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,**2
*
Nutritional Sciences Program,
Departments of Biochemistry,
Pharmacology, and
**
Pathology and Anatomical Sciences, University of Missouri, Columbia, MO 65212
2To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • polyphenols • liver • chronic ethanol • rats • antioxidant
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 1997
and 1998
). The development of
alcoholic liver disease
(ALD)3
involves complex signaling pathways complicated by factors such as
diets, hormonal regulation and disease states (Lands 1995
). In the liver, ethanol alters basic biochemical
metabolism, including the redox mechanism and fatty acid biosynthesis
(Lieber 1990
and 1997
). There is increasing attention to
understanding the induction of cytochrome P450 2E1 by ethanol, a
process associated with increases in oxidative stress and generation of
oxygen free radicals (Albano et al. 1996
, French et al. 1997
, Nordmann et al. 1992
). Several
novel strategies have aimed at retarding the progression of alcoholic
liver disease through reducing the oxidative insults (Corbett et al. 1991
, Dannenberg and Nanji 1998
,
French et al. 1998
, Karpe et al. 1984
, Morimoto et al. 1995
, Pirozhkov et al. 1992
).
Many plant products, including some fruits and vegetables, contain
polyphenolic compounds (bioflavonoids), which are potent antioxidants
(Rice-Evans et al. 1995
). Compounds such as resveratrol
and quercetin are high in grape skin and seeds, and they have been
regarded as the active ingredients in red wine that protect against
coronary heart disease (Pace-Asciak et al. 1995
). The
ability of these compounds to inhibit platelet aggregation and to
reduce susceptibility of LDL to oxidation (Frankel et al. 1993
, Xia et al. 1998
) has provided a support
for the "French Paradox" (Renaud and de Lorgeril 1992
). In addition to these effects on the
cardiovascular system, our recent study has demonstrated the ability of
dietary supplementation of polyphenols from grape skin and seeds (GP)
to ameliorate oxidative insult to the brain synaptic membranes due to
chronic ethanol consumption (Sun et al. 1999
). Because
liver is the major organ for ethanol metabolism, it is reasonable to
consider that dietary GP supplementation may similarly ameliorate the
hepatic lipid changes and oxidative damages resulting from chronic
ethanol administration. In this study, Sprague-Dawley rats were
given a Lieber-DeCarli (L-D) liquid diet (Lieber and DeCarli 1970
) in which ethanol and GP were the two factors. This
dietary regimen was used to test whether GP supplementation could offer
protection against the changes in liver resulting from chronic ethanol
consumption.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Male Sprague-Dawley rats (~180 g) were purchased from Harlan
Sprague Dawley (Indianapolis, IN). They were individually housed in
suspending cages in a room with constant temperature and a 12-h
light:dark cycle (University of Missouri Animal Sciences Research
Center). Rats were randomly divided into four groups (n
= 8) and given the following diets for 2 mo: 1)
Lieber-DeCarli liquid diet (# 710260, Dyets, Bethlehem, PA) with
isocaloric amount of maltose-dextrin as for 50 g/L ethanol (Basal),
2) Basal diet with 50 g/L ethanol (EtOH) (36% of total
energy), 3) Basal diet with 50 mg/L of grape polyphenols
(GP), and 4) ethanol diet supplemented with GP (EtOH +
GP). The high fat L-D diet is nutritionally complete with 18%
total energy as protein, 47% as carbohydrate and 35% as fat (a
mixture of olive-corn oil and 2% linoleate to avoid essential
fatty acid deficiency) (Lieber and DeCarli 1970
). The GP
was added to the diet just before mixing with a blender. All diets were
stored at 4°C and were made fresh from the powder each day. Food
intake from EtOH and EtOH + GP rats was recorded daily; rats in the
Basal and GP groups were fed the mean of the EtOH group based on the
previous day's intake. Body weight was obtained weekly. By the end of
2 mo, body weights of the control rats had reached 309 ± 7.3 g (n = 8) compared with 277.6 ± 10.7 g
(n = 8) in the EtOH group (P < 0.0001). There was no difference in dietary intake and in body weights
due to supplementation with GP.
