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Department of Internal and Occupational Medicine (DIMIL), University of Bari, 70124 Bari, Italy;
*
Departments of Internal Medicine, Cardioangiology and Hepatology and
Surgical, Anesthesiological and Transplant Sciences, University of Bologna, Policlinico S.Orsola, 40138 Bologna, Italy
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSLiver injuryBiochemical variablesDISCUSSIONREFERENCES |
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-tocopherol, thiobarbituric acid-reactive
substances (TBARS) and protein carbonyls (PC) were measured. Fed rats
with FL had significantly greater TBARS and lower -tocopherol and
vitamin C levels than those with CL, whereas GSH and PC concentrations
were not affected. Starvation impaired the oxidative balance in both
groups. However, compared with the other groups, FL from
food-deprived rats generally had the lowest hepatic concentrations
of -tocopherol, vitamin C and GSH. Unlike in CL, protein oxidation
occurred in FL. These data indicate that fatty liver induced by
consumption of a choline-deficient diet is associated with a lower
level of antioxidants, which results in lipid peroxidation. Starvation
further affects these alterations and extends the damage to proteins.
In conclusion, steatosis and starvation may act synergistically on the
depletion of antioxidants, predisposing fatty livers to a reduced
tolerance to oxidative injury.
KEY WORDS: • antioxidants • carbonyl proteins • choline-deficient diet • lipid peroxidation • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSLiver injuryBiochemical variablesDISCUSSIONREFERENCES |
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). Several human conditions are associated with fat
infiltration of the liver, such as chronic consumption of ethanol or
some medications, hyperlipidemia and diabetes (Alpers et al. 1993
).
Fatty infiltration, in the absence of concomitant inflammation or
fibrosis, is generally considered an innocuous and reversible
condition. Indeed, hepatocellular function is preserved globally in
steatotic livers (Alpers et al. 1993
). However, early
graft failure after liver transplantation, the so-called primary
nonfunction
(PNF),3
is much more frequent when donor fatty livers (FL) are transplanted
(Strasberg et al. 1994
). For this reason, surgeons
discard a considerable number of procured donor livers because they are
fatty. Safe transplantation of steatotic livers might expand the donor
pool and reduce the mortality of patients waiting for a liver
transplant (Trevisani et al. 1996
). Although clinical
and experimental observations clearly indicate that the high incidence
of PNF is due to a reduced tolerance of FL to the
ischemia-reperfusion injury occurring during the transplant
procedure (Adam et al. 1991
, D’Alessandro et al. 1991
, Husberg et al. 1994
, Nakano et al. 1997
, Teramoto et al. 1993
), the intracellular
disorders, which are causative of or consequent to lipid accumulation
and which predispose FL to this injury, are understood only partially.
Evidence of an increased generation of reactive oxygen species (ROS)
has been described in several animals models of FL, including alcohol
administration (Lieber, 1988
), caffeine administration
(Dianzani et al. 1991
) and various
lipotrope-deficient diets (Ghoshal and Farber 1993
).
Thus, conditions depleting the cellular content of free radical
scavengers may increase the vulnerability of FL cells to oxidative
injury. In normal livers, prolonged fasting is known to affect the
antioxidant capacity of the cell (Martensson 1986
)
because of the lack of cysteine and precursor amino acids for the
glutathione (GSH) synthesis (Shimizu and Morita 1992
).
Total GSH was reduced after 18 h of starvation by 39% in mouse
liver (Di Simplicio et al. 1997
). Food deprivation may
be even more deleterious in steatotic hepatocytes, which present an
alteration of the transsulfuration pathway (Pascale et al. 1982
, Sieger et al. 1982
) with decreased
sulfhydryl concentration (Poulsen et al. 1981
) and
consequent reduced detoxification capacity. However, no data are
available concerning FL.
