Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 481 and Centre Claude Bernard de Recherches sur les Hépatites Virales, Hôpital Beaujon, 92118 Clichy, France
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ABSTRACT |
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Rich
diet and lack of exercise are causing a surge in the prevalence of
obesity and hepatic steatosis, which causes "primary" steatohepatitis in some patients. Ultrastructural mitochondrial lesions, decreased activity of respiratory chain complexes, and impaired ability to synthesize ATP are observed in these patients. Reactive oxygen species (ROS) may increase tumor necrosis factor- (TNF-
) production and also oxidize fat deposits. TNF-
and lipid peroxidation products impair the flow of electrons along the
respiratory chain, causing overreduction of respiratory chain
components and enhanced mitochondrial ROS formation. Steatohepatitis
can also be due to alcohol, drugs, or other causes that either directly increase ROS formation or first impair respiration, which secondarily increases ROS formation. Higher ROS formation in secondary
steatohepatitis could cause more lipid peroxidation, cytokine
induction, and fibrogenesis than in primary steatohepatitis.
mitochondria; hepatitis; reactive oxygen species; superoxide dismutase
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INTRODUCTION |
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DUE TO A RICH DIET and lack of exercise, the populations of affluent countries are becoming increasingly obese, with a concomitant increase in the prevalence of hepatic steatosis, characterized by the accumulation of fat droplets within the cytoplasm of hepatocytes (19). Patients with this "primary" form of steatosis exhibit various combinations of central obesity, diabetes, and hypertriglyceridemia, with insulin resistance as the common feature (19). In some patients, this hepatic steatosis remains isolated (without other liver lesions). In other patients, however, it triggers mild liver cell necrosis, a mild inflammatory cell infiltrate, and the slow development of hepatic fibrosis that can progressively evolve into cirrhosis of the liver over a period of many years (19). The association of steatosis with these other liver lesions is called steatohepatitis (19).
In addition to this primary form, there are also several "secondary" forms of hepatic steatosis and steatohepatitis, including alcohol abuse, some drugs, Wilson's disease, jejunoileal bypass, or total parenteral nutrition (19). Steatohepatitis tends to be more severe in these secondary cases (19).
The purposes of this short review are to 1) recall the role of mitochondria in fat metabolism and energy production and the modifications of fat and glucose metabolism that occur in obese persons, 2) present evidence for mitochondrial dysfunction in patients with steatohepatitis or obese animals, and 3) discuss the possible mechanisms of these mitochondrial alterations and possible implications in pathogenesis. Additional references may be found in a previous review (19).
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ROLE OF MITOCHONDRIA IN FAT METABOLISM AND ENERGY PRODUCTION |
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Hepatic free fatty acids (FFAs) are synthesized de novo within the
hepatocytes, are taken up by the liver from plasma FFAs released by
adipose tissue, or are generated in the liver from the hydrolysis of
chylomicrons from the intestine (Fig. 1)
(19). These hepatic FFAs either enter mitochondria to
undergo mitochondrial -oxidation or are esterified into
triglycerides (a storage form of 3 FFA molecules bound by ester bonds
to glycerol) (18). These hepatic triglycerides, in turn,
either accumulate as fat droplets (surrounded by a single monolayer of
phospholipids) within the cytoplasm of hepatocytes or are secreted as
very low-density lipoproteins (VLDL), a droplet of triglycerides (and
cholesterol esters) surrounded by phospholipids and a large protein
termed apolipoprotein-B.
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The entry of long-chain FFAs into the mitochondria is critically
dependent on carnitine palmitoyl transferase I (CPT-I; Fig. 1), an
outer membrane enzyme whose activity is inhibited by malonyl-CoA (18). Malonyl-CoA is formed by acetyl-CoA carboxylase and
is the first step in the synthesis of fatty acids from acetyl-CoA (18). After a carbohydrate meal, high glucose and insulin
levels cause brisk hepatic fatty acid synthesis (18). High
malonyl-CoA levels inhibit CPT-I and thus FFA entry into mitochondria
and -oxidation (18). FFAs are not degraded and are
instead directed toward the formation of triglycerides, which are
secreted as VLDL (18). In contrast, in the fasting state,
FFAs are released by adipose tissue and taken up by the liver. Hepatic
FFA synthesis and thus malonyl-CoA levels are low, permitting extensive
mitochondrial import of FFAs and extensive
-oxidation. Successive
-oxidation cycles split FFAs into acetyl-CoA subunits. Although
acetyl-CoA can then be completely degraded to CO2 by the
tricarboxylic acid cycle, during fasting conditions acetyl-CoA is
mostly condensed into ketone bodies that are secreted by the liver to
be oxidized in muscles and other peripheral tissues (18).
