Obesity Increases Sensitivity To Endotoxin Liver Injury - Implications For The Pathogenesis of Steatohepatitis (Yang Et Al, 1997 2557-2562)

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Obesity increases sensitivity to endotoxin liver injury:
Implications for the pathogenesis ofsteatohepatitis
Shi Qi Yang (/search?author1=Shi+Qi+Yang&sortspec=date&submit=Submit)
*
,
Hui Zhi Lin (/search?author1=Hui+Zhi+Lin&sortspec=date&submit=Submit)
*
,
M. Daniel Lane (/search?author1=M.+Daniel+Lane&sortspec=date&submit=Submit)
,
Mark Clemens (/search?author1=Mark+Clemens&sortspec=date&submit=Submit)
, and
Anna Mae Diehl (/search?author1=Anna+Mae+Diehl&sortspec=date&submit=Submit)
*
Genetically obese fatty/fatty rats and obese/obese mice exhibit increased sensitivity to endotoxin
hepatotoxicity, quickly developing steatohepatitis after exposure to low doses of lipopolysaccharide (LPS).
Among obese animals, females are more sensitive to endotoxin liver injury than males. LPS induction of
tumor necrosis factor (TNF), the proven affecter of endotoxin liver injury, is no greater in the livers, white
adipose tissues, or sera of obese animals than in those of lean controls. Indeed, the lowest serum
concentrations of TNF occur in female obese rodents, which exhibit the most endotoxin-induced liver injury.
Several cytokines that modulate the biological activity of TNF are regulated abnormally in the livers of obese
animals. After exposure to LPS, mRNA of interferon , which sensitizes hepatocytes to TNF toxicity, is
overexpressed, and mRNA levels of interleukin 10, a TNF inhibitor, are decreased. The phagocytic activity of
liver macrophages and the hepatic expression of a gene encoding a macrophage-specific receptor are also
decreased in obesity. This new animal model of obesity-associated liver disease demonstrates that hepatic
macrophage dysfunction occurs in obesity and suggests that this might promote steatohepatitis by
sensitizing hepatocytes to endotoxin.
cytokines (/search?fulltext=cytokines&sortspec=date&submit=Submit&andorexactfulltext=phrase)
leptin (/search?fulltext=leptin&sortspec=date&submit=Submit&andorexactfulltext=phrase)
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lipopolysaccharide (/search?fulltext=lipopolysaccharide&sortspec=date&submit=Submit&andorexactfulltext=phrase)
Obesity is a risk factor for a number of diverse diseases, including type II diabetes, hyperlipidemia,
cardiovascular disease, osteoarthritis, and various infections (1). Although liver disease is not widely
appreciated as a complication of obesity, epidemiologic evidence suggests that obesity increases the risk for
cirrhosis. For example, in autopsy series, obesity was identified as the only risk factor for liver disease in
12% of cirrhotic subjects (2). Conversely, cirrhosis is approximately six times more prevalent in obese
individuals than in the general population (24).
The pathogenesis of liver disease associated with obesity is unknown. Gradual progression from hepatic
steatosis to steatohepatitis and, eventually, to cirrhosis is thought to occur (57). Hepatic steatosis is
common in obese individuals and has been documented in individuals who are as little as 10% above ideal
body weight (3). Although at least 40% of morbidly obese patients who undergo abdominal surgery to treat
obesity exhibit hepatic steatosis (8, 9), only a fraction of obese individuals with steatosis develop cirrhosis.
Disease progression appears to require one or more antecedent episodes of steatohepatitis. The histologic
features of obesity-related steatohepatitis resemble those of alcohol-induced steatohepatitis (10, 11).
Steatohepatitis is thought to trigger a fibrogenic response that is likely to result in significant deposition of
collagen and hepatic nodularity, i.e., cirrhosis. This is supported by data that indicate that fewer than 10% of
obese subjects with steatohepatitis exhibit normal liver morphology 5 years later and that almost 40% have
become cirrhotic (5, 6). Steatohepatitis is also an important prerequisite for alcohol-related cirrhosis (12,
13), so it is tempting to speculate that, like alcohol, obesity predisposes individuals to steatohepatitis.
Experimental evidence suggests that gut-derived products, including bacterial lipopolysaccharide (LPS) and
endotoxin, are involved in the pathogenesis of alcohol-related steatohepatitis (14). Of interest, jejunoileal
bypass surgery, a procedure that increases portal endotoxemia, is no longer preferred as a treatment for
morbid obesity because it is associated with an extremely high incidence of steatohepatitis and cirrhosis in
these individuals (8, 9). Taken together, these observations suggest that obesity might predispose
individuals to liver disease by increasing hepatic sensitivity to endotoxin. To test this hypothesis, two
different strains of genetically obese rodents (and their lean littermates) were treated with low levels of LPS,
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after which appearance of liver-specific enzymes in the blood, liver histology, and survival rates were
compared. Our results demonstrate increased hepatotoxicity and decreased survival after exposure to LPS
in both of the obese strains and suggest two mechanismsaltered Kupffer cell function and increased
hepatocyte sensitivity to tumor necrosis factor (TNF)that might mediate obesity-related sensitivity to
endotoxin.
