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Acta Biochim Biophys |
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doi:10.1111/j.1745-7270.2005.00081.x |
Effects of Shark Hepatic Stimulator Substance on the Function and
Antioxidant Capacity of Liver Mitochondria in an Animal Model of Acute Liver
Injury
Qiu-Ling FAN1,2, Cai-Guo HUANG2*, Yan JIN2, Bo FENG2,
Hui-Nan MIAO2, Wen-Jie LI2, Bing-Hua JIAO2,
and Qin-Sheng YUAN1*
1
State
Key Laboratory of Bioreactor Engineering, East China University of Science and
Technology, Shanghai 200237, China;
2
Department
of Biochemistry and Molecular Biology, Second Military Medical University,
Shanghai 200433, China
Received: January
5, 2005
Accepted: June 20,
2005
This work was supported
by a grant from the SK Research and Development Foundation of Shanghai (No.
2003003-S)
*Corresponding
authors:
Qin-Sheng YUAN:
Tel, 86-21-64252255; Fax, 86-21-64252255; E-mail, [email protected]
Cai-Guo HUANG:
Tel, 86-21-25071457; Fax, 86-21-65334344; E-mail, [email protected]
Abstract This study was carried
out to investigate whether shark hepatic stimulator substance (HSS) can prevent
acute liver injury and affect mitochondrial function and antioxidant defenses in
a rat model of thioacetamide (TAA)-induced liver injury. The acute liver injury
was induced by two intraperitoneal injections of TAA (400 mg/kg) in a 24 h
interval. In the TAA plus shark HSS group, rats were treated with shark HSS (80
mg/kg) 1 h prior to each TAA injection. In this group, serum liver enzyme
activities were significantly lower than those in the TAA group. The
mitochondrial respiratory control ratio was improved, and the mitochondrial
respiratory enzyme activities were increased in the TAA plus shark HSS group.
The mitochondrial antioxidant enzyme activities and glutathione level were
higher in the TAA plus shark HSS group than in the TAA group. These results
suggest that the protective effect of shark HSS against TAA-induced acute liver
injury may be a result of the restoration of the mitochondrial respiratory
function and antioxidant defenses and decreased oxygen stress.
Key words shark hepatic stimulator
substance; acute liver injury; mitochondrion; respiratory function; antioxidant
capacity
There is ample growing evidence suggesting that the altered
mitochondrial function and morphology are linked to liver diseases. The hepatic
mitochondrial function is impaired in rats with CCl4-induced
cirrhosis as a result of the reduced mitochondrial volume and impaired
metabolism of the remaining mitochondria [1]. Mitochondria extracted from the
rat liver 24 h after treatment with CCl4 were shown to
have lost their respiratory control ability [2].
Energy required for all cellular processes is supplied by
mitochondria through the process of oxidative phosphorylation, and reactive
oxygen species (ROS) are formed as by-products [3]. The mitochondrion is a
major source of ROS within eukaryotic cells [4]. ROS can react with cellular
components, especially membrane lipids, and lead to cell damage [5]. In a
normal liver, the level of ROS is low, and antioxidant defenses are adequate to
protect the liver from oxidative damage [6]. However, this delicate balance
can be broken easily, leading to cellular dysfunction [7,8]. Mitochondrial
dysfunction is accompanied by the increase in the release of ROS [9,10], the
oxidative alteration of membrane proteins and lipids [11] and the decrease in
ATP production [8].