The oxidation of FFAs in mitochondria and of other fuels both elsewhere and in mitochondria is associated with the conversion of oxidized cofactors (NAD+ and FAD) into reduced cofactors (NADH and FADH2, Fig. 1) (19). These reduced cofactors are then reoxidized by the mitochondrial respiratory chain, which regenerates the NAD+ and FAD necessary for other cycles of fuel oxidation (19).
During their reoxidation, NADH and FADH2 transfer their electrons to the first complexes of the respiratory chain. A fraction of these electrons directly reacts with oxygen to form the superoxide anion radical and other reactive oxygen species (ROS) (19). Most electrons, however, migrate all the way along the respiratory chain, up to cytochrome-c oxidase, where they safely combine with oxygen and protons to form water (Fig. 1) (19). This transfer of electrons along the respiratory chain is coupled with the extrusion of protons from the mitochondrial matrix into the mitochondrial intermembrane space. This creates a large electrochemical potential across the inner membrane, thus creating a reservoir of latent, potential energy (19). When energy is needed, protons reenter the matrix through the F0 portion of ATP synthase, causing the rotation of a molecular rotor in the F1 portion of ATP synthase and the conversion of ADP into ATP. The adenine nucleotide translocator then extrudes the formed mitochondrial ATP in exchange for cytosolic ADP (19). Cytoplasmic ATP is then used to power all the cell processes that require energy.
Although this whole process was well adapted to finely tune energy storage and disposal under conditions that prevailed in the past, it is no longer adapted to the new lifestyle habits that have been spreading in affluent countries.
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OBESITY AND CHANGES IN FAT AND GLUCOSE METABOLISMS |
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In the past, prolonged overeating was self-regulating, because excess weight soon impaired the physical fitness required to gather food and handle predators or foes (19). For the first time in history, a large fraction of the population in affluent countries can concomitantly indulge in rich food and physical idleness, causing a surge in obesity (19). About 22.5% of United States citizens are obese, and this prevalence could reach 40% by the year 2025 (19) unless drastic lifestyle changes can curb present trends.
Not only does obesity cause the engorgement of adipocytes with
triglycerides, it also modifies fat repartition and glucose metabolism
in the whole body (Fig. 2). Obesity
increases plasma FFAs, hepatic FFAs, hepatic triglycerides, and plasma
triglycerides and also causes resistance to the action of insulin, a
pancreatic hormone whose main role is to mediate the translocation of
glucose receptors from the interior of the cell up to the plasma
membrane of adipocytes and muscle cells, thus promoting the cellular
uptake and utilization of glucose in these tissues (22).
In obese persons, insulin resistance tends to increase blood glucose
levels, which causes a compensatory increase in the release of insulin
by pancreatic -cells (the insulin-secreting cells of the pancreas).
In some subjects, however, this compensatory increase is not enough or, secondarily, fails, and diabetes develops (19).
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How obesity triggers this wide range of changes is not yet totally understood. Ironically, the answer may be found in transgenic mice that lack adipose tissue (9). These lipoatrophic mice have very little white adipose tissue and develop increased plasma FFA levels, fatty liver, raised plasma triglycerides, insulin resistance, and raised blood glucose levels, thus mimicking features found in obese persons (9). Transplantation of small adipocytes from young, wild-type mice into these transgenic mice causes glucose uptake by the transplanted adipocytes, improves glucose uptake by muscles, and decreases serum FFAs, triglycerides, glucose, and insulin (9). These beneficial effects, however, tend to wear off after several weeks, possibly due to enlargement/engorgement of the transplanted adipocytes (9). What fatless mice and overweight people could have in common is decreased adipocyte storing reserve (19). Normally, the adipocytes in thin people store fat after meals and later release FFAs during fasting. In obese persons, fat-engorged adipocytes may continue to release FFAs in the immediate postprandial period, despite high insulin levels (which normally would block adipocyte lipolysis in lean people) (19).
