondria (51)
Reduces fatty liver (53, 54)

to human alcoholic liver injury. Even in rats massive The two most conspicuous features of alcoholic fatty
choline supplementation failed to prevent the ethanol- liver are the deposition of fat and the enlargement of
induced lesion (39). Furthermore, the fatty liver in- the organ. This hepatomegaly was traditionally at-
duced in the rat by choline deficiency differs from that

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induced by ethanol. Some of these differences are
illustrated in Table 1. Among the similarities, we
should mention that both types of fatty liver are asso-
ciated with delayed export of plasma proteins, such as
albumin (55,56) and both lead to the development of
cirrhosis.
Mechanisms of the ethanol-induced accumulation
of fat in the liver
Fatty liver involves not only marked alterations in
hepatic lipid metabolism, but also profound alterations
in protein metabolism, which may have important im-
plications in the ability of the liver to handle lipids.
PROTEIN
.----
OTHER
CONTROL ETHANOL
RATS FED RATS
Fig. 3. Effect of ethanol feeding on hepatic dry weight, lipid,
and protein contents. These three differences are significant
( P e 0.01) (57).
tributed to fat accumulation, but it has been recently
shown in ethanol-fed rats that fat accounts for only
half of the increase in liver dry weight. The other half
is almost totally accounted for by an increase in pro-
tein (57) (Fig.3). This protein increase is not associated
with changes in total liver protein concentration or
weddry weight ratios, indicating that the accumulation
of protein is accompanied by a proportional retention
of water. These increases in lipid, protein, and water
are associated with an increase in size of the hepatocytes
(57). The protein accumulation is due, at least in part,
to retention of secretory proteins in the liver (56).
There is no convincing evidence that ethanol by
itself, rather than its oxidation, causes these changes.
The effects of alcohol dehydrogenase (ADH) inhibitors
(such as pyrazole) on acute alcoholic fatty liver have
been inconclusive, prevention being found by some
(58, 59), no effect at all by others (60, 61), or effects
depending on the experimental conditions such as
dose of the drug (62) or sex of the animal (63). This
variability is not unexpected from the conspicuous
role of stress on the pathogenesis of acute alcoholic
fatty liver. Chronic administration of inhibitors to-
gether with ethanol have been reported to increase the
effects of ethanol on the liver with appearance of
inflammation and cell necrosis (64,65). The interpre-
tation of the latter results have been complicated by
the inherent toxicity of the inhibitors (66) and the
possibility that toxicity could result from oxidation of
ethanol through pyrazole-insensitive pathways. Both
the protein and lipid changes have been linked to the
consequences of ethanol oxidation in the liver, some
essential features of which are summarized below.

292 Journal of Lipid Research Volume 20, 1979

Metabolism .f ethanol
The oxidation of ethanol represents a metabolic
burden for the liver. Though trace amounts of ethanol
can be synthesized endogenously (67), it is essentially
a foreign compound that originates as a waste product
of microorganisms (yeasts). Moreover, ethanol has a
high caloric value (7.1 Cals/g) and is readily absorbed
from the gastrointestinal tract. Since only 2- 10% of
the amount absorbed is eliminated through lungs and
kidneys, the rest must be oxidized and the bulk of its
oxidation takes place in the liver. This organ specificity
is further aggravated by the absence of storage and a
feedback regulation to adjust its oxidation to cellular
needs. Therefore, the oxidation of ethanol produces
striking metabolic imbalances in the liver.
The main hepatic pathway for ethanol oxidation in-
volves alcohol dehydrogenase (ADH), an enzyme of
the cytosol, which catalyzes the conversion of ethanol
to acetaldehyde. Hydrogen is transferred from ethanol
to the cofactor nicotinamide adenine dinucleotide
(NAD), which is converted to its reduced form (NADH).
As a net result, ethanol oxidation generates an excess
of reducing equivalents in the liver, primarily as NADH
and, by transhydrogenation (68), probably also as
NADPH, the reduced form of nicotinamide adenine
dinucleotide phosphate (69). In addition, ethanol can
also be oxidized to acetaldehyde by an accessory path-
way that requires NADPH as a cofactor and is localized
in the endoplasmic reticulum (70). Unlike ADH, this
microsomal ethanol-oxidizing system (MEOS) in-
creases in activity during chronic alcohol consump-
tion (70). There is also debate on a possible role of
catalase (an enzyme of peroxisomes) in the conversion
of ethanol to acetaldehyde.
It was reported more than 10 years ago that alcohol
feeding results in proliferation of the smooth mem-
branes of the hepatic endoplasmic reticulum (50). This
finding was subsequently confirmed (7 1-73) and
established on a biochemical basis by the demonstra-
tion of an increase in both phospholipid and total
protein content of the smooth membranes (74). The
mechanism of these microsomal alterations is un-
known. By analogy with the proliferation of this
organelle induced by other drugs or foreign com-
pounds that utilize microsomes during their metabo-
lism, it has been linked to the fact that ethanol can
be oxidized at this site.
The various metabolic effects of ethanol can be
attributed either to the excess of reducing equivalents
or to the interaction of other microsomal functions
in association with the development of the MEOS path-
way. Since microsomes utilize rather than produce
Baraona and Lieber
reducing equivalents, the enhancement in microsomal
activities produced by chronic alcohol consumption
tends to reduce the changes in redox state generated
by the ADH-dependent alcohol oxidation.
Some of the effects can also be due to metabolites of
ethanol, such as acetaldehyde and acetate. Acetalde-
hyde is the first major oxidation product of ethanol
when the latter is oxidized by any of the previously
described pathways. Acetaldehyde oxidation proceeds
via aldehyde dehydrogenase, 80% of the activity of
which has been located in the mitochondria (75).
Under normal conditions, the rates of ethanol and
acetaldehyde oxidations are similar, and the concen-
tration of acetaldehyde in liver and blood remains
very low. However, the increased rate of ethanol oxi-
dation that follows prolonged alcohol consumption
results in increased acetaldehyde levels (76), particu-
larly because the oxidation of acetaldehyde in the
mitochondria is not increased, but is actually decreased
after ethanol consumption (77). Part of the metabolic
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effects of acetaldehyde may result from generation of
NADH during its oxidation, as discussed before in the
case of ethanol. Acetaldehyde, however, is a very reac-
tive compound which may exert some toxic effects of
its own.
Finally, most of the ethanol oxidized is recovered as
free acetate in the hepatic vein (78). It is uncertain
whether acetyl-coA results directly from acetaldehyde
oxidation o r is formed from free acetate, but its pres-
ence is indicated by the incorporation of labeled etha-
nol in a variety of metabolites (such as fatty acids and
cholesterol) that use acetyl-coA as a precursor. Al-
though, in vitro, the liver readily utilizes acetate,
in vivo most of the acetate is utilized by peripheral
tissues (79). During ethanol oxidation, hepatic oxida-
tion of acetate is further decreased as a result of the
inhibition of the citric acid cycle (80). The possible
consequences of this abnormal generation of free
acetate in the liver are largely unknown.
Origzn OJthe increased liver lipids and mechanisms
f o r their accumulation
Ethanol-induced fatty liver could result from an
increased supply of lipids to the liver from three main
sources: dietary lipids, adipose tissue lipids, and lipids
synthesized in the liver itself. Alternatively, lipids can
accumulate if their disposal by oxidation, lipolysis, or
secretion into serum or bile is inadequate. Depending
on the experimental condition, the various sources
and possible mechanisms can be implicated. The
mechanisms for liver fat accumulation are illustrated
in Fig. 4.
Effects of ethanol on lipid metabolism 293