Several experimental models of FL have been developed in rodents, such
as steatosis in genetically obese rats (Husberg et al. 1994
), or induced by alcohol administration (Lieber 1988
), lipotrope-deficient diets and choline deficiency
(Ghoshal and Farber 1993
). The absence of choline, which
is essential for the synthesis of VLDL, blocks the transport outside
the hepatocytes of triglycerides, leading to a rapid accumulation of
lipids within the cells (Ghoshal and Farber 1993
).
The aim of this study was to investigate the occurrence of oxidative stress in FL and the additional effect of food deprivation by using the experimental model of steatosis induced in rats by feeding a choline-deficient diet.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSLiver injuryBiochemical variablesDISCUSSIONREFERENCES |
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Male Wistar rats (Charles-River, Calco, LC, Italy) weighing 250–280 g,
were allowed to acclimate to the animal quarters and were given free
access to a nonpurified diet and water for 1 wk. Liver steatosis was
induced by feeding the rats a choline-deficient diet for an
additional 10 d. Control rats consumed a semipurified diet
containing adequate levels of choline. Both diets were purchased from
Dyets (Bethlem, PA) and their compositions are reported in Table 1
. All reagents used were purchased from Sigma-Aldrich, Milan, Italy.
All procedures involving rats were conducted according to the
guidelines for the care and use of laboratory animals approved by our
Institutions.
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Total glutathione (GSH).
The livers were homogenized in 0.1 mol/L potassium-phosphate buffer
(pH 7.4) containing 5 mmol/L EDTA, precipitated with 40 g/L
sulfosalicylic acid and centrifuged at 700 g for 10 min. The
supernatant was analyzed for GSH by the enzymatic method of
Tietze (1969)
.
Thiobarbituric acid-reactive substances (TBARS).
The hepatic levels of TBARS were determined with the spectrophotometric
method described by Slater and Sawyer (1971)
. Liver (
100 mg) was homogenized in 5 volumes of 180 mmol/L KCl, 50 mmol/L
Tris-HCl and 10 mmol/L EDTA (pH 7.4) containing 0.2 g/L BHT. The
homogenate was then precipitated with 10g/L tricholoroacetic acid (TCA)
and the supernatant was incubated at 100°C for 45 min with an equal
volume of 6.7 g/L thiobarbituric acid. After cooling, the supernatant
was extracted with 1 mL of n-butanol and the absorption
peak was measured at 532 nm.
Protein carbonyls.
Equal aliquots of homogenate (2 mg of proteins) were incubated for
1 h at room temperature with 1 mL of 2 g/L dinitrophenylhydrazine
(DNPH) in 2 mol/L HCl or 1 mL of 2 mol/L HCl as control blank. Next,
proteins were precipitated with 200 µL of 500 g/L TCA and washed
three times with 1:1 (wt/v) ethanol:ethylacetate and three times with
100 g/L TCA. The final precipitate was solved in 6 mol/L guanidine and
the spectrum of the DNPH vs. HCl controls was followed at 350–375 nm
(Levine et al. 1990
). The concentration of carbonyl
groups was then calculated using 21.5
(mmol/L-1)·cm-1 as
the extinction coefficient for aliphatic hydrazones.
Vitamin C.
Liver homogenates were precipitated with 30 g/L metaphosphoric acid and
centrifuged at 7,000 g for 10 min. The supernatant was adjusted to pH
3.5 with 0.44 mol/L citrate buffer and mixed with
dichlorophenolindophenol (Bhuyan and Bhuyan 1977
).
Absorbance was read spectrophotometrically at 510 nm.
-Tocopherol.
Tissue -tocopherol was determined by the use of a HPLC method with
fluorescent detection (Hatam and Kayden 1979
). The
samples were saponified in saturated KOH in a water bath (70°C),
extracted with hexane, dried under nitrogen gas and resuspended in
methanol/ascorbic acid before injection onto the chromatograph.
Excitation and emission wavelengths were 205 and 340 nm, respectively.
Total protein.
Total protein concentration in liver homogenate was determined with the
method of Lowry et al. (1951)
. The concentration of
protein in guanidine dissolved samples was determined using a
Bio-Rad protein assay kit (Bio-Rad GmbH, Munchen, Germany).