The sustained release of FFAs by adipocytes augments plasma FFAs, thus increasing FFA uptake by the liver (Fig. 2). At the same time, the high insulin and glucose levels due to insulin resistance may increase hepatic FFA synthesis from glucose (Fig. 2) (11). Thus both an increased uptake of FFAs from the adipose tissue and increased synthesis of FFAs in the liver may add their effects to increase hepatic FFAs (Fig. 2).
This increased load of hepatic FFAs causes an increase in hepatic
mitochondrial -oxidation (Fig. 2) (21). Although both insulin and malonyl-CoA tend to decrease CPT-I activity in lean persons, these effects might not occur in insulin-resistant obese persons. In diabetic BB Wistar rats, the activity of CPT-I is markedly
increased, and, furthermore, its sensitivity to inhibition by
malonyl-CoA is also markedly decreased (5). If similar
effects occur in insulin-resistant obese persons, these CPT-I changes might permit high FFA mitochondrial import and
-oxidation, despite high insulin and malonyl-CoA levels.
Although mitochondrial -oxidation is increased in obese patients
with nonalcoholic steatohepatitis (NASH) (21), this is not
sufficient to handle the increased load of hepatic FFAs (Fig. 2)
(19). The remaining FFAs are converted into
triglycerides, which are partly stored in the cytoplasm, causing
steatosis, and partly secreted into the plasma as VLDL, causing
hypertriglyceridemia (Fig. 2) (19). Whereas insulin tends
to decrease hepatic VLDL secretion in normal persons, this effect does
not occur in obesity-associated diabetes mellitus, probably due to
resistance to this normal action of insulin (19).
Although the mechanism for insulin resistance has not been completely clarified, it may be due, in part, to a defect in the insulin-mediated uptake of glucose into adipocytes and myocytes (22). In adipocytes, the synthesis of the glucose transporter is decreased; in myocytes, this synthesis is normal, but the transport of the glucose transporter to the plasma membrane is decreased, perhaps due to the accumulation of triglycerides within myocytes (22).
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LIVER INJURY, OXIDATIVE STRESS AND MITOCHONDRIAL DYSFUNCTION IN OBESE PERSONS AND OBESE MICE |
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The increasing proportion of overweight people has caused a concomitant surge in the prevalence of fatty liver. Hepatic steatosis has become the main cause of liver test abnormalities in adolescents and the second or third cause in adults (19). In some patients, this steatosis remains isolated (without other liver lesions) and has no severe clinical consequences. In other overweight persons, however, liver lesions develop that resemble but are milder than those observed in alcoholic patients and are called NASH (19). These NASH lesions include not only steatosis, but also mild liver cell necrosis, a mild inflammatory cell infiltrate, as well as fibrosis, which can progressively evolve into cirrhosis (19).
Patients with NASH due to the obesity/hypertriglyceridemia/insulin resistance syndrome exhibit ultrastructural mitochondrial lesions (with the presence of linear crystalline inclusions in megamitochondria) (21). Activity of respiratory chain complexes is decreased (20); hepatic ATP levels tend to be low, and these patients slowly resynthesize ATP in vivo after a fructose challenge that causes acute hepatic ATP depletion (6). Finally, they may develop oxidative stress-mediated deletions of mitochondrial DNA (a genome that is located in the mitochondrial matrix and encodes some of the polypeptides of the mitochondrial respiratory chain) (2).
Genetically obese ob/ob mice have increased hepatic FFA synthesis from
glucose (11), increased hepatic triglyceride levels (15), increased hepatic lipid peroxidation (i.e., the
oxidation of fat deposits by ROS), decreased hepatic mitochondrial
content of cytochrome c (one of the components of the
respiratory chain) (25), increased production of ROS by
hepatic mitochondria (25), and decreased hepatic ATP
levels (3, 15). These ob/ob mice also have increased
hepatic levels of tumor necrosis factor- (TNF-
)
(15), increased hepatic FFA levels (24),
increased levels of an uncoupling protein 2-like protein
(3), as well as a slightly increased proton leak (i.e., a
direct reentry of protons through the inner membrane, which bypasses
ATP synthase and tends to decrease ATP formation) (3).