Fig. 4. Theoretical mechanisms for alcoholic fatty liver. Ethanol intake could result in fatty liver either by
enhancing the pathways illustrated by wide arrows o r by blocking those illustrated by broken lines (307).
a) Increased supply of lipids from the small intestine.
After consumption of ethanol for several days with
diets containing a characteristic fatty acid composition,
the fatty acids that accumulate in the liver derive pri-
marily from dietary fat (38, 81, 82). Acute alcoholic
fatty liver is exaggerated by oral administration of fat
(83) and diminished by diversion of the lymph carry-
ing lipids from the intestine (84). As emphasized
before, after chronic alcohol feeding, the degree of
hepatic lipid accumulation is also influenced by the fat
content of the diet. However, even the restriction of
dietary fat to only the required essential fatty acids
does not fully prevent the development of ethanol-
induced fatty liver (2 1).
Acute administration of ethanol to naive rats in-
creases the intestinal lymph flow and output of both
dietary (85) and nondietary (86) lipids. The major
determinant of this increase in lymph lipid output
appears to be the stimulatory effect of ethanol on
splanchnic circulation (87-89) and the mesenteric
lymph flow (85). However, the lymphagogue effect of
ethanol decreases in rats fed ethanol chronically and,
after several weeks of ethanol feeding, the lymph lipid
output of ethanol-fed rats was similar to that of pair-
fed controls despite persistence of the fatty liver (85).
The in vivo changes in lymph lipid output did not cor-
relate with in vitro changes in intestinal lipid metabo-
lism. After 12-20 hr of administration of a high etha-
nol dose or after chronic alcohol feeding, there was
increased ability of the gut to oxidize fatty acids (90)
294 Journal of Lipid Research Volume 20, 1979
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and to synthesize triglycerides (90-93) and cholesterol
(94), but this increased ability was not associated with
significant increases in the output of lipid in the lymph.
By contrast, 1-3 hr after administration of an acute
ethanol dose, fatty acid oxidation and esterification by
intestinal slices were depressed (go), despite the fact
that the net output of lipids in the lymph increased (85).
Thus, dietary lipids play a permissive role for the
full development of ethanol-induced fatty liver, but
the fatty liver is not due primarily to increased lipid
absorption or production by the gastrointestinal tract.
6) Increased mobilization of fatty acids from the adipose
tissue. The fatty acids that accumulate in the liver after
administration of one large dose of ethanol resemble
those of adipose tissue (81, 95). Mobilization of pre-
labeled fatty acids from epididymal fat pads and con-
centrations of plasma FFA were found either increased
(95,96) or unchanged (97,98).The effects of ethanol
on plasma FFA depend upon the dose. Administration
of a moderate dose of alcohol to man (0.5- 1 g/kg body
weight per hr) produces a rapid fall of short duration
in the plasma concentration of FFA (99), decreased
FFA turnover (loo), and a concomitant reduction in
circulating glycerol (101). This inhibitory effect of
ethanol on FFA mobilization was found to be mediated
by acetate (102), the major final product of hepatic
ethanol oxidation. The metabolic consequences of this
substitution of acetate for FFA, the major normal fuel
for many tissues, are unknown. By contrast, the ad-
ministration of doses that result in blood ethanol levels
over 200 mg/100 ml produces a significant increase
in plasma FFA (24, 103). Since stressful doses of etha-
nol probably stimulate fatty acid mobilization (via
cathecholamine release) and depress it (via acetate
production), the net effect may depend on the particu-
lar experimental condition. An initial fall in FFA fol-
lowed by a secondary rise has been confirmed (104,
105), the stimulatory response being inhibited by ad-
ministration of &adrenergic blocking agents (105).
c) Increased uptake of fatty acids by the liver. Although
the flux of plasma FFA is not affected by a moderate
alcohol dose, the fraction of the total flux that is taken
up by the liver is increased (106) because of the stimu-
latory effects of ethanol on hepatic blood flow (87-89,
107). After intraperitoneal injection of a very small
dose (0.7 g/kg body weight), the increased uptake of
FFA accounted for the rate of hepatic fatty acid accu-
mulation and release; this contribution decreased at
higher but still moderate doses of ethanol (106). The
contribution of this mechanism to the fatty liver that
follows chronic ethanol ingestion remains to be
determined.
d) Increased synthesis of fatty acids in the liver. When
ethanol is given with a low-fat diet, endogenously syn-
thesized fatty acids are deposited in the liver (38, 42,
8 1).This could derive from normal carbohydrate pre-
cursors or from ethanol itself. It is noteworthy that
in vitro a large fraction of the carbon skeleton of
ethanol is incorporated into fatty acids (108, 109).
Although the liver can utilize two-carbon fragments
from ethanol, in vivo, most of them are released into
circulation as acetate (78), which completes its oxida-
tion to CO, in peripheral tissues. Therefore, the pos-
sibilities of in vivo conversion of ethanol into liver fat
appears limited. The incorporation of acetate (110,
1 11) and pyruvate (1 11) into liver fatty acids increases
in the presence of ethanol. However, the total rate of
fatty acid synthesis from precursors other than ethanol
has been found unaffected or decreased (109, 112-
114), suggesting that the increased acetate incorpora-
tion takes place through the fatty acid elongation path-
way of the mitochondria. This may represent a way to
dispose of the excess of reducing equivalents gener-
ated by ethanol oxidation, but the contribution of
enhanced fatty synthesis to the hepatic accumulation
of fat remains unsettled.
e) Increased esterijication of fatty acids in the liver. The
increased NADH/NAD ratio generated by the oxida-
tion of ethanol via ADH also favors the production a
a-glycerophosphate from dihydroxyacetone phos-
Baraona and Lieber
phate (1 15). This increase facilitates the formation of
glycerides such as triglycerides and phospholipids in
isolated hepatocytes incubated with ethanol (1 16).
Also, in vivo, ethanol-fed rats incorporate significantly
more labeled glycerol into hepatic triglycerides,
phophatidylcholine, and (to a lesser extent) phos-
phatidylethanolamine (1 17), despite ethanol-induced
inhibition of glycerol uptake by splanchnic organs
(118) and possible dilution by greater hepatic con-
centrations of a-glycerophosphate (115). For the cal-
culation of rates of glyceride synthesis in ethanol-fed
rats, the size of the precursor pools needs assessment.
However, the postulated increased triglyceride syn-
thesis is in keeping with observations that indicate
enhanced activity of enzymes involved in these proc-
esses during chronic alcohol feeding. Indeed, ethanol
consumption enhances the activity of hepatic micro-
somal L-a-glycerophosphate acyltransferase ( 119),
as well as other microsomal acyltransferases involved
in phospholipid synthesis (120), though the latter ef-
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fect depends on the type of fatty acid given together
with ethanol (120). These increases in microsomal
enzyme activities have been linked to the proliferation
of the endoplasmic reticulum induced by chronic
ethanol feeding,
f ) Increased synthesis of cholesterol in the liver. Another
microsomal process that is enhanced by chronic etha-
nol feeding is cholesterol synthesis. Indeed, liver slices
obtained from ethanol-fed rats display increased ability
to incorporate labeled acetate (but not mevalonate)
into cholesterol, even when incubated in the absence
of ethanol (12 1). Enhanced cholesterogenesis also
occurs with other drugs (such as phenobarbital) that
induce proliferation of the endoplasmic reticulum
(122), but (unlike ethanol feeding) this is not associated
with significant accumulation of cholesterol in the liver.
Ethanol feeding mainly increases cholesterol esters
(19). However, cholesterol esterification has been
found unaffected after acute ( 1 16) or chronic (123)
ethanol administration, suggesting that the accumula-
tion of esters may be due to decreased disposal rather
than to increased production, as discussed later.
g) Decreased oxidation of fatty acids in the liver. De-
creased fatty acid oxidation produced by ethanol has
been demonstrated in liver slices (1 10, 124), perfused
liver (40),isolated hepatocytes (116),and in vivo (125).
This reduction offers the most likely explanation for
the deposition in the liver of dietary fat (when available)
or fatty acids derived from endogenous synthesis (in
the absence of dietary fat) after chronic alcohol con-
sumption. Fatty acid oxidation occurs in the mito-
Effects of ethanol on lipid metabolism 295
chondria. This process is impaired by both functional
and structural changes that take place in this organelle.
Reducing equivalents resulting from ethanol oxida-
tion by ADH in the cytosol are transferred into the
mitochondria by various shuttle mechanisms. The
activity of the citric acid cycle is depressed (40, 126),
in part, because of the slowing of the reactions of the
cycle that require NAD. The electron transport chain
will use reducing equivalents originating from ethanol,
rather than from the oxidation through the citric acid
cycle of two carbon fragments derived from fatty acids.
Thus, fatty acids that normally serve as the main
energy source of the liver (127) are supplanted by
ethanol. In addition, the increased NADH/NAD ratio
in the mitochondria consequent to ethanol oxidation
restricts P-oxidation at the acyl CoA dehydrogenase
and P-hydroxyacyl CoA dehydrogenase sites, promot-
ing accumulation of long-chain fatty acyl CoA. Indeed,
P-oxidation is depressed when isolated hepatocytes
are incubated with ethanol (1 16).
In addition to these functional changes in the mito-
chondria as a consequence of the metabolism of etha-
nol, chronic alcohol abuse results in persistent altera-
tions of this organelle. Indeed, swelling and disfiguration
of the mitochondria, disorientation of the cristae,
and intramitochondrial crystalline inclusions are
prominent in alcoholics (128, 129). Similar alterations
were reproduced by isocaloric substitution of ethanol
for carbohydrate in otherwise nutritionally adequate
diets given to rats (50), baboons, (22) or man, with
(25, 71) and without (26) a history of alcoholism, indi-
cating a direct effect of ethanol rather than of mal-
nutrition. Degenerated mitochondria are conspicuous
and the debris of these degraded organelles is also
found within autophagic vacuoles and residual vacuo-
lated bodies (130). These ultrastructural changes of
the mitochondria are associated with increased fragility
and permeability (13 1- 133), decreased phospholipid
content (134), and altered fatty acid composition (135).
Essential fatty acid deficiency partially protects the
mitochondria from developing the increased fragility
induced by chronic ethanol feeding (136). Increased
serum activity of the mitochondrial enzyme, glutamate
dehydrogenase, is found in alcoholics and has been
proposed as a good indicator of the degree of liver
cell necrosis in these patients (137). The mechanism
of the alteration of the mitochondrial membranes is
unknown, but could possibly be linked to the depres-
sion of mitochondrial protein synthesis induced by
ethanol consumption (132).
The striking structural changes of the mitochondria
are associated with corresponding functional abnor-
malities. These altered mitochondria have a reduction
296 Journal of Lipid Research Volume 20, 1979
in cytochrome a and b content (132) and in succinic
dehydrogenase activity (132, 138). The respiratory
capacity of this organelle is depressed (139- 142),
including the oxidation of two-carbon fragments from
fatty acids (143, 144). By contrast, P-oxidation of the
fatty acids is enhanced (144). The accumulation of
acetyl-coA could result in increased ketogenesis,
which indeed develops after chronic alcohol ingestion
(145). In man, alcohol ingestion is associated with a
progressive increase in ketonemia and ketonuria,