EXPERIMENTAL PROCEDURES
Zucker fatty/fatty (fa/fa) rats, obese/obese (ob/ob) mice, and their lean littermates were from The Jackson
Laboratory. Escherichia coli LPS was obtained from Sigma. Kits to measure TNF protein and recombinant
rat TNF standard were purchased from BioSource International (Camarillo, CA). Kupffer cell-specific gene
(KCR) cDNA was provided by G. W. Hoyle (University of North Carolina, Chapel Hill, NC) (15).
Oligonucleotide primers and probes for analysis of specific cytokine gene expression were synthesized to
match GenBank sequences unique to TNF, interleukin (IL) 10, IL-12, transforming growth factor (TGF) -1,
or interferon (IFN) .
Obese animals and their lean littermates were injected i.p. with LPS. Three different levels of LPS (500 g of
LPS/kg body weight, 200 g of LPS/animal, and 100 g of LPS/animal) were administered. Animals were
killed before (n = 6/group) or at various times after (30 min, 1, 6, or 24 h) LPS treatment (n = 6
18/group/time point) to harvest serum, liver, and adipose tissue. All experiments were performed in
accordance with National Institutes of Health and Johns Hopkins University guidelines to ensure humane
treatment of animal subjects.
Serum concentrations of glucose, triglyceride, cholesterol, alanine aminotransferase (ALT), aspartate
aminotransferase (AST), and alkaline phosphatase were measured by a multichannel automated analyzer in
the clinical chemistry laboratory at the Johns Hopkins Hospital. Serum concentrations of TNF were assayed
in triplicate aliquots of each serum sample by a commercial ELISA using rat recombinant TNF protein as
standard. Liver histology was evaluated after staining sections of paraffin-embedded, formalin-fixed tissues
with hematoxylin and eosin.
Total RNA was isolated from liver and white adipose tissue according to the method of Chomczynski and
Sacchi (16), and Northern blot analysis was performed as described (17). To ensure data reproducibility, at
least four different Northern blot analyses, each containing RNA isolated from a different rat at each time
point, were evaluated by densitometry. On each blot, KCR mRNA was normalized to Pu-1 mRNA, a
constitutive monocyte gene product, at the same time point, and results from different blots were analyzed
by ANOVA.
To assess treatment-related differences in cytokine gene expression, total RNA was reverse transcribed,
and specific cytokine primers were used to amplify cytokine cDNAs as described (18). Conditions were
established for each set of cytokine primers to ensure that each PCR reaction permitted semiquantitative
amplification of a specific cytokine cDNA within a log-linear range (19). Reverse transcriptase PCR products
were separated, blotted, and visualized by chemiluminescence after hybridization with cytokine-specific
probes (18). Reverse transcriptase PCR assays were repeated with input RNA from at least three different
rats from each group at each time point. The resultant Southern blots were evaluated by densitometry, and
densitometric data were analyzed ANOVA.
Intravital microscopy was used to evaluate Kupffer cell function in obese and nonobese animals. A small,
midline abdominal incision was performed under anesthesia, and the right lobe of the liver was exteriorized
and placed on the microscope stage. fa/fa rats (n = 3) and their lean littermates (n = 3) were then injected
i.v. with 1-m fluorescent beads, and the time course and zonal pattern of fluorescent bead uptake by the
liver were recorded continuously on videotape for the next hour. Computer-assisted analysis of videotapes
was performed as previously described (20).
RESULTS
As expected, male fa/fa rats had significantly greater body weights, serum glucose concentrations, and
serum lipid levels before LPS treatment than their lean male littermates (?/fa) (Table 1). Although total liver
weights of the fa/fa rats were greater than those of lean controls, liver weight normalized to body weight was
comparable in the two groups. Significant hepatic steatosis was not observed in the lean controls; however,
liver steatosis (histologic grades 34) was evident in all fa/fa rats (compare Fig. 1 A and D). Serum markers
of liver injury (AST and ALT) were slightly increased in the fa/fa rats compared with the lean controls before
LPS was given (Table 1).
Characteristics of ?/fa and fa/fa rats before exposure to
LPS
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Liver histology before and after treatment with LPS. (A)
Micro- and macrovesicular steatosis in a representative
fa/fa rat before LPS treatment. Area of (B) hepatocyte
apoptosis and (C) steatohepatitis in two distinct, but
representative, fa/fa rats 24 h after treatment with LPS
(0.5 g/g). (D) Normal liver histology in a representative
?/fa rat before LPS. (E and F) Normal liver histology in
two distinct, but representative, ?/fa rats 24 h after
treatment with LPS (0.5 g/g). (Final magnification 400.)