Hepatic lipids.
Total hepatic lipids were extracted from freeze-dried samples by
chloroform:methanol (2:1) and measured according to Folch et al. (1957)
. Triglycerides, total cholesterol and phospholipids in
the tissue extract were determined enzymatically in an autoanalyzer
(Hitachi 736, Tokyo, Japan) using commercial kits (Triglycerides,
Infinity Cholesterol Reagent and Reagents for inorganic phosphorous
assay, Sigma-Aldrich) and the values were compared with those obtained
from analysis by gas chromatography (HP-1, Hewlett Packard, Cernusco,
Italy).
Serum transaminases.
Blood (1 mL) was collected under anesthesia from the inferior vena cava at the time of killing (0900 h). The enzymatic assays of serum aspartate (AST) and alanine (ALT) transaminase activities were performed spectrophotometrically using a commercially available kit test (Infinity AST and ALT Reagents, Sigma-Aldrich).
Histology.
A section of liver tissue measuring 5 mm in thickness was cut from
the center of each lobe and fixed in 100 g/L buffered formalin,
processed by standard techniques and embedded in paraffin. The tissue
was cut at 4 
m and the sections were stained with
hematoxylin-eosin. The histological analysis was performed without
knowledge of the treatment.
Statistical analysis.
Statistical analysis was performed by using the Wilcoxon rank-sum test for simple comparison between groups. Data are expressed as means ± SD In all instances, P < 0.05 was considered as the minimum level of significance.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSLiver injuryBiochemical variablesDISCUSSIONREFERENCES |
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The hepatic total lipid, triglyceride, cholesterol and phospholipid
concentrations were significantly higher in rats fed the
choline-deficient diet than in rats fed the
choline-supplemented diet. Triglycerides represented the highest
proportion of lipid components of the fat vesicles (Table 2)
.
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Liver injury |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSLiver injuryBiochemical variablesDISCUSSIONREFERENCES |
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Hepatocytes and sinusoidal cells in rats fed the
choline-supplemented diet exhibited normal morphology. Liver
specimens from rats fed the choline-deficient diet showed massive
fatty infiltration, predominantly macrovesicular.
Single-cell necrosis was rarely observed. No evidence for
inflammation and/or fibrosis was present. The serum transaminase
activities in fed rats were greater in those with FL than in those with
CL (P < 0.05; Table 3
).
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Livers from fed and food-deprived rats fed the control diet did not differ structurally. In contrast, FL in rats fed the choline-deficient diet showed areas containing cells with abnormal nuclei (pyknosis, condensed chromatin pattern, irregular margins); the coalescence of 2–3 fat globules as a result of cell membrane rupture could be also identified.
Although no differences were observed in ALT between starved and fed
rats with CL, compared with the fed condition, starvation increased the
ALT level in rats with FL (P < 0.01, Table 3
). Serum
AST activities presented a similar pattern, except that starved rats
with CL had significantly higher AST than fed rats with CL.
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Biochemical variables |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSLiver injuryBiochemical variablesDISCUSSIONREFERENCES |
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FL induced by the choline-deficient diet had significantly lower
concentrations of -tocopherol (P < 0.001) and
vitamin C (P < 0.001) (Fig. 1
) compared with CL. No significant difference in the level of GSH was
noted between FL and CL (Fig. 2
). The hepatic levels of TBARS (P < 0.001) (Fig. 3
) were significantly greater and the ratios -tocopherol/total lipids
and -tocopherol/TBARs were significantly lower in steatotic livers
compared with CL (0.07 ± 0.02 vs. 1.23 ± 0.12 and 5.8
± 0.4 vs. 36.3 ± 2.6, respectively). A significant inverse
correlation (r = -0.685, P < 0.01)
was found between the -tocopherol and TBARS concentrations
(Fig. 4
). No difference between the two groups was observed in the protein
carbonyl level (Fig. 3)
.