which are most pronounced in the fasting state, in the
absence of ethanol in the blood (145). Moreover, en-
hanced ketogenesis occurs in liver slices from ethanol-
fed rats in the absence of ethanol (145). This contrasts
with the inhibition of ketogenesis reported in isolated
hepatocytes when incubated with ethanol (1 16).
These metabolic alterations of the mitochondria
from ethanol-fed animals can be reproduced, at least
in part, by incubation of normal mitochondria with
acetaldehyde (146), a product of ethanol metabolism,
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the oxidation of which is in turn impaired in mito-
chondria from ethanol-fed animals (77). Furthermore,
altered mitochondria from ethanol-fed animals
develop increased susceptibility to the injurious effects
of acetaldehyde (147). Therefore, it has been postu-
lated that generation of acetaldehyde may play a patho-
genic role in the progressive impairment of the mito-
chondria and consequent alterations in fatty acid
oxidation beyond those produced acutely by the
altered redox state during ethanol oxidation.
h) Decreased hydrolysis of fatty acid esters in the liver,
The increase in triglycerides, phospholipids, and
cholesterol esters that follows chronic alcohol con-
sumption could result from decreased hydrolysis of
these esters, an activity that is predominantly carried
out by acid lipase and esterase of the lysosomes (148-
150). Inhibitors of lysosomal lipase (such as sulfonyl-
ureas) promote accumulation of liver triglycerides (151).
Though there is no information of the activity of this
lipase after ethanol, other lysosomal enzymes are vari-
ably affected by acute and short-term ethanol ad-
ministration (152- 154) and they are increased after
prolonged alcohol consumption (155). In addition to
this acid lipase of the lysosomes, there are other lipase
and esterase activities (which are optimal at alkaline
pH) in other subcellular fractions. Some of these ac-
tivities are involved in the hydrolysis of triglycerides
and cholesterol esters from chylomicron or lipoprotein
remnants. Hydrolysis of cholesterol esters, (a step
prior to their secretion into blood or bile, or to their
conversion to bile salts) has been found decreased
after chronic ethanol administration to rats (123).
 i) Decreased excretion ofliverf a t into the bile. T h e major
lipids excreted in the bile are phospholipids (mainly
lecithin) and free cholesterol, the concentration of which
was unaffected in the bile of ethanol-fed rats (156)
despite the increases of lecithin and esterified cholesterol
in the liver. Most of the cholesterol is, however, excreted
as bile salts. Bile salt concentration was also found
unaffected after chronic ethanol consumption ( 156).
After acute ethanol administration or when blood
ethanol levels are elevated in rats chronically fed alco-
hol, bile secretion was depressed (157, 158). By con-
trast, in rats fed ethanol-containing diets for 2-4
weeks, but withdrawn from alcohol for several hours,
the flow of bile, and the secretion of both bile salt-
dependent and the bile salt-independent fractions of
the bile increased (156, 158). However, the increased
secretory rate of bile salts may merely reflect their en-
larged hepatic pool, since turnover rates and daily
excretion of both cholic and chenodesoxycholic acid
were significantly depressed in ethanol-fed rats (12 1).
Moreover, ethanol feeding supresses the normal in-
crease in bile acid production that follows cholesterol
feeding, leading to a striking increase in the concen-
tration of esterified cholesterol in the liver (121). The
mechanism of this inhibition has not been clarified.
The reduction in bile acid excretion could be secondary
to a decrease in cholesterol 7-a-hydroxylase activity
(159). Regardless of the mechanism, the block of this
major catabolic pathway of cholesterol may be re-
sponsible for the hepatic accumulation.
j ) Decreased release of serum lipoproteins. A block in the
hepatic synthesis and/or release of serum lipoproteins
has been proposed as the most likely mechanism of the
fatty liver produced by a variety of toxic agents (such as
carbon tetrachloride (160), ethionine (161), or orotic
acid (162)) as well as that produced by dietary de-
ficiencies in choline (49) and protein (163, 164). How-
ever, in contrast with these fatty livers, that produced
by chronic alcohol consumption develops in association
with hyper- rather than hypolipemia, both in man
(24, 165) and experimental animals (48, 166). During
the initial stages of liver damage, alcoholic hyperlipemia
involves increased hepatic release of serum lipopro-
teins, excluding a block of this pathway as a primary
mechanism of the steatosis. However, lipoprotein re-
tention could result if the increased production is not
matched by efficient secretion. Ethanol has been shown
to interfere with secretion of other export proteins
with an associated decrease in liver microtubules (56).
Microtubule alterations induced by other drugs (such
as colchicine) interfere with the secretion of lipopro-
teins as well as other proteins (167, 168).
Baraona and Lieber
PATHOGENESIS OF ALCOHOLIC
HYPERLIPEMIA
Etiologic role of ethanol
Alcoholic hyperlipemia follows diabetes as the second
major cause of nonfamilial hyperlipemias (169). It was
first recognized as a transient or recurrent condition
following bouts of excessive drinking ( 1 70), generally
associated with fatty liver (17 1) and sometimes with
pancreatitis ( 172) or hemolytic anemia ( 173).
Hyperlipemia is more prominent in alcoholics with
fatty liver than in patients with well-established cir-
rhosis (174, 175). Particulate fat behaves mainly as
very low density lipoproteins (VLDL)on ultracentrifu-
gation and as pre-P lipoproteins on electrophoresis.
Thus, alcoholic hyperlipemia is usually classified as
Type IV (176). Increased chylomicron or chylomicron-
like particles are also found in some alcoholics even
in the fasting state (169). In addition to the hyper-
triglyceridemia, there are also increased concentra-
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tions of serum cholesterol and phospholipids with
corresponding increases in P- and a-lipoproteins. The
serum lipid pattern changes rapidly after alcohol with-
drawal. Triglyceride clearance is the fastest, whereas
the clearance of cholesterol and phospholipids is
slower (Fig. 5 ) . Initially, the hypercholesterolemia is
mainly due to an increase in free cholesterol. After
the hypercholesterolemia has subsided, the esterified
fraction may increase, probably reflecting an improve-
ment of hepatic function and plasma lecithin:cholesterol
acyl transferase (LCAT) activity; the total cholesterol
may be secondarily raised (177).
In addition, it has been recently recognized that
some individuals manifest unusual sensitivity to the
hyperlipemic effects of ethanol. In these subjects,
hyperlipemia may adopt a chronic course indistin-
guishable from other forms of chronic hyperlipemia,
the role of alcohol being suspected mainly because of
the lack of response to the usual treatment and the
improvement after alcohol withdrawal. It is now ap-
parent that factors other than ethanol itself can con-
tribute to the development of alcoholic hyperlipemia,
including subclinical abnormalities of lipid metabo-
lism which can be exaggerated or unmasked by alcohol
consumption.
Acute or chronic alcohol administration has repro-
duced only partially these clinical features of alcoholic
hyperlipemia.
Acute effects of ethanol on serum lipidc
The oral or intravenous administration of ethanol
to volunteers, resulting in inebriating concentrations
Effects of ethanol on lipid metabolism 297
 .1 1tein fractions are also found in the postprandial state
( 185). Blood cholesterol and phospholipids remain
4-\
T R I GLYCER I DES
IO W
0 .
-
.
-
e consistent hyperlipemia. After administration of high
IO00 PHOSPHOLlPl DS
500
0 changing the dose of ethanol administered (197). In
0 4 8 12 16 20 24 28 32
DAYS
Fig. 5. Changes in plasma lipid fractions of' a patient during re-
covery from alcoholic hyperlipemia (177).
(140-250 mg/100 ml of blood) produced a rapid in-
crease in serum triglycerides (104, 165, 178) whereas
smaller doses did not produce consistent changes in
either pre- or postprandial triglyceride values (179).
The administration of a high ethanol dose (180 g of
ethanol in 6 hr) to chronic alcoholics produced hyper-
triglyceridemia due to increases in pre-fl lipoproteins,
chylomicron-like particles in the fasting state and in
some of the lipoproteins, with characteristics inter-
mediate between VLDL and low density lipoproteins
(LDL) (180), which may represent VLDL rem-
nants (181).
The effects of ethanol on serum triglycerides are
greatly enhanced if alcohol administration is followed
or accompanied by a fat-containing meal (182- 185).
Under these conditions, doses of ethanol that result in
blood ethanol concentrations of less than 100 mg/100
ml usually produce a several-fold increase in serum
triglycerides which persists for more than 12 hr. The
lipemic response to the combination of fat and ethanol
is significantly higher than the sum of the individual
changes due to fat or ethanol given alone (185). The
hypertriglyceridemia occurs mainly in the VLDL frac-
tion, which exhibits a pre-fl mobility on electrophore-
sis, but increases in chylomicrons and other lipopro-
298 Journal of Lipid Research Volume 20, 1979
1 unchanged (177, 178, 180, 186) unless alcohol ad-
ministration is continued for several days in which
case a moderate increase was observed (24, 187).
Unlike its effect on man and in rabbits (188, 189),
acute ethanol administration to rats does not produce
doses of ethanol to fasting rats (over 5 g/kg body
weight), a lipemic response has been described after a
few hours of administration, especially in male rats
( 190). Other investigators, however, found either no
changes in serum triglycerides (97, 191- 194) or even
a decrease 3-4 hr after alcohol administration (195,
196). Increases, no change, and decreases in plasma
esterified fatty acids have been produced in mice by
general, high ethanol concentrations in the blood are
associated with hypolipemia, whereas moderate levels
have variable results after acute ethanol administration
Downloaded from www.jlr.org by guest, on April 20, 2017
to animals. This difference in species susceptibility
may be due to differences in the ability to remove
lipids from the blood.
Another type of hyperlipemia occurring 10-16 hr
36 40
after administration of an acutely large dose of ethanol
to rats has been reported by some (83, 198),but not by
others (97, 191, 192, 194). This late hyperlipemia is
enhanced if a lipid load is given simultaneously with
ethanol (83, 199) and has been used as a model for the
study of postprandial alcoholic hyperlipemia ( 199).
However, the same effect is observed whether the lipids
are administered orally, intraperitoneally, or intra-
venously (83). In every case this enhancement of lipe-
mia was associated with increased accumulation of fat
in the liver. Since at the time when hyperlipemia
occurs, hepatic lipid accumulation has reached its
maximum and the blood alcohol levels are greatly
decreased, this hyperlipemia probably reflects recovery
from a transient fatty liver. The relevance of this model
to human alcoholic hyperlipemia is therefore ques-
tionable, since the latter is a prompt response to alco-
hol administration and subsides rapidly after ethanol
withdrawal (177, 200).
In contrast to man, the rat develops only mild hyper-
lipemia or none after an oral load of fat (166, 201)
and this effect is not changed significantly if ethanol
(3 g/kg body weight) is administered together with the
fat-containing meal (166).
Chronic effects of ethanol on serum lipids
Experiments both in human volunteers and in ani-
mals indicate that prolonged exposure to ethanol is a
key factor in the development of hyperlipemia.
Administration of ethanol together with nutritionally
 adequate diets for several weeks to alcoholic volun-
teen
produces
striking
(24, 103, 177, 178).
modificationsserum
of lipids
l ' h e ingestion of 200-300 g of
ethanol per day, resulting in blood ethanol concentra-
110-
A PATIENTS
WITH
1
7_7
0 PATIENTSWITHFATTY LIVER ( 5 )
CIRRHOSIS ( 8 )
0 CONTROLSUBJECTS (6)