Exposure to low levels of LPS led to dramatically different outcomes in male fa/fa and male ?/fa rats. Within
12 h of i.p. injection of LPS (0.5 mg/kg), 21 2% of the fa/fa rats died (P < 0.001 vs. controls). By 24 h after
treatment with this amount of LPS, all surviving fa/fa rats had developed steatohepatitis, i.e., histologic
evidence of focal hepatocyte necrosis, hepatic inflammation (Fig. 1 B and C), and increased serum AST and
ALT (Fig. 2A). In contrast, ?/fa rats treated with LPS exhibited little toxicity. None of these animals died or
developed evidence of steatohepatitis (Figs. 1 E and F and 2A).
Effect of LPS on serum activities of liver-associated
enzymes. (A) AST and ALT in fa/fa rats and ?/fa controls
24 h after exposure to 0.5 g/g LPS. (B) ALT in fa/fa and
?/fa rats 24 h after treatment with 100 or 200 g of LPS.
(C) AST and ALT in ob/ob and ?/ob mice 24 h after
treatment with LPS (0.5 g/g). (D) AST and ALT before
and 24 h after treatment with LPS (0.5 g/g) in female (F)
and male (M) fa/fa rats. IU/L, units per liter for AD.
Although the liver constituted 3% of total body weight in both fa/fa and ?/fa rats, fa/fa rats weighed
considerably more than their lean littermates and thus received, on average, almost twice as much LPS per
animal. Because this might have biased the results, subsequent experiments compared liver enzymes after
treatment of obese and lean rats with identical amounts (100 or 200 g) of LPS. No mortality occurred in
either group. However, serum liver enzymes (Fig. 2B) were significantly greater in fa/fa rats than in ?/fa rats
after treatment with either level of LPS. Thus, hepatotoxicity was significantly more pronounced in fa/fa rats
than in ?/fa rats whether or not the amount of LPS administered was normalized to body weight.
To determine if similar heightened sensitivity to the hepatotoxic effects of endotoxin occurred in other models
of genetic obesity, experiments were repeated with male ob/ob mice and their lean male (?/ob) littermates.
As shown in Fig. 2C, serum AST and ALT increased substantially after LPS (0.5 mg/kg) in the ob/ob group
to a level 10 times greater than in ?/ob mice. These increases in circulating liver enzymes correlated with
histologic evidence of progression from steatosis to steatohepatitis in the ob/ob animals.
Alcohol-related steatohepatitis tends to be more severe in women than in men (13) and women might be
more susceptible to obesity-associated steatohepatitis (2, 5, 6, 10, 11, 21, 22), so LPS sensitivity was
compared in male and female fa/fa rats. Liver weight, body weight, and serum AST and ALT were similar in
male and female fa/fa rats before LPS injection. However, 24 h after exposure to LPS, serum AST and ALT
were significantly greater in female fa/fa rats than in male fa/fa rats (Fig. 2D).
Endotoxin is known to provoke the release of proinflammatory cytokines, including TNF. TNF has been
identified as a proximal mediator of endotoxin-induced injury to many tissues, including the liver (23, 24).
Endotoxin delivered i.p. is normally cleared from portal blood by hepatic macrophages (Kupffer cells). This
minimizes endotoxin stimulation of LPS-sensitive cells that reside in extrahepatic sites and attenuates
systemic production of TNF but apparently does not preclude local TNF production by resident Kupffer cells
because the latter are presumed to play an important role in the pathogenesis of endotoxin-mediated liver
injury (25). To determine if fa/fa rats were more susceptible to LPS-induced liver injury because of increased
TNF production in response to endotoxin, the expression of TNF was compared in fa/fa and ?/fa rats after
LPS injection.
As shown in Fig. 3A, neither fa/fa nor ?/fa rats expressed appreciable TNF mRNA in the liver before
treatment with LPS. However, within 1 h after LPS injection in both groups, the level of hepatic TNF
transcripts increased significantly. Surprisingly, the induction of hepatic TNF mRNA by LPS was no greater in
obese rats than in their lean littermates. Circulating levels of TNF protein also increased significantly after
LPS injection in both fa/fa and lean rats, reaching a maximum 1 h after LPS administration in both groups.
Consistent with the liver RNA results, TNF protein concentrations were not higher in male or female fa/fa rats
than in the respective lean controls at any of the time points evaluated (i.e., at 30 min or 1, 6, or 24 h) after
LPS treatment. Indeed, as shown in Fig. 3B, the lowest TNF concentrations occurred in female fa/fa rats,
which exhibited the greatest hepatotoxicity after LPS. The ELISA method used might not distinguish
biologically active TNF from that which is inactivated by circulating soluble TNF receptors, so the assay was
repeated several times after diluting samples to dissociate potential inhibitors. However, dilution did not
increase immunoreactive, free TNF in any serum sample, suggesting that circulating inhibitors did not
account for the observed differences in TNF concentrations among the groups.