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POSSIBLE MECHANISMS FOR MITOCHONDRIAL DYSFUNCTION IN PRIMARY STEATOHEPATITIS |
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Although the mechanisms for mitochondrial alterations are not
completely understood, they could involve FFAs, lipid peroxidation, and
TNF-.
Mild uncoupling of mitochondrial respiration by FFAs.
FFAs are increased in the livers of ob/ob mice (24) and
could uncouple respiration from ATP formation. FFAs are weak acids which exist in an equilibrium of the ionized species
(RCOO) and the protonated, uncharged species (R-COOH). In
the acidic intermembrane space of mitochondria, this equilibrium is
displaced toward RCOOH, which is soluble within phospholipids and
easily crosses the inner mitochondrial membrane to enter the
mitochondrial matrix. Once inside the matrix, which is more alkaline,
RCOOH dissociates into a proton and RCOO
, which may cross
back through the inner membrane through the adenine nucleotide
translocator, the dicarboxylate carrier, or uncoupling proteins
(10). An uncoupling protein 2-like protein is increased in
ob/ob mice (3) and could favor the cycling of FFAs across
the inner membrane (10). The movement of one FFA molecule
back and forth across the inner membrane therefore causes the reentry
of one proton from the intermembrane space into the matrix at each
cycle. Because ATP synthase is bypassed, the energy of respiration is
partly wasted to produce heat instead of ATP. This effect, however,
appears to be moderate in obesity (3). Although the proton
leak is slightly increased, the respiratory control ratio is not
significantly decreased in genetically obese ob/ob mice
(3).
Possible impairment of respiration by lipid peroxidation and
TNF-.
Some of the electrons that are transferred to the respiratory chain by
NADH or FADH2 directly react with oxygen to form the superoxide anion, which is transformed into
H2O2 by mitochondrial manganese superoxide
dismutase (MnSOD) (19). Mitochondria are the most
important cellular source of ROS, which oxidize the unsaturated lipids
of fat deposits to cause lipid peroxidation (Fig.
3) (19). In mice, acute or
chronic steatosis due to 11 different treatments was always associated
with lipid peroxidation, as indicated by increased ethane exhalation
(an in vivo index of lipid peroxidation) and increased hepatic
thiobarbituric acid reactants (14). After a single dose of
tetracycline or ethanol, maximal ethane exhalation occurred at the same
time as maximal hepatic triglyceride accumulation (14).
Whereas a single dose of doxycycline or glucocorticoids did not
increase hepatic triglycerides or ethane exhalation, repeated doses did (14). Extensive lipid peroxidation was also
observed in rats with steatohepatitis caused by a diet deficient in
methionine and choline (13).
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ADDED MECHANISMS OF MITOCHONDRIAL DYSFUNCTION IN SECONDARY STEATOHEPATITIS |
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In addition to the primary steatohepatitis associated with the obesity/hypertriglyceridemia/insulin resistance syndrome, secondary steatohepatitis can be triggered by alcohol abuse, certain drugs, Wilson's disease, jejunoileal bypass, and total parenteral nutrition (19). In these secondary forms, mitochondrial alterations may be more severe, because the causative disease itself directly or indirectly increases ROS formation and mitochondrial damage (19).
Alcohol abuse. Ethanol metabolism increases the NADH-to-NAD+ ratio, which may cause the reduction of ferric iron to ferrous iron, a potent generator of the hydroxyl radical (19). Ethanol also increases cytochrome P-450 2E1, which leaks ROS and forms the 1-hydroxyethyl radical. In mice, a single, high dose of ethanol causes extensive mtDNA degradation and depletion within 2 h (16). These effects are prevented by 4-methylpyrazole (blocking ethanol metabolism) or melatonin (an antioxidant) (16). During chronic alcoholism, the repetition of mtDNA strand breaks causes mtDNA deletions in humans (8). ROS-mediated mtDNA strand breaks, lipid peroxidation-generated mtDNA adducts, oxidized mtDNA bases, mtDNA depletion, and oxidation of mitochondrial proteins and lipids may partially block the transfer of electrons in the respiratory chain, and thus increase mitochondrial ROS formation in alcoholic patients (19).