100 -
tionsbetween 100 and 200 mg/l00 ml, produces a
4-foldincreasein
serum
triglycerides and
somein-
creases in cholesterol and phospholipids (Fig. 6). This
-
U
\
-
90-

effect does not result solely from caloricoverload,

since comparable hyperlipemia was produced when
ethanol was given in substitution for other calories
( 1 77). In these patients, the lipemic response is self-
limited and, after 2-3weeks of ethanol administration,
serum triglycerides return to normal levels despite
continuation of or even an increase in the alcohol in-
take. The same (butless marked) trend is followed by
phospholipids and cholesterol. Plasma FFA concentra-
tion remains unchanged until high blood alcohol levels
(over 250 mg/100 ml) are achieved by increasing the
dose (24, 95, 103). T h e mechanism of the transient
nature of the hyperlipemia remains unknown. Pro-

Downloaded from www.jlr.org by guest, on April 20, 2017

gressive deterioration of liver function or an effect of
minated
been
concentrations
ethanol
have high as 1 1

possible
disappearance
hyper-
the causes
for
of 2 4 6 8 IO
king.ethanol
continued
lipemia upon HOURS
It has recently been shown (202) that chronic alcohol Fig. 7. Serum triglycerideconcentrationsafreringestion o f a high-
consumption promotes a n increased to develop l i t meal in nonalcoholiccontrol subjects and i n alcoholics with
either limy liver or cirrhosis (SOX).