TNF expression in fa/fa and ?/fa rats pre- and 1 h
posttreatment with LPS (0.5 g/g). (A) Total liver RNA
was isolated from three distinct rats/group at each time
point, reverse transcribed, and amplified with TNF-
specific primers. PCR products were separated on
nondenaturing agarose gels, transferred to nylon
membranes, and visualized by hybridization with TNF-
specific probes. (B) Serum TNF concentrations were
evaluated by ELISA using rat recombinant TNF as
standard. In both males and females, TNF expression
was greater in serum and liver at 1 h after LPS than at
any other time point (0, 0.5, 6, or 24 h) evaluated.
These results suggested that obese animals are more sensitive to the toxic effects of TNF. LPS is known to
stimulate the release from macrophages of several cytokines that modulate the biological activity of TNF.
These include IL-12, IFN, IL-10, and TGF (23, 26). Semiquantitative reverse transcriptase PCR analysis of
liver RNA from obese and lean animals showed that obesity is associated with alterations in the profile of
cytokines that regulate TNF, both before and after treatment with LPS. In the fa/fa rats, LPS induction of
hepatic IFN mRNA is enhanced, TGF-1 mRNA expression is unaffected, induction of IL-10 mRNA is
delayed, and expression of IL-12 mRNA is generally decreased (Fig. 4). Kupffer cells are important sources
of TNF and TNF-related cytokines (23, 26, 27), so these results suggest that Kupffer cell function might be
abnormal in the obese animals. Consistent with this theory, Northern blot analysis of liver RNA indicated that
hepatic expression of KCR is decreased in the fa/fa rats compared with controls (Fig. 5A). Lean animals
express high levels of KCR mRNA before and for the 1st h after treatment with LPS. Then, expression of this
gene is down-regulated. In contrast, obese rats express few KCR mRNA at all time points evaluated.
Hepatic expression of TNF regulatory cytokines pre- and
posttreatment with LPS (0.5 g/g). Liver RNA was
isolated from three distinct rats/group either before (pre)
or 1 and 24 h after LPS treatment and subjected to
reverse transcriptase PCR analysis with sets of primers
specific for IL-12, IFN, IL-10, or TGF-1 under
semiquantitative conditions.
Comparison of Kupffer cell function in fa/fa and ?/fa rats.
(A) Total liver RNA was isolated from two distinct
rats/group either before (pre) or 1 and 24 h after LPS
(0.5 g/g), separated by electrophoresis on denaturing
polyacrylamide gels (20 g RNA/lane), transferred to
nylon membranes, and cohybridized with [ P]-labeled
cDNAs for KCR and a constitutively expressed monocyte
transcription factor (Pu-1). (B and C) Rats were injected
intraportally with fluorescent beads, and intravital
microscopy was used to evaluate (B) the distribution of
beads in acinar zones 1 (periportal), 2 (midacinus), and 3
(pericentral) 30 minutes after injection and (C) the
cumulative hepatic uptake of the beads over time.
Results shown are representative of replicate
experiments.
Obesity also is associated with abnormal Kupffer cell function. When rats were injected i.v. with fluorescent
beads to evaluate Kupffer cell phagocytic function, striking differences in phagocytic activity were observed.
In lean animals, most of the beads were taken up in zone 1 of the hepatic acinus, and the few remaining
beads were phagocytosed in acinar zones 2 and 3. In contrast, phagocytosis in zones 1 and 2 was
decreased in obese animals. This resulted in striking differences in the net hepatic uptake of fluorescent
32
beads in the obese animals and their lean controls. As shown in Fig. 5 B and C, hepatic clearance of
intraportally delivered fluorescent beads, a function of Kupffer cell phagocytic activity, is less than 50% of
normal in fa/fa rats.
Kupffer cells are responsible for phagocytosing gut-derived endotoxin to prevent its escape into the systemic
circulation, so these results suggest that obese animals might have baseline endotoxemia and, hence,
evidence of TNF production in extrahepatic sites. To explore this possibility, the level of TNF mRNA in white
adipose tissue was evaluated. Although TNF is not detected in white adipose tissue of lean animals until they
are treated with LPS, obese mice and rats reproducibly express TNF in adipose tissue even before
treatment with exogenous endotoxin. Consistent with these results, baseline serum concentrations of TNF
protein were higher in male fa/fa rats (37.3 6.6 pg/ml) than male ?/fa rats (16 5.3 pg/ml) (P < 0.02).
DISCUSSION
Obesity has long been suspected of increasing the risk for cirrhosis (3). However, the mechanisms
responsible for this are poorly understood. Observations that obesity is strongly associated with
steatohepatitis, a pattern of liver injury that often progresses to cirrhosis in alcoholic individuals, provided a
clue that the pathogenesis of liver disease related to obesity might be similar to that of alcoholic liver injury.
Endotoxin or LPS is thought to play a role in liver injury induced by alcohol and several other hepatotoxins
(14, 25, 28). The present study indicates that obesity increases susceptibility to endotoxin-mediated liver
injury and, thus, identifies the common mechanism for both alcohol- and obesity-related liver diseases. In
addition, this work identifies a new animal model that will be useful for elucidating the pathogenesis of
steatohepatitis in general.