Hepatic stimulator substance (HSS) is a heat-stable, alcohol-precipitable
extract, which was first extracted from the cytosol of regenerating adult rat
livers and normal livers of weanling rats. HSS is a progression factor for
replication of hepatocytes in vivo and in vitro [12–14]. In comparison
with other growth factors, HSS is organ-specific, but not species-specific
[15,16]. It has been found to be able to stimulate liver regeneration when
injected intraperitoneally into partially (34%) hepatectomized rats
[13,17,18]. HSS plays an important role in the regenerative process triggered
by acute hepatic injury or partial hepatectomy. Recently, HSS has been shown to
protect the liver from failure induced by chemical poisons or drugs, such as
CCl4, D-galactosamine, cadmium, acetaminophen, thioacetamide
(TAA) or ethanol [12,19–27]. Acute administration of TAA has been reported to cause hepatic
centrilobular necrosis, triggering a regenerative process [28,29], while
chronic administration of TAA may induce biliary carcinoma and liver cirrhosis
in rats [30]. The administration of HSS enhances the hepatocyte proliferative
capacity, induced by TAA treatment, and is dependent on the duration of its
administration [25]. Compared with normal livers, cirrhotic livers have
diminished oxidative phosphorylation capabilities caused by changes in
nicotinamide adenine dinucleotide-reduced (NADH) and FADH2-linked
respiration as well as impaired antioxidant defenses following partial
hepatectomy [3]. Shark HSS protects hepatocytes from acetaminophen-induced
acute hepatic injury [21]. As liver regeneration requires a lot of energy and
control of oxidative stress, we postulated that the administration of shark
HSS could also influence liver mitochondrial function and antioxidant
capacity.
In the present study, we investigated the effects of shark HSS on
the function and antioxidant capacity of liver mitochondria in an animal model
of acute liver injury.
Materials and Methods
Materials
Sucrose, D-mannitol and Tris-(hydroxymethyl)aminomethane
were obtained from Amresco (Boise, USA). NADH, cytochrome c and rotenone were
purchased from Sigma (St. Louis, USA). The ATPase assay kit, glutathione (GSH)
assay kit, superoxide dismutase assay kit, glutathione peroxidase assay kit,
glutathione reductase assay kit, and malondialdehyde assay kit were purchased
from Nanjing Jiancheng Bioengineering Institute (Nanjing, China). Other
chemicals were purchased from China National Medicine Group Shanghai Chemical
Reagent Company (Shanghai, China).
Animals and treatment
Male Sprague-Dawley (SD) rats were obtained from Fudan University
(Shanghai, China). The animals, weighing 180–220 g each, were fed ad
libitum and kept at constant room temperature (22–25 ºC) with 12 h of light exposure (8:00–20:00) and 12 h of darkness
(20:00–8:00). All animals received humane care in compliance with the
International Guiding Principles for Animal Research. All procedures were
performed under diethylether anesthesia between 7:00 and 10:00, and the animals
were fasted for 12 h before the procedures. The animals were grouped as
following: (1) control group, intraperitoneal administration of 0.9% sodium
chloride; (2) TAA group, two intraperitoneal injections of TAA (400 mg/kg body
weight) in a 24 h interval; (3) TAA plus shark HSS group, two intraperitoneal
injections of shark HSS (80 mg/kg body weight) in a 24 h interval followed by a
TAA intraperitoneal injection (400 mg/kg body weight) 1 h after each injection
of shark HSS; and (4) shark HSS group, intraperitoneal injection of one dose of
shark HSS. The animals in each group were killed at 0 h, 12 h, 24 h, 36 h or 48
h after the final injection. Immediately after exsanguination, each liver was
removed, cleaned and weighed. A small portion of each liver was then immersed
in buffered Formalin solution for histological examination, and the remaining
portion was immediately used for mitochondria preparation.
Determination of serum enzyme activities
Serum enzyme activities of aspartic aminotransferase (AST) and
alanine aminotransferase (ALT) were assayed by an automated analysis system
(Hitachi 7600-020; Hitachi, Japan).
Preparation of liver mitochondria
The livers were quickly removed, chopped into small pieces and placed
in ice-cold isolation buffer for mitochondria (10 mM Tris-HCl, pH 7.4, 250 mM
sucrose, 0.5 mM EDTA and 0.5% bovine serum albumin). After being homogenized,
the homogenate was centrifuged at 750 g for 10 min. Next, 2 ml of the
supernatant was stored at –80 ºC and used for determination of hepatic glutathione. The
remainder was centrifuged at 10,000 g for 10 min. The mitochondrial
pellet was washed twice with isolation buffer, and then resuspended in the same
buffer solution. The freshly prepared mitochondria were used to determine the
respiratory control ratio (RCR), ADP/O ratio and mitochondrial membrane
potential. The submitochondrial particles were prepared by freezing and thawing
the mitochondrial suspension.