1 postprandial hyperlipemia even after a meal contain-

Fig. 6. Effect of prolonged alcohol intake on serum lipids in seven
chronic alcoholic individuals. The initial elevation of plasma tri-
glycerides was not maintained despitecontinuation of ethanol
intake. Serum FFA levels rose appreciably only after the ethanol
intake was raised sufficiently to increase its serum concentration
above 200 mg per 100 ml (24).
ing noalcohol. After administration ofa fat-containing
meal, alcoholicsdevelop a higher and more prolonged
elevation of serum triglycerides than nonalcoholics.
This effect is prominent in alcoholics with fatty liver
but not as marked inthose with cirrhosis (Fig. 7).
This suggests that the hyperlipemic response fades as
liver function deteriorates. The addition of alcohol to
the fat-containing meal increases postprandial hyper-
lipemia in nonalcoholics ( 1 85, 202), but only slightly
inalcoholics with fatty liver and actually decreases
it in alcoholics with cirrhosis (202).
Similarly, in the rat, the administration of alcohol-
containing diet for several weeks results in a prompt
and intense postprandial hyperlipemia (166), which
contrasts with the lack of effect of an acute dose.As in
alcoholics, striking postprandial lipemia occurs after
administration ofdiet without ethanol, though the en-
hanced response fadesrelatively rapidly after ethanol
withdrawal (166). I n these rats, ethanol (36%of total
calories) was administered in nutritionally adequate
liquid diets for 3-4weeks and its effects were studied
by comparison to controls pair-fed with diets inwhich
ethanol calories were replaced by carbohydrate. The
action of carbohydrates on serum lipids (203) may
have actually minimized the effects of ethanol.Never-