Considerable evidence suggests that the hepatotoxic effects of LPS are mediated through cytokines
(especially TNF) (29, 30). Hepatocytes are normally resistant to the cytotoxic effects of TNF. However, two
mechanisms, priming and sensitization, are known to increase hepatic susceptibility to TNF injury (23, 24).
Priming occurs when TNF-producing cells, especially tissue macrophages, are conditioned, or primed, to
release massive amounts of TNF in response to stimuli (e.g., small amounts of LPS) that normally cause only
minimal TNF release. Priming is thought to mediate liver injury due to Corynebacterium parvum (31, 32), lead
acetate (33), polyhalogenated hydrocarbons (34), ischemia reperfusion (35), cadmium, and choline
deficiency (36) but is unlikely to explain obesity-related LPS hepatotoxicity because we found no evidence
that LPS treatment induced greater expression of TNF in obese rodents than in lean controls. A second
important mechanism of TNF-induced hepatic injury involves hepatocyte sensitization to normally innocuous
amounts of TNF. Sensitization to the toxic actions of TNF might occur via several discrete mechanisms that
culminate in defective adaptation to oxidant stress (3739). The classic liver injury model of sensitization is
that of galactosamine-induced hepatotoxicity, in which galactosamine is known to sensitize hepatocytes to
TNF toxicity by depleting cellular uridine stores (40). Sensitization also appears to contribute to liver injury
caused by other hepatoxins, including carbon tetrachloride, acetaminophen, and alcohol (4143). Given that
obese and lean male rodents experienced similar induction of TNF but dramatically different degrees of liver
injury after treatment with LPS, it is reasonable to conclude that obesity promotes liver injury by a
mechanism that involves sensitization of hepatocytes to TNF toxicity. Female obese rats developed
significantly more liver injury after LPS than their male counterparts, despite less induction of TNF, so
sensitization also appears to be an important component of gender-related susceptibility to LPS
hepatotoxicity.
The molecular basis for obesity-related sensitization remains uncertain but might reflect, at least in part,
relative overexpression of IFN after LPS exposure. IFN is known to augment TNF toxicity in isolated mouse
hepatocytes (38) and is increased in many experimental models of TNF-related liver injury (32). IFN is
produced by Kupffer cells, which are also sources of other cytokines (e.g., IL-12, IL-10, and TGF) that
regulate tissue responses to TNF (44). The present study demonstrates that basal and/or LPS induction of
IL-12 and IL-10 are also abnormal in obese rats, suggesting that there might be relatively global dysfunction
of Kupffer cells in obesity. Consistent with this theory, this work has identified decreased Kupffer cell
phagocytic function in obese rats. The latter is likely to have important implications for extrahepatic cytokine
production because Kupffer cells provide the predominant barrier for egress of endogenous endotoxin from
the portal to the systemic circulations (45). Indeed, our work has reproduced previously published evidence
that basal adipose expression of TNF mRNA (46) and circulating concentrations of TNF protein (47) are
relatively increased in obesity. Others have suggested that increased peripheral production of TNF might
play a role in obesity-associated diabetes by interfering with insulin-dependent signaling in muscle and
adipose tissue (48). Our results suggest that dysfunction of hepatic macrophages might be primarily
responsible for abnormal, obesity-associated, cytokine production in peripheral tissues by permitting
chronic, low grade endotoxemia.
The present work investigated animals in which obesity resulted from defective leptin-dependent signal
transduction. Thus, it is uncertain if our results can be extrapolated to other situations that cause obesity
and/or hepatic steatosis. Pertinent in this regard are data that suggest that choline deficiency, another
cause of hepatic steatosis, promotes endotoxin liver injury by priming rather than by sensitization (36).
Interesting to note, other investigators have reported differential sensitivity to endotoxin-induced glucose
intolerance in leptin-defective rodents and in rats with streptozotocin-induced diabetes (48). Our observation
that LPS caused relatively greater release of liver enzymes in ob/ob mice, which completely lack leptin
(4951), than in fa/fa rats, which overexpress leptin but have defective leptin receptors (52), is provocative
because it suggests that competent leptin signaling might be requisite for normal tissue sensitivity to
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EXPERIMENTAL
PROCEDURES
RESULTS
DISCUSSION
Acknowledgments
Footnotes
References
endotoxin-inducible cytokines. Given the importance of these cytokines in mediating insulin responsivity, lipid
metabolism, bone turnover, vascular biology, inflammatory reactions to infections, and liver injury (23, 24),
leptin modulation of cytokine actions could have important clinical consequences.
Acknowledgments
This work was supported by grants to A.M.D from the National Institute of Alcohol Abuse and Alcoholism,
National Institutes of Health.
Footnotes
To whom reprint requests should be addressed.
M. Daniel Lane
ABBREVIATIONS
LPS,
lipopolysaccharide;
TNF,
tumor necrosis factor ;
IL,
interleukin;
TGF,
transforming growth factor;
KCR,
Kupffer cell-specific gene;
fa/fa,
fatty/fatty;
ob/ob,
obese/obese;
IFN,
interferon ;
AST,
aspartate aminotransferase;
ALT,
alanine aminotransferase
Accepted December 20, 1996.