At killing, whole blood was collected from abdominal aorta with 1 g/L EDTA as the anticoagulant. Blood alcohol concentration (BAC) was determined using an alcohol dehydrogenase kit (332-UV, Sigma Chemical, St. Louis, MO). Because the diet was removed from the rats for 6–8 h before decapitation, BAC for the EtOH groups had already declined to 329 ± 91 mg/L (7.3 mmol/L) (n = 16). Protocol for this study was reviewed and approved by the University of Missouri Animal Use and Care Committee (Protocol # 1741).
The GP were extracted from Vidal grape skin and seeds obtained from the
Robller Vineyard (New Haven, MO). After pressing, grape skin and seeds
were transported to the laboratory and kept in plastic bags at -60°C
until processing. After the grape products were washed with water,
polyphenols were extracted with ethyl acetate containing 10 mL/L
glacial acetic acid (Xia et al. 1998
). Extraction was
carried out at room temperature for 36 h. Afterwards, the solvent
was filtered through several layers of cotton gauze into a container
and evaporated under the hood. This process yielded a yellow-brown
product that was stored in a dark glass bottle at -20°C until use.
For determination of the phenolic content, the powders were partitioned
with chloroform/methanol/water (4:2:1.5, v/v/v) to remove any residual
protein contaminants. The lower organic phase was evaporated under
nitrogen, and total phenol content was determined with
phosphomolybdic-phosphotungstic acid (Folin reagent) and gallic
acid as standard (Singleton and Rossi 1965
). With this
assay protocol, phenolic content of the extract is typically ~12%.
Histological examination of liver.
Each rat was anesthetized with isoflurane and decapitated. A piece of liver tissue (~1 g) was dissected from the central lobe and immersed in 4% paraformaldehyde in PBS. The tissue was fixed at room temperature for 48 h before being embedded in paraffin. Tissue sections (6 µm) were cut on a microtome, and slides were delipidated and rehydrated by passing through graded alcohols. Specimens were stained with hematoxylin and counterstained with eosin using standard protocols. The slides were mounted with xylene and covered with a cover slip. Histologic assessment of the liver sections was carried out independently by two individuals unaware of the tissue treatment with the use of a Nikon Labophot Microscope (Nikon, Melville, NY). A grading scale of 1–5 was used with 1 indicating no abnormal histologic structure observed and 5 indicating the greatest degree of altered histologic structure present. Abnormalities were based primarily upon the presence of altered general hepatic lobule architecture and the presence and extent of steatosis within the liver acinus. The following grading scale was used and a mean and standard error was determined for each of the treatment groups:
Assay of lipid peroxidation in hepatic homogenate.
Lipid peroxidation was assessed by the complex formed between
malondialdehyde (MDA) and thiobarbituric acid (TBA)
(Placer et al. 1966
). Briefly, liver tissue (0.5 g) was
homogenized with 5 mL of PBS. The homogenate was centrifuged at 7000
x g for 15 min to sediment mitochondria and cell
debris. The postmitochondrial supernatant (1 mL) was mixed with 1 mL of
0.6 mol/L ice-cold trichloroacetic acid and 4 mL of the TBA
reagent. The reaction mixture was heated at 95°C for 10 min. After
heating, the tubes were cooled and 3 mL of n-butanol was
added. After mixing and centrifugation at 2000 x g
for 5 min, the upper phase was taken for measurement at 532 nm with a
Beckman UV-vis spectrophotometer (Beckman Instrument, Sunnyvale,
CA). Samples were compared with 1,1,3,3-tetrahyroethyl propane
standards (Sigma Chemical).
Analysis of hepatic lipids and fatty acids.
For analysis of lipids, 0.5 g of liver tissue was briefly minced with a pair of scissors and then homogenized in 10 vol of ice-cold saline using a glass homogenizer. Lipids in the homogenate were extracted with 4 vol of chloroform/methanol 2:1 (v/v), followed by brief centrifugation to facilitate separation into two phases. The lower organic phase was removed and filtered through a column containing anhydrous Na2SO4. The organic solvent was evaporated and the lipids redissolved in 2 mL of chloroform/methanol 2:1 (v/v).