Preparation of shark HSS
Shark HSS was prepared from the livers of immature sharks according
to the procedures described by LaBrecque et al. [31,32] and Fleig et
al. [13]. In brief, the livers were homogenized in ice-cold 0.9% sodium
chloride at 35:100 (W/V) using an electric homogenizer. The
homogenate was incubated at 65 ºC in a water bath for 15 min, and the insoluble
material was removed by centrifugation at 27,000 g and 4 ºC for 20 min.
Six volumes of ice-cold 40% ethanol were added to the supernatant and stirred
at 4 ºC for 2 h. After centrifugation at 27,000 g and 4 ºC for 20 min,
the precipitate was dissolved in water. The insoluble material was
precipitated by centrifugation at 27,000 g and 4 ºC for 20 min, and the
supernatant was collected, lyophilized and stored at –80 ºC. The frozen shark HSS was used within 15 d of preparation.
Determination of the respiratory control and ADP/O ratios
The RCR and ADP/O ratio were determined polarographically using a
Clark oxygen electrode (Hansatech, Pentney, UK) [33]. A mitochondrial suspension
containing 2.5 mg of protein was added to 2.5 ml of reaction buffer containing
225 mM mannitol, 75 mM sucrose, 10 mM Tris-HCl, and 5 mM Tris-H3PO4.
Oxygen consumption was measured in the absence (giving the state 4 activity)
and presence (giving the state 3 activity) of 0.25 mM ADP. Glutamate (10 mM)
and malate (10 mM) were used as the substrate for site I (NADH-linked
respiration), and 20 mM succinate for site II (FADH2-linked
respiration). The RCR was expressed as the ratio of state 3 to state 4 respiration,
while the ADP/O ratio was expressed as the ratio of ADP to oxygen atoms
consumed during state 3 respiration.
Enzyme assay of mitochondrial electron transport system
The activities of NADH-cytochrome c reductase (NCCR), succinate-cytochrome
c reductase (SCCR) and cytochrome c oxidase (CCO) were measured using the
method described by Yang et al. [3]. For the determination of NCCR
activity, 5 mg of submitochondrial particles was added to 1 ml of buffer
containing 25 mM potassium phosphate (pH 7.4), 2.5 mg/ml bovine serum albumin,
5 mM MgCl2, 10 mM ferricytochrome c and 2 mM KCN. The reaction was started by
the addition of 25 mM NADH and followed by reduction of ferricytochrome c, and
recorded at 25 ºC at 550 nm for 3 min. For the determination of SCCR
activity, 5 mg of submitochondrial particles was added to 1 ml of 50 mM
potassium phosphate (pH 7.4), 20 mM succinate, 10 mM ferricytochrome c, 2 mg/ml
rotenone and 2 mM KCN at room temperature. The change in absorbance at 550 nm
was recorded at 25 ºC for 5 min. For the determination of CCO activity, 5 mg of
submitochondrial particles was added to 1 ml of 50 mM potassium phosphate (pH
7.4) and 10 mM ferricytochrome c. The change in absorbance at 550 nm was
recorded at 25 ºC for 5 min. The extinction coefficient of cytochrome c was 19
per mM∙cm. Mitochondrial ATPase activity was assessed using an assay kit
according to the manufacturer’s instructions.
Mitochondrial antioxidant defenses
The activities of mitochondrial superoxide dismutase (SOD),
glutathione peroxidase (GPx) and glutathione reductase (GRd), and hepatic and
mitochondrial GSH levels were determined using an assay kit according to the
manufacturer’s instructions.
Measurement of lipid peroxidation products
The concentrations of malondialdehyde (MDA) in the liver and
mitochondria, measured spectrophotometrically at 532 nm, were used to quantify
the mitochondrial and homogenate lipid peroxidation (LPO) products using an
assay kit according to the manufacturer’s instructions.