Copyright 1997, The National Academy of Sciences of the USA
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Alleviated by Betaine Supplementation in Rats
J. Nutr. (The Journal of Nutrition) 2009 139 (1) 63-68
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Body-Mass Index and Progression of Hepatitis B: A Population-Based Cohort Study in Men
JCO (Journal of Clinical Oncology) 2008 26 (34) 5576-5582
Abstract (http://jco.ascopubs.org/cgi/content/abstract/26/34/5576) Full Text (HTML)
(http://jco.ascopubs.org/cgi/content/full/26/34/5576) Full Text (PDF) (http://jco.ascopubs.org/cgi/reprint/26/34/5576)
Fatigue in non-alcoholic fatty liver disease (NAFLD) is significant and associates with
inactivity and excessive daytime sleepiness but not with liver disease severity or insulin
resistance
Gut (Gut) 2008 57 (6) 807-813
New Role of Resistin in Lipopolysaccharide-Induced Liver Damage in Mice
J. Pharmacol. Exp. Ther. (Journal of Pharmacology and Experimental Therapeutics) 2008 325 (3) 801-808
Abstract (http://jpet.aspetjournals.org/cgi/content/abstract/325/3/801) Full Text (HTML)
(http://jpet.aspetjournals.org/cgi/content/full/325/3/801) Full Text (PDF)
(http://jpet.aspetjournals.org/cgi/reprint/325/3/801)
Contribution of the sympathetic hormone epinephrine to the sensitizing effect of ethanol on
LPS-induced liver damage in mice
Physiology) 2008 294 (5) G1227-G1234
Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes
J. Lipid Res. (The Journal of Lipid Research) 2008 49 (1) 84-97
Abstract (http://www.jlr.org/cgi/content/abstract/49/1/84) Full Text (HTML)
(http://www.jlr.org/cgi/content/full/49/1/84) Full Text (PDF) (http://www.jlr.org/cgi/reprint/49/1/84)
Involvement of AMP-activated protein kinase in beneficial effects of betaine on high-
sucrose diet-induced hepatic steatosis
Physiology) 2007 293 (4) G894-G902
Increased intestinal permeability in obese mice: new evidence in the pathogenesis of
nonalcoholic steatohepatitis
Physiology) 2007 292 (2) G518-G525
Dietary Oxidized Fat Prevents Ethanol-Induced Triacylglycerol Accumulation and Increases
Expression of PPAR{alpha} Target Genes in Rat Liver
Hepatocellular apoptosis during Candida albicans colonization: involvement of TNF-{alpha}
and infiltrating Fas-L positive lymphocytes
Int Immunol (International Immunology) 2006 18 (12) 1719-1728
Abstract (http://intimm.oxfordjournals.org/cgi/content/abstract/18/12/1719) Full Text (HTML)
(http://intimm.oxfordjournals.org/cgi/content/full/18/12/1719) Full Text (PDF)
(http://intimm.oxfordjournals.org/cgi/reprint/18/12/1719)
Chitotriosidase gene expression in Kupffer cells from patients with non-alcoholic fatty liver
disease
Gut (Gut) 2006 55 (9) 1313-1320
Increased T-helper interferon-{gamma}-secreting cells in obese children.
Eur J Endocrinol (European Journal of Endocrinology) 2006 154 (5) 691-697
Abstract (http://www.eje-online.org/cgi/content/abstract/154/5/691) Full Text (HTML) (http://www.eje-
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Treatment of non-alcoholic fatty liver disease.