A portion of the lipid extract was applied to a high performance thin
layer chromatography (HPTLC) plate (Whatman silica gel 60) and
developed using a solvent system containing hexane/diethyl ether/acetic
acid (85:15:2, v/v/v). This solvent system separated triacylglycerols
(Rf 0.7) and phospholipids, which
remained in the origin. Lipid bands were removed from the plates and
their fatty acids were converted to methyl esters by
base-methanolysis using 0.2 mol/L NaOH/methanol with heptadecanoic
acid (17:0) methyl esters as internal standard (Sun 1988
). Fatty acid methyl esters were analyzed by gas-liquid
chromatography (GLC) (Hewlett Packard 5890, St. Louis, MO) with
a SP2330 column (Supelco, Bellefonte, PA). Conditions for the
chromatography have been described (Sun 1988
).
For separation of individual phospholipids, an aliquot of the lipid
extract was applied to a HPTLC plate and developed in a
two-dimensional system as described by Sun (1988)
.
After development of the first solvent system, the plates were exposed
to HCl fumes to separate the diacyl-phosphatidylethanolamine (PE)
from the alkenylacyl-PE (Sun 1988
).
Statistical analyses.
Data were analyzed using a two-way ANOVA program with ethanol and GP as the two factors. When the interaction between ethanol and GP was significant, one-way ANOVA was performed, followed by Bonferroni's post-hoc t test. Phospholipid fatty acids were compared using the combined EtOH and EtOH + GP groups and the combined Basal and GP groups. All analyses were performed using the GraphPad program (V2.0, GraphPad Software, San Diego, CA). Values are means ± SEM, n = 8, with the exception of histologic evaluation for which only seven samples per group were available.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A). Tissue sections from the EtOH group showed extensive morphologic
alterations to the hepatic lobules. Paramount to these changes was the
presence of steatosis in Zone 1 of most of the lobules, which extended
throughout the liver acinus. Although there was considerable variation
of individuals within the EtOH group, Figure 1
B shows an
example of a severely affected hepatic lobule from a rat in this group,
showing a large number of lipid vacuoles and the extent of their
distribution within the lobule. Although the disruption of the radial
arrangement of the hepatic plates extending from the central vein due
to extensive branching of the plates is readily seen, higher power
examination (not shown) revealed the vesicularity of the sinusoids and
the enlarged, light-staining hepatocyte nuclei. In contrast,
histologic examination of the hepatic lobules from rats in the EtOH +
GP group showed less severe hepatic changes than those in the EtOH
group. Figure 1
C shows representative changes in the hepatic
lobules that occurred in rats in the EtOH + GP group. When steatosis
was observed in rats in this group, the lipid inclusions were small and
limited to isolated islands within Zone 3 of the liver acinus; few
acini were affected. Most rats showed hepatic lobules with some general
disorganization of the hepatic plates, consisting of increased
branching, and variable swelling and some vesiculation of the
sinusoids. Because no abnormalities were observed in tissue sections
from the Basal and GP groups (not shown), an unpaired Student's
t test was used to compare the histologic scores between the
EtOH and EtOH + GP groups. The liver slides from rats in the Basal and
GP groups had a mean score of 1.3 ± 0.3 (n = 8).
In contrast, the liver morphology score from those in EtOH group was
4.1 ± 0.4 (n = 7), whereas those given EtOH + GP
had a significantly (P = 0.017) lower mean morphologic
score of 2.5 ± 0.4 (n = 7).
|
).
|
A) but there was no significant interaction between ethanol and GP. GP
supplementation did not alter the triacylglycerol levels (Fig. 3
A). Hepatic phospholipid levels were not different among
the four groups (Fig. 3
B).