Statistical analysis
The results were given in
mean±SE. All observations were made on at least eight
animals, and the assays were performed twice. One-way analysis of variance and
the unpaired Student’s t-test were used for the statistical analysis of
the results. P<0.05 was considered to be significant.
Results
Serum enzyme activities
Serum AST and ALT were used as indices of TAA-induced hepatotoxicity.
Both AST and ALT activities were dramatically increased at all stages of the
second TAA administration, and peaked at 24 h in the TAA group compared with
the control group (P<0.05). The administration of TAA plus shark HSS
significantly reduced serum AST and ALT activities compared with the TAA group
at 12 h to 48 h (P<0.05) (Fig. 1). No differences were
observed between the AST and ALT activities of the shark HSS and control
groups.
Mitochondrial substrate oxidation
Decreased mitochondrial oxidation of both glutamate-malate and
succinate in the presence of ADP (state 3) was observed at all stages examined
after the second TAA administration, with significant changes in the ADP/O
ratio at all stages for glutamate-malate and only at 24 h for succinate. These
effects led to weakened mitochondrial control ratios [Fig. 2(B–D)] compared with the control group (P<0.05).
The administration of shark HSS elicited an increase in oxidation of ADP (state
3) at 12 h to 36 h for glutamate-malate, and at 0 h and 24 h to 48 h for
succinate, resulting in an increased RCR at all stages for glutamate-malate and
at 12 h to 48 h for substrates [Fig. 2(C)] (P<0.05).
Enzyme activities of the mitochondrial electron transport system
Mitochondria isolated from the TAA group showed significant
decreases in NCCR activity (only at 12 h), SCCR activity (at 24 h to 36 h), CCO
activity (at 0 h and 48 h) and ATPase activity (at 12 h to 48 h) compared with
the control group (Fig. 3) (P<0.05). Significant enhancement
of SCCR activity (at 24 h and 36 h), CCO activity (at all stages) and ATPase
activity (at 12 h to 36 h) was observed in mitochondria from the TAA plus
shark HSS group compared with those from the TAA group (Fig. 3) (P<0.05).
Mitochondrial antioxidant capacity
Within the mitochondria, the activities of antioxidant enzymes,
including SOD, GPx and GRd, as well as mitochondrial GSH levels were assayed.
Mitochondrial GRd activities at all stages examined were significantly reduced
in the TAA group compared to the control group [Fig. 4(B)] (P<0.05).
However, mitochondrial GPx and SOD activities in the TAA group had no
significant difference from those in the control group for the duration of the
study [Fig. 4(A,C)]. But the administration of shark HSS prior to the
second dose of TAA enhanced mitochondrial GPx activity (all stages), GRd
activity (at 12 h to 48 h) and SOD activity (at 0 h and 24 h to 48 h) compared
with the corresponding activities in the TAA group (Fig. 4) (P<0.05).
In all TAA-treated rats, the total hepatic GSH level was not significantly
different from that of the control rats, although the mitochondrial GSH level
was significantly lower at all stages examined. The hepatic GSH level in the
TAA plus shark HSS group at 0 h to 12 h and the mitochondrial GSH level at 12 h
and 36 h to 48 h were enhanced markedly, compared with those from the TAA group
(Fig. 5) (P<0.05).
Lipid peroxidation
Administration of TAA induced an increase in MDA level in the liver
at all time points examined and in mitochondria at 0 h and 48 h in TAA group
compared with control group. In TAA plus sHSS group, hepatic MDA levels at all
time points examined and mitochondrial MDA levels at 0 h to 12 h and 36 h to 48
h were significantly lower compared with TAA group (Fig. 6) (P<0.05).
Discussion
The present results show that shark HSS can protect the liver from
TAA-induced acute injury. Administration of TAA induces important alterations in
the respiratory function and antioxidant capacity of liver mitochondria,
suggesting that shark HSS can partially prevent acute injury to the liver in
TAA-treated rats by stimulating some mitochondrial pathways in liver to
increase the energy charge and by maintaining a normal mitochondrial function
in the animals administered with hepatotoxin.