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In CL, -tocopherol was significantly lower in food-deprived than
in fed rats (P < 0.02, Fig. 1
). The lowest vitamin C
concentrations were found in FL from starved rats (P < 0.002 vs. fatty fed and control starved). The hepatic concentrations of
GSH were significantly lower in food-deprived rats with FL than in
fed or starved rats with CL (Fig. 2)
. A lower concentration of TBARS
(Fig. 3)
was also observed in starved rats both with CL and FL compared
with fed rats with FL. In CL, starvation was associated with a
significantly lower -tocopherol/TBARS ratio (17.5 ± 1.3 vs.
36.3 ± 2.6). Starvation did not affect the ratio in rats with FL.
In CL, the concentrations of protein carbonyls did not differ between
fed and food-deprived rats. In contrast, in FL from
food-deprived rats, the level of protein carbonyls was
significantly higher than in other groups.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSLiver injuryBiochemical variablesDISCUSSIONREFERENCES |
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). In contrast, the proteins in the liver did not differ
among groups; therefore, a quantitative alteration of the protein
synthesis in rats fed the choline-deficient diet was excluded in
these experiments (Taneja et al. 1998
). Thus,
fatty degeneration induced by a choline-deficient diet has
important pathologic and biochemical similarities to fatty liver
development in humans, especially when an excessive dietary intake of
carbohydrates exists (Hoyumpa et al. 1975
). Under fed conditions, accumulation of lipids was associated with liver cell damage and lysis. On the basis of our results, it is conceivable that this event could derive, at least in part, from an alteration of the oxidative balance in FL. Starvation can further imbalance the system to such an extent as to induce a clear exacerbation of the hepatic injury as indicated by the elevation of serum transaminases and the worsening of hepatic histology observed solely in FL.
Fed animals.
The activity of vitamin C, -tocopherol and GSH in protecting
cellular macromolecules (lipids, proteins, nucleotides) from oxidant
damage is well known (Meister, 1992
, Tampo and Yonaha 1990
). This study shows that hepatic steatosis is
associated with a lower antioxidant capacity of hepatic cells,
characterized mainly by a reduced availability of -tocopherol and
vitamin C rather than of GSH. This condition exposes hepatic lipids to
an enhanced risk of oxidation. In fact, -tocopherol is the main
antioxidant involved in the protection of unsaturated lipids
(Yoshida and Kajimoto 1989
); clinical and experimental
conditions characterized by a decrease in -tocopherol are associated
with enhanced peroxidation of lipids and lipoproteins (Morel and Chisolm 1989
, Sokol et al. 1994
). In this
respect, our study reports high levels of TBARS and low
-tocopherol/total lipids and -tocopherol/TBARS ratios, which
clearly suggest that an increased production of lipid peroxides occurs
when -tocopherol decreases. In fact, this is strengthened by the
inverse correlation found between -tocopherol levels and TBARS
concentrations in the liver, irrespective of the study group
considered.
The redox state of -tocopherol depends on the availability of
reduced ascorbate (Bendich et al. 1984
), which is
decreased markedly in rat steatotic livers. The maintenance of ascorbic
acid in the reduced form is, in turn, closely associated with the
availability of reduced substrates and with the activity of
GSH-related enzymes (Martensson and Meister 1991
).
However, because GSH was not decreased in fatty livers, the low
intracellular concentration of vitamin C in FL was likely related to
increased consumption for recycling oxidized -tocopherol or to
decreased availability of reduced substrates.
Our results indicate that hepatic proteins, in contrast to lipids, are
not damaged oxidatively in steatotic livers. This is likely due to the
fact that the redox state of the proteins depends mainly on the
availability of GSH (Grattagliano et al. 1996
), and the
latter was not markedly decreased in FL.