|
). The EtOH and EtOH + GP groups had significantly (P < 0.05) less 16:0 and 18:0 and more18:3 and 20:4(n-6) in the
triacylglycerols compared with the Basal and GP groups. The acyl groups
of hepatic phospholipids were comprised mainly of 16:0, 18:0, 18:1,
18:2, 20:4(n-6) and 22:6(n-3) (Fig. 5
). The EtOH and EtOH + GP groups had significantly (P < 0.01) less 16:0 and 20:4(n-6) and more 18:0, 18:1, 18:3 and 20:3 in the
phospholipids compared with the Basal and GP groups (Fig. 5)
. The only
fatty acid showing an interactive effect (P = 0.029)
between GP and ethanol was 22:6(n-3), which was significantly
(P < 0.001) higher in the EtOH + GP group compared
with the other three dietary groups (Fig. 5)
.
|
|
). In PC, the EtOH and EtOH + GP groups had significantly less 16:0 and
more 18:0 and 18:1 than those in the Basal and GP groups. Similar
differences were observed in PE, i.e., the EtOH and EtOH + GP groups
had significantly less 16:0 and more 18:1 than those in the Basal and
GP groups. Only minor differences were found in the fatty acids of PS
and PI. There was also significantly less 20:4(n-6) in PE in the EtOH
and EtOH + GP groups compared with the Basal and GP groups (Table 1)
.
Although 22:6(n-3) comprised only 1–4 g/100 g of the fatty acids of
these phospholipids, the EtOH and EtOH + GP groups had significantly
more 22:6(n-3) (P < 0.01) in PC and PS compared with
the Basal and GP groups (Table 1)
.
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|
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Nanji 1998
). Although
ethanol administration did not alter the hepatic phospholipid levels,
obvious changes in the acyl group composition were found. In
particular, there was a decrease in the proportion of 16:0 and an
increase in 18-carbon fatty acids. This change in fatty acid profile
seems to reflect the ability of ethanol not only to provide two carbon
units (acetyl-CoA) for synthesis of fatty acids but also the elongation
of 16:0 to 18:0 fatty acids. Although the increase in 18:1 or monoenoic
fatty acids in hepatic phospholipids after chronic ethanol consumption
has been reported previously (Morimoto et al. 1995
,
Ristic et al. 1995
), this is the first study reporting
the contrasting changes between 16- and 18-carbon fatty acids. Because
liver is the major site for de novo fatty acid biosynthesis,
ethanol-induced changes in these nonessential fatty acids in
phospholipids may lead to alteration of membrane phospholipid
functions.
Several studies in rats have associated the decrease in polyunsaturated
fatty acids in hepatic phospholipids with chronic ethanol ingestion
(Corbett et al. 1991
, Cunnane et al. 1987
, French et al. 1997
, Ristic et al. 1995
). In this study, chronic ethanol administration did not
alter 18:2 levels, albeit a decrease in 20:4(n-6) was observed in PE.
Although ethanol did not alter 20:4 (n-6) in PC and PI, there was a
significant increase in the level of 20:3(n-6), a precursor for
synthesis of 20:4(n-6). These results seem to support the hypothesis
that the desaturase responsible for the conversion of 20:3(n-6) to
20:4(n-6) is sensitive to the effect of ethanol (Reitz 1993
).
An interactive effect between ethanol and GP was observed on the
22:6(n-3) in phospholipids. Despite a relatively low level of this
fatty acid in hepatic phospholipids, its sensitivity to ethanol has
been noted in several previous studies. For example, there was a
decrease in 22:6(n-3) in the PC in mitochondria upon chronic ethanol
administration to rats (Foudin et al. 1986
). A similar
decrease in 22:6(n-3) was observed in serum PC in swine fed EtOH
(Foudin et al. 1984
) and in plasma phospholipids in
alcoholic subjects (Sun et al. 1988
). In this study, we
did not find an obvious decrease in 22:6(n-3) in the phospholipids in
the EtOH group, but a higher level of this fatty acid was found in the
EtOH + GP group. Because 22:6(n-3) is especially susceptible to
oxidative stress, the changes are likely due to the ability of GP to
protect this fatty acid from oxidative insult.