Postgrad. Med. J. (Postgraduate Medical Journal) 2006 82 (967) 315-322
Abstract (http://pmj.bmjjournals.com/cgi/content/abstract/82/967/315) Full Text (HTML)
(http://pmj.bmjjournals.com/cgi/content/full/82/967/315) Full Text (PDF)
(http://pmj.bmjjournals.com/cgi/reprint/82/967/315)
Feeding a corn oil/sucrose-enriched diet enhances steatohepatitis in sedentary rats
Physiology) 2006 290 (2) G386-G393
Tumour necrosis factor related apoptosis inducing ligand (TRAIL) induces hepatic steatosis
in viral hepatitis and after alcohol intake
Gut (Gut) 2005 54 (11) 1590-1596
Effects of a High-Fiber Diet on Hepatocyte Apoptosis and Liver Regeneration After Partial
Hepatectomy in Rats With Fatty Liver
Insulin resistance and steatosis in hepatitis C virus infection
Gut (Gut) 2005 54 (7) 903-906
Full Text (HTML) (http://gut.bmjjournals.com/cgi/content/full/54/7/903) Full Text (PDF)
Steatohepatitis develops rapidly in transgenic mice overexpressing Abcb11 and fed a
methionine-choline-deficient diet
Physiology) 2005 288 (6) G1321-G1327
Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the
hypozincemia of the acute-phase response
Proc. Natl. Acad. Sci. USA (PNAS) 2005 102 (19) 6843-6848
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(/cgi/reprint/102/19/6843)
Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic
steatohepatitis and hepatic neoplasia
(/cgi/reprint/102/11/4120)
Association Between Elevated Liver Enzymes and C-Reactive Protein: Possible Hepatic
Contribution to Systemic Inflammation in the Metabolic Syndrome
Arterioscler. Thromb. Vasc. Bio. (Arteriosclerosis, Thrombosis, and Vascular Biology) 2005 25 (1) 193-
197
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(http://atvb.ahajournals.org/cgi/content/full/25/1/193) Full Text (PDF) (http://atvb.ahajournals.org/cgi/reprint/25/1/193)
Bile secretory function in the obese Zucker rat: evidence of cholestasis and altered
canalicular transport function
Gut (Gut) 2004 53 (12) 1837-1843
High dissemination and hepatotoxicity in rats infected with Candida albicans after stress
exposure: potential sensitization to liver damage
Int Immunol (International Immunology) 2004 16 (12) 1761-1768
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(http://intimm.oxfordjournals.org/cgi/content/full/16/12/1761) Full Text (PDF)
(http://intimm.oxfordjournals.org/cgi/reprint/16/12/1761)
Leptin deficiency enhances sensitivity of rats to alcoholic steatohepatitis through
suppression of metallothionein
Physiology) 2004 287 (5) G1078-G1085
Approach to the Pathogenesis and Treatment of Nonalcoholic Steatohepatitis
Diabetes Care (Diabetes Care) 2004 27 (8) 2057-2066
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(http://care.diabetesjournals.org/cgi/content/full/27/8/2057) Full Text (PDF)
(http://care.diabetesjournals.org/cgi/reprint/27/8/2057)
Hepatocyte Proliferation is the Possible Mechanism for the Transient Decrease in Liver
Injury During Steatosis Stage of Alcoholic Liver Disease
Toxicol Pathol (Toxicologic Pathology) 2004 32 (5) 567-576
Abstract (http://tpx.sagepub.com/cgi/content/abstract/32/5/567) Full Text (PDF)
(http://tpx.sagepub.com/cgi/reprint/32/5/567)
Early-Phase Alcoholic Liver Disease: An Update on Animal Models, Pathology, and
Pathogenesis
International Journal of Toxicology (International Journal of Toxicology) 2004 23 (4) 217-231
Abstract (http://ijt.sagepub.com/cgi/content/abstract/23/4/217) Full Text (HTML)
(http://ijt.sagepub.com/cgi/content/full/23/4/217) Full Text (PDF) (http://ijt.sagepub.com/cgi/reprint/23/4/217)
p53 Involvement in the Pathogenesis of Fatty Liver Disease
J Biol Chem (Journal of Biological Chemistry) 2004 279 (20) 20571-20575
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(http://www.jbc.org/cgi/content/full/279/20/20571) Full Text (PDF) (http://www.jbc.org/cgi/reprint/279/20/20571)
Kupffer Cell Activity Is Involved in the Hepatoprotective Effect of Dietary Oligofructose in
Rats with Endotoxic Shock
Oxidative Stress and Enzymatic Antioxidant Status in Patients with Nonalcoholic
Steatohepatitis
Ann Clin Lab Sci (Annals of Clinical & Laboratory Science) 2004 34 (1) 57-62
Abstract (http://www.annclinlabsci.org/cgi/content/abstract/34/1/57) Full Text (HTML)
(http://www.annclinlabsci.org/cgi/content/full/34/1/57) Full Text (PDF)
(http://www.annclinlabsci.org/cgi/reprint/34/1/57)
Peroxisome Proliferator-activated Receptor {alpha} (PPAR{alpha}) Agonist Treatment
Reverses PPAR{alpha} Dysfunction and Abnormalities in Hepatic Lipid Metabolism in
Ethanol-fed Mice
Ethanol Induces Fatty Acid Synthesis Pathways by Activation of Sterol Regulatory Element-
binding Protein (SREBP)
Blocking the Secretion of Hepatic Very Low Density Lipoproteins Renders the Liver More
Susceptible to Toxin-induced Injury
Nonalcoholic Steatosis and Steatohepatitis: IV. Nonalcoholic fatty liver disease
abnormalities in macrophage function and cytokines
Physiology) 2002 282 (1) G1-G5
(http://ajpgi.physiology.org/cgi/content/full/282/1/G1) Full Text (PDF) (http://ajpgi.physiology.org/cgi/reprint/282/1/G1)
Leptin regulation of the immune response and the immunodeficiency of malnutrition
FASEB J. (The FASEB Journal) 2001 15 (14) 2565-2571
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(http://www.fasebj.org/cgi/content/full/15/14/2565) Full Text (PDF) (http://www.fasebj.org/cgi/reprint/15/14/2565)
Increased severity of alcoholic liver injury in female rats: role of oxidative stress,
endotoxin, and chemokines
Physiology) 2001 281 (6) G1348-G1356
Alteration of Hepatic Fatty Acid Metabolism After Burn Injury in Pigs
Abstract (http://pen.sagepub.com/cgi/content/abstract/25/6/310) Full Text (PDF)
(http://pen.sagepub.com/cgi/reprint/25/6/310)
Fatty liver vulnerability to endotoxin-induced damage despite NF-{kappa}B induction and
inhibited caspase 3 activation
Physiology) 2001 281 (2) G382-G392
Hepatic Hyperplasia in Noncirrhotic Fatty Livers: Is Obesity-related Hepatic Steatosis a
Premalignant Condition?