Because choline deficiency is reported to induce a certain level of
lipid peroxidation of the polyunsaturated fatty acids contained in the
mitochondrial and nuclear membranes (Ghoshal and Farber 1993
), the exact role of fatty degeneration in these results
remains unclear. However, all of the most widely used experimental
models of liver steatosis (alcohol, caffeine,
CCl4, lipotrope-deficient diet) are
associated with increased ROS generation (Dianzani et al. 1991
, Ghoshal and Farber 1993
, Letteron et al. 1996
, Lieber 1988
, Recknagel and Ghoshal 1966
). Thus, steatosis appears to be associated with
oxidative events regardless of the specific cause. Our experimental
model is certainly representative of this hepatic condition.
Effect of starvation.
This study shows that food deprivation did not affect GSH in CL but
reduced GSH in FL. This finding deserves consideration because GSH
plays a critical role in the maintenance of the protein sulfhydryl
groups in the reduced form (Kinoshita and Merola 1973
)
and also has been reported to function as a cysteine reservoir during
starvation (Cho et al. 1981
).The utilization of GSH for
these purposes may account for the decreased concentration of GSH in
the liver as observed previously during starvation or fatigue
(Di Simplicio et al. 1997
). Interestingly, food
deprivation did not affect the concentration of GSH and the redox state
of proteins in CL; in FL, however, in which GSH was significantly
lower, a greater accumulation of oxidized proteins was noted. This
observation confirms that GSH may function in the protection of
proteins from oxidation and that the rate of protein oxidation
increases when GSH falls below certain levels (Grattagliano et al. 1996
).
Starvation lowered the concentration of hepatic -tocopherol in CL
and vitamin C in FL. In particular, the lower hepatic vitamin C in FL
of starved rats was dramatic, and this likely affected the
concentration of -tocopherol, which was also consumed to offset the
excessive peroxidation of lipids shown by the high levels of TBARS in
starved rats. On the other hand, there is also evidence that oxidized
lipids can accelerate manifestations of tocopherol deficiency, such as
the stimulation of lipid peroxidation (Fukuzawa and Sato 1975
). In agreement with these observations, the ratios
-tocopherol/total lipids and -tocopherol/TBARS resulted to be
significantly lower in starved than in fed rats.
Taken together, all these findings support the hypothesis that hepatic steatosis is characterized by a decreased availability of reduced substrates and antioxidants, which results in an oxidative damage to lipids. Starvation, in addition to fatty infiltration, further affects these alterations and extends the damage to proteins. In conclusion, steatosis and starvation appear to act synergistically on the depletion of antioxidants, predisposing FL to a reduced tolerance to oxidative injury.
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FOOTNOTES |
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3 Abbreviationhs used: CL, control liver; DNPH, dinitrophenylhydrazine; FL, fatty liver; GSH, glutathione; PNF, primary nonfunction; ROS, reactive oxygen species; TBARS, thiobarbituric acid-reactive substances; TCA, trichloroacetic acid.
Manuscript received November 25, 1999. Initial review completed March 1, 2000. Revision accepted April 28, 2000.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSLiver injuryBiochemical variablesDISCUSSIONREFERENCES |
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 C. Ueno, K. Fukatsu, Y. Maeshima, T. Moriya, E. Shinto, E. Hara, H. Nagayoshi, H. Hiraide, and H. Mochizuki Dietary Restriction Compromises Resistance to Gut Ischemia-Reperfusion, Despite Reduction in Circulating Leukocyte Activation JPEN J Parenter Enteral Nutr, September 1, 2005; 29(5): 345 - 352. [Abstract] [Full Text] [PDF]
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 A. Wu, X. Sun, F. Wan, and Y. Liu Modulations by dietary restriction on antioxidant enzymes and lipid peroxidation in developing mice J Appl Physiol, March 1, 2003; 94(3): 947 - 952. [Abstract] [Full Text] [PDF]
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 A. Wu, F. Wan, X. Sun, and Y. Liu Effects of Dietary Restriction on Growth, Neurobehavior, and Reproduction in Developing Kunmin Mice Toxicol. Sci., December 1, 2002; 70(2): 238 - 244. [Abstract] [Full Text] [PDF]
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