Raraona and Lkhm Effects of ethanolon lipid metabolism 299

theless, serum lipids (mainly as VLDL) increase and
reach their peak 90 min after an acute administration
of diet. At this time, marked turbidity or even lactes-
cence of the serum is observed (48, 166). When ethanol
is administered chronically in drinking water (a method
that results in much lower ethanol intake), the lipemic
response is variable. Dajani and Kouyoumjian ( 195)
showed that a large dose of ethanol decreases serum
triglycerides within a few hours, both in control rats
and in rats fed alcohol in drinking water for 6 weeks.
However, it is apparent from their results that the
ethanol-pretreated rats had higher serum triglycerides
than the controls after the acute administration of
either ethanol or water. In rabbits, the lipemic effect of
acute ethanol administration can also be enhanced by
chronic ethanol feeding (204). On the other hand,
the lipemia observed in rats 16 hr after a high dose of
ethanol was not different from that of rats given alco-
hol chronically in the drinking water (205).
Injluence of other factors on the development
of alcoholic hyperlipemia
Ethanol-induced hyperlipemia is usually moderate
and requires relatively high ethanol doses. However,
some patients develop marked hyperlipemia with
moderate alcohol intake and the hyperlipemia promptly
disappears after alcohol withdrawal. This suggests
that some associated conditions in these patients may
enhance the effect of ethanol on the development of
hyperlipemia.
A possible role of a defect in postheparin lipoprotein
lipase activity (PHLA) was reported to contribute to
the hyperlipemia in 6 of 8 alcoholics with marked
hyperlipemia (177). Similar patients were found to
have a decrease in fractional turnover rate of intra-
venously injected exogenous triglycerides (169, 206).
However, in either case, these alterations in lipid re-
moval persisted after abstinence from alcohol. Thus,
one factor in the development of marked hyperlipemia
in some alcoholics could be the co-existence of alcohol-
ism with a defective removal of serum lipids. Further-
more, some of the reported alcoholic patients with
marked hyperlipemia had other conditions, such as
diabetes (177, 207) or pancreatitis (172), which can
contribute to hyperlipemia. An inhibitor of PHLA has
been reported in association with pancreatitis (208,209).
It has also been observed (207) that some patients
(with normal PHLA) have unusual susceptibility to the
lipemic effects of ethanol: they developed hyper-
lipemia with doses of ethanol (120- 160 g per day) that
did not affect serum lipids of normal subjects or indi-
viduals with endogenous type IV hypertriglyceridemia.
However, one must wonder whether the difference in
response to ethanol between these groups is secondary,
300 Journal of Lipid Research Volume 20, 1979
at least in part, to the prior alcohol consumption,
which by itself increases the ability of ethanol to pro-
mote hyperlipemia.
Another factor that may contribute to exacerbation
of alcoholic hyperlipemia is the pre-existence of a type
IV hyperlipemic defect. Alcoholics with a primary
type IV hyperlipemia show striking elevation of serum
triglycerides during alcohol consumption, whereas
only moderate increases are found in patients with a
similar degree of alcoholism but without the pre-
existing lipoprotein disorder (2 10). Moreover, when
the lipemic effect of ethanol is compared in nonalco-
holics, patients with pre-existing type IV hyperlipemia
develop higher hypertriglyceridemia than controls
and this was manifested with amounts of ethanol within
the boundaries of social drinking (21 1). This raises
the possibility that moderate alcohol consumption may
unmask subclinical hyperlipemic states which are rela-
tively common (212, 213).
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Mechanism of the ethanol-induced hyperlipemia
While serum triglycerides are hydrolyzed extensively
in the body and their component fatty acids are oxi-
dized by many tissues or stored in adipose tissue, they
are produced at two main sites: the intestine and the
liver. By contrast, cholesterol is produced in many
tissues and transported to the liver for excretion into
the bile, either as neutral sterols or as bile salts. To
fulfill these transport needs, the liver produces very
low density (VLDL) and high density (HDL) lipopro-
teins. VLDL serves to carry fat from the liver to other
tissues. The major function of HDL appears to be the
transport of extrahepatic cholesterol back to the liver
for excretion (214). It is not clear whether there is a
net transport of phospholipids from or to the liver,
or whether phospholipids merely play a functional
and/or structural role in serum lipoproteins.
Accumulation of lipids in the blood occurs when
their rate of entry into the blood exceeds their rate
of removal. Thus, hyperlipemia can be produced either
by an excessive production and release of lipids into
circulation or by defective removal from the blood or
by combination of these mechanisms. The various pos-
sible mechanisms of ethanol-induced hyperlipemia
are illustrated in Fig. 8.
Increased production of serum lipids from the intestine
The enhancement of post-alimentary lipemia by
ethanol has long been suspected to be due to altera-
tions in the rates of gastric emptying and/or fat absorp-
tion. The effects of ethanol on gastric emptying are
concentration dependent. Concentrations of ethanol
of about 8- 10 g/lOO ml are needed to exhibit signifi-
cant changes in gastric emptying. At these concentra-
 I ADIPOSE VSSUE
Fig. 8. Theoretical mechanisms for alcoholic hyperlipemia. Ethanol intake could result in hyperlipemia
either by enhancing the pathways illustrated with wide arrows or by blocking those illustrated with broken lines.
tions, ethanol has been reported to accelerate (2 15,
216) as well as to delay (217) gastric emptying. At
higher concentrations, ethanol effects on gastric
emptying are consistently inhibitory (216, 218). It has
been argued that this inhibition of gastric emptying
may account for the delayed appearance of hyper-
lipemia in rats given a high dose of ethanol acutely
(2 19). However, a similarly delayed hyperlipemia oc-
curs in the fasting state (83). Moreover, hyperlipemia
was produced in ethanol-fed rats, despite equal rates
of fat disappearance from the gastrointestinal tract (48).
Ethanol could also increase the release of nondietary
lipids from the intestine into the lymph. Indeed, it was
shown that infusion of rat intestine with ethanol at a
high concentration (10 g/lOO ml) increased the output
of VLDL in the intestinal lymph (198). It was postu-
lated that this increase in nondietary lymph lipids,
though small, may contribute to alcoholic hyperlipemia.
This appears unlikely, however, because the much
greater increase in lymph lipid output (including
VLDL) induced in rats by acute administration of
ethanol and fat was insufficient to produce significant
hyperlipemia ( 166). Moreover, the administration of
orotic acid, an agent that blocks the hepatic but not
the intestinal release of triglycerides, abolishes ethanol-
induced hyperlipemia in rats (220). Thus, the increased
output of lipids into the lymph after ethanol does not
seem to play a major role on the development of alco-
holic hyperlipemia.
Increased production of serum lipids from the liver
Alcoholic hyperlipemia can be reproduced experi-
mentally even if the participation of the intestine is
Baraona and Lieber
ILIVER I
Downloaded from www.jlr.org by guest, on April 20, 2017
excluded, leaving the liver as the major possible source
of the increased serum lipids, particularly triglycerides.
Indeed, in rats diverted of their own mesenteric lymph,
intravenous administration of equal loads of lymph
lipids to both ethanol-fed and control rats reproduces
the alcoholic hyperlipemia in the ethanol-fed rats ( 166).
If lymph depletion is not prevented by intravenous
replacement, hepatic and plasma lipids decrease and
alcoholic hyperlipemia does not occur. This indicates
that although an adequate supply of dietary lipids
represents a permissive factor needed to induce alco-
holic hyperlipemia in the rat, the major site of origin
of the increased serum lipids is a nonintestinal one,
most likely the liver.
T o determine whether the accumulation of serum
lipids results from increased release of triglycerides
from the liver, three major types of assessment have
been used: the rate of lipid entry into the blood after
blocking its removal with Triton WR 1339, the incor-
poration of labeled precursors into serum lipoproteins,
and the release of triglycerides by isolated liver
preparations.
Triton WR 1339 inhibits lipoprotein lipase by com-
plexing with the lipid moiety of serum lipoproteins
(221). The accumulation of serum lipids following a
Triton block has been used to measure the rate of
entry of lipids into the blood (222). As might be ex-
pected from the difficulty in producing consistent
hyperlipemia after acute ethanol administration to
rats, the effects of the Triton block have also been
extremely variable in this experimental model. Triton-
induced hypertriglyceridemia has been reported in-
Effects of ethanol on lipid metabolism 301
creased (220, 223), decreased (195), or unchanged
(224) by acute ethanol administration to rats. The
type of response has been found to depend on the
dose of ethanol administered, higher doses resulting
in inhibition and smaller doses in stimulation of hepatic
lipid secretion (197). The effects of a large acute dose
of ethanol may be complicated by the effects of stress
on triglyceride secretion, since acute stress inhibits
Triton-induced lipemia (225). Finally, the same group
of investigators have found inhibition (226)and stimu-
lation (106) in different series of rats submitted to
apparently the same acute administration of ethanol.
After several weeks of feeding liquid diets containing
ethanol, rats develop marked hyperlipemia after ad-
ministration of dietary lipids with or without ethanol.
Complete block of the blood lipid removal by Triton
produces greater accumulation of serum lipids in the
ethanol-fed rat than in pair-fed controls (48), despite
the fact that neither Triton nor ethanol affects lipid
absorption. This indicates that alcoholic hyperlipemia
induced by chronic administration of ethanol is due to
excessive production of lipids from the liver.
The incorporation of labeled fatty acids into serum
lipoproteins increases during induction of hyperlipe-
mia by acute ethanol administration to man (100,227)
and rabbits (188) or by chronic ethanol administration
to rats (48, 166). However, these changes in triglyceride
labeling are not conclusive evidence of enhanced syn-
thesis because they may reflect changes in the fatty acid
pools preceding serum triglyceride formation. Better
evidence has been obtained by using amino acid pre-
cursors of triglyceride-carrying lipoproteins. Indeed,
the incorporation of intravenously injected [14C]lysine
into the protein moiety of VLDL increases in rats
rendered hyperlipemic by chronic ethanol administra-
tion (48, 166), whereas the incorporation into other
liver or serum proteins was not similarly affected. This
indicates that the increased incorporation was not due
to different degrees of isotopic dilution in amino acid
pools preceding protein synthesis. Moreover, in
ethanol-fed rats, the increased incorporation of lysine
into VLDL-protein was associated with increased
specific activity, suggesting that the increased labeling
is not due to retention of the protein in the plasma
but rather to increased synthesis.
The studies in isolated liver preparations have not
reproduced the conditions under which alcoholic
hyperlipemia develops. Livers from naive rats have
been perfused with solutions containing ethanol. The