Drugs.
Diethylaminoethoxyhexestrol, perhexiline, amiodarone, and tamoxifen can
cause steatohepatitis (19). These cationic amphiphilic compounds have a lipophilic moiety and an amine function that can
become protonated (19). The unprotonated, lipophilic form easily crosses the mitochondrial outer membrane and is protonated in
the acidic intermembranous space (1). This
positively charged, protonated form is "pushed" inside
mitochondria by the high electrochemical potential existing across the
mitochondrial inner membrane and thus reaches high intramitochondrial
concentrations (1). These high concentrations inhibit
-oxidation (causing steatosis) and block the transfer of electrons
along the respiratory chain (1). Intermediary respiratory
chain components become overly reduced and increasingly transfer their
electrons to oxygen to form the superoxide anion radical and other ROS
(1).
Wilson's disease. Wilson's disease can also cause steatohepatitis (19). Wilson's disease is caused by diverse mutations of a nuclear gene encoding a copper transporting P-type ATPase (17). Decreased biliary elimination of copper causes progressive accumulation within hepatocytes. Copper may cycle between the oxidized and the reduced states, thus generating the hydroxyl radical. Copper forms Cu-DNA complexes, so ROS are generated close to DNA, making it an elective target (17). Finally, copper selectively accumulates within mitochondria during copper overload so that mtDNA is particularly affected (17). Despite their young age, one-half of patients with Wilson's disease already had one or several mtDNA deletion(s), whereas only 3% of older controls carried one mtDNA deletion (17). Mitochondrial ROS also target proteins, and patients with Wilson's disease have decreased activity of respiratory chain complexes, which may further increase mitochondrial ROS formation (19).
Jejunoileal bypasss and total parenteral nutrition. Although nutritional deficits or imbalances may play an important role in these conditions, bacterial proliferation in the excluded/unused intestine may release endotoxins, cytokines, and nitric oxide, which all impair mitochondrial respiration thus secondarily increasing ROS formation (19).
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IMPLICATIONS IN FIBROGENESIS AND NECROINFLAMMATION |
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Thus enhanced mitochondrial ROS formation may occur in all causes
of primary or secondary steatohepatitis. In primary steatohepatitis, this may be due to several vicious cycles involving steatosis, lipid
peroxidation, mitochondrial damage, enchanced ROS formation, increased
TNF-, and depletion of antioxidants (Fig. 3).
In secondary steatohepatitis, the situation is even worse, because the causative disease itself either directly increases ROS formation (e.g., alcohol abuse or Wilson's disease) or first impairs the transfer of electrons along the mitochondrial respiratory chain, which secondarily increases mitochondrial ROS formation (e.g., steatohepatitis-inducing drugs and possibly jejunoileal bypass and total parenteral nutrition; Fig. 3). This added effect of the causative disease may further aggravate the increase in mitochondrial ROS formation caused by steatosis alone. This "second hit" could explain why necroinflammation is much more severe and fibrosis develops sooner in secondary steatohepatitis than in primary steatohepatitis.
In varying degrees, however, the basal mechanism might be the same, namely increased mitochondrial ROS formation. This could trigger fibrogenesis and other liver lesions due to the combined action of ROS-induced lipid peroxidation and ROS-induced-cytokine formation (19).
Fibrogenesis.
Hepatic fibrosis is due to deposition of collagen fibers synthesized by
activated hepatic stellate cells, which are located between the
hepatocytes and the endothelial cells of the hepatic sinusoids. ROS
oxidize accumulated unsaturated fatty acids, causing lipid
peroxidation, which releases reactive aldehydes (malondialdehyde and
4-hydroxynonenal) that increase hepatic fibrogenesis in two ways
(19). First, these lipid peroxidation products enhance the
hepatic production of transforming growth factor 1 (TGF-
1), which
activates hepatic stellate cells into collagen-secreting myofibroblasts. Second, lipid peroxidation products also directly enhance collagen production by hepatic stellate cells
(19).