Cancer Res. (Cancer Research) 2001 61 (13) 5016-5023
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(http://cancerres.aacrjournals.org/cgi/content/full/61/13/5016) Full Text (PDF)
(http://cancerres.aacrjournals.org/cgi/reprint/61/13/5016)
Relationship between Upper Body Obesity and Periodontitis
JDR (Journal of Dental Research) 2001 80 (7) 1631-1636
Abstract (http://jdr.sagepub.com/cgi/content/abstract/80/7/1631) Full Text (PDF)
(http://jdr.sagepub.com/cgi/reprint/80/7/1631)
Troglitazone stimulates pancreatic growth in congenitally CCK-A receptor-deficient OLETF
rats
Am. J. Physiol. Regul. Integr. Comp. Physiol. (American Journal of Physiology - Regulatory, Integrative
and Comparative Physiology) 2001 280 (5) R1332-R1340
Abstract (http://ajpregu.physiology.org/cgi/content/abstract/280/5/R1332) Full Text (HTML)
(http://ajpregu.physiology.org/cgi/content/full/280/5/R1332) Full Text (PDF)
(http://ajpregu.physiology.org/cgi/reprint/280/5/R1332)
Is bacterial ash the flash that ignites NASH?
Gut (Gut) 2001 48 (2) 148-149
Full Text (HTML) (http://gut.bmjjournals.com/cgi/content/full/48/2/148) Full Text (PDF)
The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and
tumour necrosis factor {alpha} in the pathogenesis of non-alcoholic steatohepatitis
Gut (Gut) 2001 48 (2) 206-211
The Transcriptional and DNA Binding Activity of Peroxisome Proliferator-activated Receptor
alpha Is Inhibited by Ethanol Metabolism. A NOVEL MECHANISM FOR THE DEVELOPMENT OF
ETHANOL-INDUCED FATTY LIVER
Leptin in the regulation of immunity, inflammation, and hematopoiesis
J. Leukoc. Biol. (Journal of Leukocyte Biology) 2000 68 (4) 437-446
Abstract (http://www.jleukbio.org/cgi/content/abstract/68/4/437) Full Text (HTML)
(http://www.jleukbio.org/cgi/content/full/68/4/437)
Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity: Role of
tumor necrosis factor alpha and IL-18
(/cgi/reprint/97/5/2367)
Obesity Induces Expression of Uncoupling Protein-2 in Hepatocytes and Promotes Liver ATP
Depletion
Phenotypic abnormalities in macrophages from leptin-deficient, obese mice
Am. J. Physiol. Cell Physiol. (American Journal of Physiology - Cell Physiology) 1999 276 (2) C386-C394
Abstract (http://ajpcell.physiology.org/cgi/content/abstract/276/2/C386) Full Text (HTML)
(http://ajpcell.physiology.org/cgi/content/full/276/2/C386) Full Text (PDF)
(http://ajpcell.physiology.org/cgi/reprint/276/2/C386)
Leptin Is an Endogenous Protective Protein against the Toxicity Exerted by Tumor Necrosis
Factor
JEM (Journal of Experimental Medicine) 1999 189 (1) 207-212
Abstract (http://jem.rupress.org/cgi/content/abstract/189/1/207-a) Full Text (HTML)
(http://jem.rupress.org/cgi/content/full/189/1/207-a) Full Text (PDF) (http://jem.rupress.org/cgi/reprint/189/1/207-a)
Leptin deficiency enhances sensitivity to endotoxin-induced lethality
Am. J. Physiol. Regul. Integr. Comp. Physiol. (American Journal of Physiology - Regulatory, Integrative
and Comparative Physiology) 1999 276 (1) R136-R142
Abstract (http://ajpregu.physiology.org/cgi/content/abstract/276/1/R136) Full Text (HTML)
(http://ajpregu.physiology.org/cgi/content/full/276/1/R136) Full Text (PDF)
(http://ajpregu.physiology.org/cgi/reprint/276/1/R136)
Fatty acid-induced {beta} cell apoptosis: A link between obesity and diabetes
(/cgi/reprint/95/5/2498)
The Transcriptional and DNA Binding Activity of Peroxisome Proliferator-activated Receptor
alpha Is Inhibited by Ethanol Metabolism. A NOVEL MECHANISM FOR THE DEVELOPMENT OF
ETHANOL-INDUCED FATTY LIVER

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