After the second TAA treatment, a significant decrease in substrate
oxidation was induced in the mitochondria, especially when respiration was
stimulated by the addition of ADP [Fig. 2(B)]. This means that the
oxidative phosphorylating capacity of mitochondria was damaged, as shown by the
low RCR [Fig. 2(C)] and the diminished rate of ATP synthesis [Fig.
2(B,D)]. It is known that the mitochondrial respiration ratio is dependent
on the availability of ADP in the assay medium [34]. The respiration ratio is
very low in the absence of ADP, but it increases several times with the
addition of an appropriate amount of ADP. The mitochondria from the TAA plus
shark HSS group had a significantly higher O2 consumption
rate (state 3 respiration) and RCR compared with those from the TAA group.
Previous report [35] had shown that HSS isolated from rats can increase
mitochondrial respiratory activity, and that the protective effect induced by
HSS is correlated with restoration of mitochondrial respiratory activity
induced by CCl4. These results are consistent with our findings. Energy required
for all cellular processes is supplied by mitochondria through the process of
oxidative phosphorylation, and a series of enzyme complexes are involved in
this process that is coupled with oxidation of the electron donors. After TAA
treatment, the NCCR and SCCR activities were reduced, suggesting that
NADH-linked and FADH2-linked oxidations may be impaired, and
these coincided with a significantly lower substrate oxidation of both sites I
and II [Fig. 2(B)]. These results show that TAA-induced damage to liver
mitochondria is not site-specific. Therefore, the decrease in NAD+-linked
and succinate-supported respiration may be the result of impairment to the
activities of the respiratory chain enzymes. Shark HSS administration induced a
significant increase in respiratory enzyme activities compared with that in the
TAA group, suggesting that the stimulatory effect of shark HSS on the
oxidative phosphorylation system might be mediated by an activation or
induction of different enzyme complexes involved in this process. These
results comply with the fact that electron flow through the respiratory chain
also regulates the oxidative phosphorylation process, specifically the
irreversible reaction catalyzed by cytochrome c oxidase [36].
The mitochondrial respiratory chain is one of the major sources of
detrimental free radicals in the human body [37]. Free-radical production comes
from the reaction of mitochondrial electron carriers, such as ubiquinol, with
oxygen to form superoxides [38]. Mitochondria have their own antioxidant
defenses to protect against oxidative damage, including Mn-SOD to dismutate
superoxides into hydrogen peroxide, GPx to detoxify peroxides and GRd to reduce
oxidized glutathione to maintain the mitochondrial GSH pool in a reduced state
[39]. MDA has been used as the primary indicator of oxidative stress. Other
indicators, such as Cu,Zn-SOD and Mn-SOD, have been used as secondary markers
of oxidative stress and correlate significantly with MDA [40]. The
mitochondrial GSH level in the livers of rats treated with TAA was found to be
significantly lower than that of rats in the control group, and a decrease in
mitochondrial GSH level has been associated with impairment of GRd activity
[41]. The mitochondrial GSH level and the activities of mitochondrial GPx, GRd
and SOD in the TAA plus shark HSS group were significantly higher than those in
the TAA group, indicating that shark HSS can improve mitochondrial antioxidant
defenses. Lipid peroxidation is the result of an imbalance between oxidants
and antioxidants or an impairment in the transport of GSH from cytosol to
mitochondria. An increase in oxygen free radicals has been shown to occur
during liver regeneration after partial hepatectomy [42]. In the mitochondria
isolated from TAA-treated rats, the increase in ROS may contribute to the
increase of mitochondria MDA level. Lipid peroxidation occurred in the whole
liver of rats treated with TAA, as reported previously [43–45]. Administration of shark HSS could induce a decrease in hepatic
MDA level and suppress hepatic lipid peroxidation (Fig. 6).
The present study has shown that acute liver injury induced by TAA
is a result of an impairment to the mitochondrial respiratory function and
antioxidant capacity and hepatic lipid peroxidation, which can be partially
prevented by the administration of shark HSS. This suggests that shark HSS
may be used for the treatment of clinical liver disease.
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