Necroinflammatory activity.
Although necroinflammation is absent or mild in primary NASH, it can be
extensive in secondary NASH. Extensive ROS formation in secondary NASH
could play a role in necroinflammation (19). Normally,
hepatocytes express Fas (a membrane receptor) but not Fas ligand,
preventing them from killing their neighbors. However, several
conditions leading to increased ROS formation, such as drugs, alcohol
abuse, or Wilson's disease, cause Fas ligand expression by hepatocytes
so that Fas ligand on one hepatocyte can now interact with Fas on
another hepatocyte to cause fratricidal apoptosis (19). ROS also increase the synthesis of several cytokines
in the liver, particularly TNF-, which can cause both
apoptosis and necrosis (19). Indeed, TNF-
released by Kupffer cells seems to play an important role in
experimental alcohol-induced liver injury, which is attenuated by
gadolinium chloride (toxic to Kupffer cells), by the administration of
anti-TNF-
antibodies or an absence of TNF receptor-1
(19).
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IMPLICATIONS IN GENETIC SUSCEPTIBILITY |
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In both primary and secondary hepatic steatosis, the tendency of different subjects to develop steatohepatitis varies considerably (19). For the same amount of excess weight or the same alcohol consumption, some subjects only have steatosis, whereas others develop cirrhosis.
A genetic dimorphism affects the mitochondrial targeting sequence of
MnSOD, causing the incorporation of either alanine or valine at
position 9 of this presequence (7). The
alanine-containing sequence may confer an
-helical structure to the
import peptide, causing better mitochondrial import than the valine
sequence, which confers a
-sheet structure to the peptide. At least
in some animal models of ethanol intoxication (7) or
obesity (25), there is a basal imbalance between MnSOD
(which is increased by ROS) and glutathione peroxidase (which may be
inactivated by ROS). Indeed, MnSOD was increased by 70%, whereas
glutathione peroxidase activity was decreased by 30% in genetically
obese ob/ob mice (25). In patients with two
alanine-encoding MnSOD alleles, lesser MnSOD expression in the inner
mitochondrial membrane and higher expression in the mitochondrial
matrix may further increase the steady-state levels of hydrogen
peroxide, which forms the hydroxyl radical in the presence of iron.
Homozygosity for alanine in the mitochondrial targeting sequence of MnSOD is a major risk factor for the development of liver cirrhosis in alcoholic patients (7), and similar results are found in another and much larger group of French alcoholic patients with hepatic cirrhosis (and without hepatocarcinoma). Homozygosity for alanine also increases fibrosis in overweight patients (A. Sutton, unpublished data).
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IMPLICATIONS IN CLINICAL MANAGEMENT |
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Although overweight patients must lose weight, severe dieting or total fasting increases peripheral lipolysis and the release of FFAs, which uncouple and inhibit mitochondrial respiration (19). Fasting may also cause glutathione depletion, which enhances lipid peroxidation and cytokine-mediated cell death (19). Rapid weight loss due to starvation, severe dieting, jejunoileal bypass, or gastroplasty paradoxically increases liver inflammation and fibrosis in these patients (19).
Instead, the combination of physical exercise and a moderately hypocaloric diet (high in green and red vegetables but low in sugar, amidon, and fat), with sometimes the help of a hypolipidemic drug or an antidiabetic agent as needed, can progressively decrease adipocyte fat stores, improve liver tests, and stop fibrogenesis (19). Vitamin E could also become adjunct therapy (12) if its beneficial effects are confirmed.
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CONCLUSIONS |
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In affluent countries, new lifestyle habits have caused a surge in obesity and fatty liver, which can cause steatohepatitis in some patients. Several vicious cycles involving lipid peroxidation, mitochondrial damage, ROS formation, depletion of antioxidants, and cytokine release may cause hepatic fibrogenesis in genetically susceptible patients.
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FOOTNOTES |
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Address for reprint requests and other correspondence: D. Pessayre, INSERM U481, Hôpital Beaujon, 100 boulevard du Général Leclerc, 92118 Clichy, France (E-mail: pessayre{at}bichat.inserm.fr).
10.1152/ajpgi.00426.2001
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