effects on triglyceride secretion depend upon the con-
centration of ethanol. With very high concentrations
(400 mg/100 mi) the hepatic release of triglycerides
in the perfusate is inhibited (157). At lower concentra-
tions, however, this process remains unaltered (111).
302 Journal of Lipid Research Volume 20, 1979
When livers from ethanol-fed rats were perfused with
ethanol (200 mg/100 ml), a marked stimulation of
triglyceride release was observed (228). However, the
ability of these livers to secrete triglycerides was greatly
diminished in the basal state (without ethanol) com-
pared to that of controls. It must be pointed out that
the technique of chronic ethanol administration used
in this study did not result in the production of either
fatty liver or hyperlipemia.
Decreased removal of serum lipids by extrahepatic tissues
Plasma and tissue lipoprotein lipase activities are not
affected by ethanol in vitro (177, 178, 229). In man,
acute administration of ethanol does not change post-
heparin lipoprotein lipase activity (178, 185, 207),
postheparin plasma clearing activity (183), and the
triglyceride extraction by the forearm tissues (227).
In the rat, the lipolytic activity that can be measured
in the fasting plasma even in the absence of heparin,
has been found decreased after an acute large dose of
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ethanol (229). However, the much greater activity that
follows the injection of heparin is not changed by the
administration of ethanol (229, 230). Tissue lipopro-
tein lipase activities have also been found either un-
changed (230) or increased (231) after ethanol.
The clearance of chylomicron-triglycerides from the
blood remains unchanged after acute (224) or chronic
(48, 8 1) ethanol administration regardless of whether
these particles are obtained from normal or ethanol-
treated rats (48). In alcoholics, as emphasized before,
there are individual variations in lipoprotein lipase
activity (177) and blood lipid clearance (169, 232).
When these activities are decreased, the alteration per-
sists after alcohol withdrawal (177,206),suggesting an
associated defect rather than a direct effect of ethanol.
Decreased removal of serum lipids by the liver
Although most of the triglyceride removal from
chylomicrons and VLDL is carried out in extrahepatic
tissues, part of the triglyceride removal and most of
the cholesteryl ester removal is carried out by the
liver. A triglyceride lipase, located in the plasma mem-
brane of the hepatocyte, can hydrolyze triglyceride-
rich remnants of chylomicrons and VLDL. A decrease
in this activity could cause hypertriglyceridemia. After
injection of heparin, this enzyme is released into the
plasma where it can be separated from lipoprotein
lipase. In patients with various types of liver damage,
including alcoholic hepatitis, the activity of the hepatic
triglyceride lipase has been found decreased, whereas
lipoprotein lipase activity remained unaffected (233,
234). Possible accumulation of intermediate density
lipoproteins, considered to be remnants of partially
metabolized chylomicrons and VLDL, has been sug-
gested in alcoholics with liver disease (235, 236).
Recently, it has been shown that, contrasting with the
lack of significant changes in the removal of chylo-
micron-triglycerides, the removal of chylomicron-
cholesteryl esters was delayed in ethanol-fed rats (237),
suggesting that accumulation of remnants also con-
tributes to alcoholic hyperlipemia.
INTERRELATIONSHIPS BETWEEN SERUM
AND LIVER LIPIDS DURING PROGRESSION
OF ALCOHOLIC LIVER INJURY
The association of fatty liver development with en-
hanced hepatic production of serum lipoproteins sug-
gests that alcoholic hyperlipemia may play a compen-
satory role in counteracting fat accumulation, since the
other major pathway of disposition for liver fat (fatty
acid oxidation) is inhibited. Intrahepatic lipid avail-
ability is one of the major determinants of lipoprotein
synthesis (238,239). However, in the rat, the increased
availability of fatty acids in the liver that follows a
single ethanol ingestion does not appear to be sufficient
to increase lipoprotein production to a degree result-
ing in consistent hyperlipemia, which develops only
after chronic alcohol consumption (166). In other
species, including man, hyperlipemia can be elicited
after a single dose of ethanol, but even in man this
lipemic response is enhanced by chronic alcohol inges-
tion (202). This suggests an adaptation of the hepatic
capacity for lipoprotein production in response to the
increased availability of liver fat. In keeping with this
interpretation, the activity of key enzymes involved in
the synthesis of the lipid (1 19) and carbohydrate (240)
moieties of serum lipoproteins have been shown to in-
crease after chronic alcohol feeding. Moreover, this
increased capacity is manifested even after a load of
fat without ethanol (166, 202).
The full development of alcoholic hyperlipemia after
approximately one month of feeding 36% of calories
as ethanol to rats coincides with the cessation of the
accumulation of fat in the liver, and this situation
remains unaltered for most oE the animal life span
despite continuation of the alcohol administration (2 1).
Although the enhancement of the hepatic capacity to
dispose of liver lipids as serum lipoprotein could
contribute to the stabilization of the steatosis, it is also
obvious that this compensatory effort is only partially
effective and fatty liver is not fully prevented. This
relative inefficiency may be due, at least in part, to
other effects of ethanol that tend to decrease serum
lipoprotein production. After acute administration,
ethanol exerts inhibitory effects on protein synthesis
(241-250), which might involve lipoproteins as well.
Baruona and Lieber
Although protein synthesis is restored or even en-
hanced after chronic alcohol intake, (241, 251, 252)
the secretion of protein from the liver into the plasma
remains altered (56). It is reasonable to anticipate that
such a defect in export might also involve serum lipo-
proteins. In keeping with this possibility, marked
accumulation of VLDL-like particles in the Golgi ap-
paratus is observed in ethanol-fed rats (50). The
operation of mechanisms that produce opposite effects
on lipoprotein release probably explains also the
marked variations in the lipemic effects of ethanol
that can be produced by apparently minor changes
in experimental design.
When alcoholic fatty liver progresses to more ad-
vanced stages of liver damage, the relative inefficiency
of the lipemic response becomes an absolute one,
namely, hyperlipemia decreases whereas hepatic
steatosis is exaggerated. This has been recently docu-
mented in baboons fed 50% of calories as ethanol for
several years (202), an animal model that reproduces
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the entire spectrum of alcoholic liver disease (37).
Inverse correlations between the degree of alcoholic
hyperlipemia and the severity of the liver damage
have been long recognized (174, 175). The in-
corporation of labeled fatty acids into serum triglycer-
ides is decreased in cirrhosis and the degree of impair-
ment varies directly with the severity of the liver
damage (253). The inability has been proposed to dif-
ferentiate hepatocellular from obstructive jaundice
(254). More recently, it has been observed that the
changes in serum lipids, particularly the decrease in
VLDL or pre-P lipoprotein, could be an early indicator
of the transition from fatty liver to more advanced
lesions (202), and could be an important consideration
in the recognition of those alcoholics prone to progress
to severe hepatic lesions upon continued drinking.
At this stage of liver damage, the decrease of VLDL
from previously elevated values is associated with
proportional decreases in pre-p lipoproteins, but as
the severity of the hepatic injury increases, profound
alterations in the structure of serum lipoproteins
occur. These changes are indistinguishable from
those observed in nonalcoholic forms of liver disease
and reflect a marked impairment of hepatic function.
Some degree of hypertriglyceridemia can be observed
in alcoholics with severe liver damage. Although the
mechanism of this alteration is not fully elucidated,
the present evidence suggests that it is probably due to
decreased hepatic removal of triglyceride-rich rem-
nants of chylomicrons and/or VLDL (233, 234).
Characteristically, serum cholesterol decreases at the
expense of the esterified fraction with relative or ab-
solute increase in free cholesterol and lecithin. These
lipid changes are associated with alterations in the
Effects of ethanol on lipid metabolism 303
electrophoretic mobility of serum lipoproteins that
reflect striking changes in apoprotein composition.
There is a decreased concentration of both CY and pre-P
lipoproteins, and a single broad band in the /3 position
can be seen on electrophoresis in patients with severe
liver disease (255). Both VLDL and HDL isolated by
ultracentrifugation manifest a /3 or close to /3 mobility
on electrophoresis. T h e alterations in VLDL seem to
be secondary to the alterations in HDL, since pre-/3
mobility can be restored by incubation with normal
HDL, especially with added LCAT (256). Since the
liver is the major site of synthesis of both LCAT and
HDL, which provides the activator (mainly apoA) and
the substrates for this enzyme, it could be anticipated
that liver disease would affect the function of this
system. Indeed, decreased LCAT activity has been re-
ported in a variety of liver diseases (257), including
those due to alcohol (236). This deficiency can be
responsible for the increases in free cholesterol and
lecithin (which are the substrates for LCAT), com-
monly observed in severe liver disease, with corre-
sponding decreases in the products of LCAT reaction,
namely cholesterol ester and lysolecithin. Much less
clear is the relationship between the decreased LCAT
activity in liver disease and the profound structural
abnormalities of serum lipoproteins, including the
appearance of discoidal bilamellar structures (236).
These alterations are similar to those observed in
familial LCAT deficiency (258) and similar discoidal
lipoproteins are produced by 5,5-dithionitrobenzoic
acid (DTNB) (259), an inhibitor of LCAT. In patients
with extra- or intrahepatic cholestasis, there are also
similar abnormalities in the lipoproteins, which cul-
minate in the formation of lipoprotein-)< (a very ab-
normal lipoprotein which carries albumin as apopro-
tein) (260). Although a lipoprotein very similar to
lipoprotein-X is also found in familial LCAT deficiency
(261),cholestasis is not generally associated with LCAT
deficiency unless marked hepatocellular damage co-
exists (262). Thus, these associations do not exclude
the possibility that the protein abnormalities and the
LCAT deficiency night be independent manifesta-
tions of the liver injury.
ALCOHOL, ATHEROSCLEROSIS AND
HIGH DENSITY LIPOPROTEINS
T h e role of alcohol on the development of athero-
sclerosis and coronary heart disease (its most severe
complication) has been a matter of lively controversy
since the beginning of the century. The opinion that
alcohol could be a major etiologic factor in these dis-
eases prevailed during the last century. This opinion
304 Journal of Lipid Research Volume 20, 1979
was challenged by the observation of Cabot (263), who
showed that the incidence of atherosclerotic lesions
in autopsies from patients with a history of alcoholism
was remarkably low. Thereafter, the opinion that alco-
hol was protective against atherosclerosis was ex-
pressed in a number of studies (264,265).A dissenting
position was adopted by Wilens (266), who indicated
that the low incidence of atherosclerosis in chronic
alcoholism could be due to the younger age of the