When a crude liver microsome fraction was used to determine lipid
peroxidation activity, there was a significant increase in the EtOH and
EtOH + GP groups compared with the Basal and GP groups, indicating that
GP was unable to reduce the ethanol-induced increase in lipid
peroxidation. The increase in MDA may be due to a higher amount of
triacylglycerol present in the samples from rats fed alcohol. Results
here seem to be at variance with those obtained by Roig et al. (1999)
who gave rats free access to red wine, ethanol or water
for 45 d or 6 mo. At 6 mo, MDA levels in liver were lower in the
group ingesting red wine compared with the water or ethanol groups.
Interestingly, plasma MDA levels were lower than controls in both red
wine and EtOH groups.
Histologic examination indicated no abnormal morphologic changes in
liver in the Basal and GP groups despite consumption of a high fat
diet. On the other hand, obvious morphologic changes were observed in
liver samples from the EtOH group. Many samples in the EtOH group
showed extensive disorientation of the sinusoids, loss of cellular
integrity and the appearance of lesions and lipid vacuoles.
Interestingly, GP supplementation elicited a significant improvement in
histologic scores in the EtOH + GP group compared with the EtOH group.
These results are surprising because GP did not alter the
EtOH-induced increase in hepatic lipids. Therefore, this study
demonstrated a clear distinction between ethanol-induced changes in
hepatic lipids and the ability of GP to protect hepatic cell damage.
These results are in agreement with the hypothesis that wine
consumption can offer protection to the liver against the development
of ALD (Bode et al. 1998
). Because chronic ethanol
consumption increases oxidative insult to lipids and proteins through a
number of mechanisms, it is possible that GP can protect liver damage
through events other than lipid peroxidation. Obviously, more studies
are required to examine the mechanism underlying the protective effect
of GP on liver.
Many flavonoids from plants possess antioxidant properties
(Rice-Evans et al. 1995
). Over two decades ago,
Kuhnau (1976)
recognized the importance of this class of
compounds in human nutrition and regarded them as semiessential food
components. In a recent study, solids from grapefruit juice and red
wine but not white wine were found to effectively inhibit human
cytochrome P450 3A4 present in intestine (Chan et al. 1998
). Flavonoids are capable of scavenging superoxide anions
(Robak and Gryglewski 1988
) and inhibiting NADPH
diaphorase in mouse brain (Tamura et al. 1994
). Our
results with plasma lipoproteins (Xia et al. 1998
) and
synaptic membranes (Sun et al. 1999
) seem to suggest
that GP can protect lipoproteins from oxidative insult and loss of
enzyme activities from synaptic membranes due to chronic EtOH
administration. Studies with astrocytes have demonstrated the ability
of polyphenolic compounds, e.g., resveratrol, to inhibit cytokine
induction of inducible nitric oxide synthase and secretory
phospholipase A2 (Li and Sun 1998
). However,
administration of resveratrol alone did not protect the liver from the
effects of ethanol (French et al. 1998
). On the other
hand, in a population study, wine consumption was negatively correlated
with the consumption of pig products and beer (Bode et al. 1998
). There is also evidence that isoflavonoids, such as those
extracted from Pueraria lobata, could shorten sleep time
and suppress alcohol consumption in the group of rats that demonstrated
an alcohol preference (Lin et al. 1996
, Xie et al. 1994
).
In summary, results from this study illustrate the changes in morphology and lipids in rat liver resulting from chronic ethanol ingestion and indicate that although dietary supplementation of GP did not alter ethanol-induced lipid changes, it partially prevented ethanol-induced changes in hepatic morphology.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: ALD, alcoholic liver
disease; BAC, blood alcohol concentration; EtOH, ethanol; GLC,
gas-liquid chromatography; GP, grape polyphenols; HPTLC, high
performance thin layer chromatography; L-D, Leiber-DeCarlie; MDA,
malondialdehyde; PC, phosphatidylcholine; PE, phosphatidylethanolamine;
PI, phosphatidylinositol; PS, phosphatidylserine; TBA, thiobarbituric
acid.
Manuscript received February 3, 1999. Initial review completed March 5, 1999. Revision accepted July 4, 1999.
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