alcoholics in the necropsy material and to a lesser
degree of association between alcoholism and other
conditions known to favor the development of athero-
sclerosis, such as hypertension, diabetes, and obesity.
He noted however that alcoholics had a lower ten-
dency to develop lesions in the heart and brain in the
presence of hypertension. It should be emphasized
that coronary heart disease is the result of thrombosis
as well as atherosclerosis. While some further studies
confirmed the low incidence of coronary heart disease
in alcoholics who died with cirrhosis of the liver (267-
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269), others failed to observe significant correlations
(270) or showed negative correlation with cirrhosis,
but not with alcoholism (271).
Both Ruebner, Miyai, and Abbey (272) and Parrish
and Eberly (273) interpreted the rarity of myocardial
infarction in cirrhotics as a statistical fallacy, resulting
from the low likelihood of two fatal diseases occuring
together and from the heavy contribution of cases with
atherosclerotic and hypertensive heart disease to
autopsy series, making any study group appear to
exhibit some protective effect. In autopsy series
composed of victims of automobile accidents or other
sudden and unexplained deaths, either there was no
correlation between alcoholism and atherosclerosis
(274) or even a positive correlation was reported (275).
These series, by contrast, are heavily weighed with
cases of alcoholism (276). Prospective clinical studies
have shown either positive correlations (277-279) or
or correlation (280-283). Alcoholism is frequently as-
sociated with smoking, a recognized risk factor of
coronary heart disease. When the role of smoking has
been accounted for, a negative correlation between
alcohol consumption and coronary heart disease has
emerged in several, but not all, recent studies (284-
287), reviving the possibility of a protective effect of
alcohol on atherosclerosis and ischemic heart disease.
It must be pointed out, however, that alcoholism
involves a variety of psychological, sociological, and
probably biochemical and genetic determinants, and
the validity of the controls used in epidemiologic
studies is likely to be the subject of criticism. One
factor that may be particularly relevant to this problem
is the variable ability of the alcoholics to develop hyper-
lipemia, depending upon the degree of hepatic injury
and the presence of other associated conditions. Al-
though hyperlipemia is consistently produced by
administration of ethanol to man and animals, espe-
cially in the postprandial state, this change is mild,
decreases with progression of the liver damage, and
disappears rapidly after alcohol withdrawal. Thus,
clinically significant hyperlipemia (which is measured
in the fasting state and generally after alcohol with-
drawal) occurs only in a minority of alcoholics. More-
over, since ethanol enhances (and perhaps unmasks)
other subclinical hyperlipemic states, it is likely that
patients of this type contribute heavily to those classified
as hyperlipemic alcoholics. If this were the case, one
would expect that when the frequency of ischemic
heart disease is studied in alcoholics with hyperlipemia
(288), alcohol hyperlipemia appears to represent a risk
with regard to ischemic heart disease similar to that of
hyperlipemias of other origins.
The difficulty in selecting adequate controls in
epidemiologic studies makes the experimental ap-
proach highly desirable. However, thus far this type of
assessment has been hampered by the lack of develop-
ment of animal models that can be considered relevant
to either human alcoholism or atherosclerosis. This is
witnessed by the paucity of experimental work on the
possible relationships between these two leading causes
of death. T h e most classical experimental study was
performed by Eberhard (289) in rabbits fed a high
cholesterol diet for approximately 20 weeks. He found
that the inclusion of 25% ethanol in the drinking water
produced a significant increase in the concentrations
of cholesterol in the liver and the plasma, whereas
both lesions of the aorta and the cholesterol content
of the vessel were reduced. Using a similar model (but
over a much shorter time), Feller and Huff (290) con-
firmed the hypercholesterolemic effect of ethanol, but
found neither significant changes in the aortic content
of nonsaponifiable lipids (the major fraction of which
is cholesterol) nor in the incorporation of labeled ace-
tate into these lipids. More recently, however, similar
experiments have been repeated by Goto et al. (291),
using a larger number of rabbits fed cholesterol-
enriched diets for a period more akin to that used by
Eberhard, and again a protective effect of ethanol on
this cholesterol-induced atherosclerosis was indicated.
Daily intragastric administration of 0.5 g of ethanol
per kg body weight to rabbits on atherogenic diet
failed to prevent electrocardiographic changes follow-
ing hypoxia, exercise, and other strains (292).
Using other animal species, other investigators failed
to detect any protective effect. Nichols et al. (293)
found no effect of ethanol or wine on either the spon-
taneous variety of atherosclerosis observed in fowls
(cockerels) or the stimulation of this process by stilbes-
Baraona and Lieber
trol. Since a large proportion of these birds did not
develop lesions at all, the severity of the alteration was
increased by adding cholesterol and low-protein diets
(294). Under these conditions, 7% alcohol in the drink-
ing water did not significantly influence the experi-
mentally induced lesions (295). Furthermore, in rats
made atherosclerotic by administration of diets con-
taining both 1% cholesterol and 0.3% cholic acid,
Gottlieb et al. (296) found that the addition of 20%
alcohol to the drinking water increased the extension
of the vascular sudanophilia (a morphological counter-
part of the lipid deposition).
The major problem of the experimental work per-
formed thus far is the question of relevance with regard
to both alcoholic and atherosclerotic diseases. With
regard to alcoholism, we have learned that the tech-
nique of alcohol administration used in these studies
results in minimal or no elevations of blood ethanol
concentrations because of the natural aversion of the
animals to the consumption of alcohol. Moreover,
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ethanol administration reduces the intake of food and
can produce protein malnutrition, which, by itself,
exaggerates cholesterol-induced atherosclerosis (294).
With regard to atherosclerosis, the criticism has been
made that the lesions produced by high cholesterol
feeding in these species resemble human essential
xanthomatosis (with lipid-laden histiocytes and mono-
cytes) more than human atherosclerosis (297). In the
latter, initial lipid deposition occurs in smooth muscle
cells proliferating in the intima of the vessels (298).
Moreover, striking differences in cholesterol metabo-
lism exist between these species and man (299), par-
ticularly with regard to the ability of dietary cholesterol
to produce hypercholesterolemia and to increase
cholesterol pools. In view of these facts, it is not sur-
prising that the concept that human atherosclerosis is
related to the consumption of cholesterol or predictable
by the levels of cholesterolemia (extrapolations from
animal experiments) has been discredited (300). The
problem of clinical relevance has switched the interest
toward the use of nonhuman primates as experimental
models of atherosclerosis. Indeed, primates share
relative inability to absorb cholesterol, stong mecha-
nisms of negative feedback of cholesterol synthesis,
and the ability to dispose cholesterol excesses into bile
salts (299). Moreover, atherosclerosis has been pro-
duced in rhesus monkeys (Macaca mulattu) by a table-
prepared average American diet, with a rather low
degree of hypercholesterolemia (30 1).
Though atherosclerosis is a multifactorial process,
in which not only lipid disturbances but also vascular
and hematological abnormalities contribute to the
pathogenesis, accumulation of cholesterol esters is a
key factor in its pathogenesis (302). The effect of etha-
Effects of ethanol on lipid metabolism 305
no1 on this process is unknown. Alcohol could act
directly on cholesterol metabolism in peripheral tissues
or indirectly, through modifications of hepatic lipid
metabolism and serum lipoproteins. Experiments in
rats indicate that alcohol increases cholesterol synthe-
sis in the liver (12 1) and the small intestine (94) whereas
it decreases cholesterol disposition as bile salts (12 I),
promoting accumulation of cholesterol esters in the
liver and hypercholesterolemia. Ethanol feeding to
rats increases all lipoprotein classes; though the
changes are proportionally greater in VLDL, there are
also increases in the cholesterol-rich fractions, LDL
and HDL (48).The increase in HDL has been empha-
sized in alcoholics by Johansson and Laurel1 (303)
and Johansson and Medhus (304). Recent epidemio-
logic evidence indicates that decreased levels of HDL
are several times more predictive of coronary heart
disease than increased levels of LDL (305),suggesting
a possible defect in cholesterol removal from the vessel
as a major factor in the pathogenesis of the disease.
It is tempting to speculate that the elevation of HDL
induced by alcohol could participate in the apparent
protective effect of alcohol on the development of
atherosclerosis.
SUMMARY
Alcohol promotes accumulation of fat in the liver
mainly by substitution of ethanol for fatty acids as the
major hepatic fuel. The degree of lipid accumulation
depends on the supply of dietary fat. Progressive
alteration of the mitochondria, which occurs during
chronic alcohol consumption, decreases fatty acid oxi-
dation by interfering with citric acid cycle activity.
This block is partially compensated for by increased
ketone body production, which results in ketonemia.
Thus, mitochondrial damage perpetuates fatty acid
accumulation even in the absence of ethanol oxidation.
Alcohol facilitates esterification of the accumulated
fatty acids to triglycerides, phospholipids, and choles-
terol esters, all of which accumulate in the liver. The
accumulated lipids are disposed of in part as serum
lipoprotein, resulting in moderate hyperlipemia. In
some individuals with pre-existing alterations of lipid
metabolism, small ethanol doses may provoke marked
hyperlipemia which responds to alcohol withdrawal.
Inhibition of the catabolism of cholesterol to bile salt
may contribute to the hepatic accumulation and hyper-
cholesterolemia. The capacity for lipoprotein produc-
tion and hyperlipemia development increases during
chronic alcohol consumption, probably as a result of
the concomitant hypertrophy of the endoplasmic
reticulum and Golgi apparatus. However, this com-
306 Journal of Lipid Research Volume 20, 1979
pensation is relatively inefficient in ridding the liver of
fat. This inefficiency may be linked to alterations of
hepatic microtubules induced by ethanol or its metab-
olites, which interfere with the export of protein from
liver to serum, promoting hepatic accumulation of
proteins as well as fat. As liver injury aggravates,
hyperlipemia wanes and liver steatosis is exaggerated.
Derangements of serum lipids similar to those found
in other types of liver disease also become apparent.
The changes in serum lipids may be a sensitive indi-
cator of the progression of liver damage in the alcoholic.
m
Original studies were supported by USPHS grants AA
03508, AA 00224, AM 1251 1, T h e Medical Research Service
of the Veterans Administration, and the National Council
on Alcoholism.
lManucrrzpt wcriurd 4 Apral 1978; accepted 30 May 1978.
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