Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many factors could potentially affect the process of arsenic-induced liver fibrosis. The present study was undertaken to examine the effect of high fat diet on arsenic-induced liver fibrosis and preneoplastic changes. Mice were given sodium arsenite (As3+, 200 ppm) or sodium arsenate (As5+, 200 ppm) in the drinking water for 10 months, and provided a normal diet or a diet containing 20% added fat. Serum aspartate aminotransferase (AST), indicative of liver injury, was elevated in both arsenite and arsenate groups, and a high fat diet further increased these levels. Histopathology (H&E and Masson stain) showed that liver inflammation, steatosis (fatty liver), hepatocyte degeneration, and fibrosis occurred with arsenic alone, but their severity was markedly increased with the high fat diet. Total liver RNA was isolated for real-time RT-PCR analysis. Arsenic exposure increased the expression of inflammation genes, such as TNF-alpha, IL-6, iNOS, chemokines, and macrophage inflammatory protein-2. The expression of the stress-related gene heme oxygenase-1 was increased, while metallothionein-1 and GSH S-transferase-pi were decreased when arsenic was combined with the high fat diet. Expression of genes related to liver fibrosis, such as procollagen-1 and -3, SM-actin and TGF-beta, were synergistically increased in the arsenic plus high fat diet group. The expression of genes encoding matrix metalloproteinases (MMP2, MMP9) and tissue inhibitors of metalloproteinases (TIMP1, TIMP2) was also enhanced, suggestive of early oncogenic events. In general, arsenite produced more pronounced effects than arsenate. In summary, chronic inorganic arsenic exposure in mice produces liver injury, and a high fat diet markedly increases arsenic-induced hepatofibrogenesis.
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PMID:High dietary fat exacerbates arsenic-induced liver fibrosis in mice. 1829 43

The pathogenesis of alcohol-induced liver disease (ALD) is still poorly understood. One of the clues to its progression relates to the alcohol-mediated susceptibility of hepatocytes to cell death by reactive oxygen species (ROS) and inflammatory cytokines. Tumor necrosis factor alpha (TNF) has been considered a key ALD mediator with acidic sphingomyelinase (ASMase)-mediated ceramide generation playing a critical role. TNF receptor 1 and 2 knock-out mice or ASMase(-/-) mice exhibit resistance to alcohol-mediated fatty liver and cell death. Furthermore, alcohol feeding has been shown to sensitize hepatocytes to TNF due to the limitation of mitochondrial glutathione (mGSH) through impaired import of GSH from the cytosol due to altered membrane order parameter caused by mitochondrial cholesterol increase. Selective pharmacological depletion of mGSH sensitizes hepatocytes to TNF-mediated cell death, which reproduces the observations found with alcohol feeding. TNF signaling analyses in hepatocytes with or without mGSH depletion indicate that mGSH prevents cardiolipin peroxidation (CLOOH) formation by TNF-induced ROS via ASMase and that CLOOH cooperates with oligomerized Bax to cause mitochondrial outer membrane permeabilization through destabilization of the lipid bilayer via increased bilayer-to-inverted hexagonal phase transitions. Thus, activation of ASMase and cholesterol-mediated mGSH depletion both collaborate to promote alcohol-induced TNF-mediated hepatocellular damage, suggesting novel therapeutic opportunities in ALD.
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PMID:Cholesterol and sphingolipids in alcohol-induced liver injury. 1833 73

To study the effect of bicyclol on lipid disorder and liver damage induced by tetracycline in mice, mice were given (ig) bicyclol (75, 150, and 300 mg x kg(-1)) three times before or after administration of tetracycline (180 mg x kg(-1)). The contents of hepatic lipids, MDA and GSH, serum lipids and ALT/AST levels were measured 24 hours after the injection (ip) of tetracycline. The beta-oxidation rate of hepatic mitochondrial fatty acid and hepatic secretion of VLDL were also observed. Bicyclol (150 and 300 mg x kg(-1)) provided significant protection against fatty liver by inhibiting the elevation of hepatic TG and CHO, adjusting abnormal serum lipids, inhibiting the elevation of serum ALT, AST, and ameliorating the severity of pathological changes. Furthermore, bicyclol significantly accelerated the VLDL (TG) secretion and reversed the impairment of mitochondrial oxidation, resulting in the lipid homeostasis. The increase of MDA formation and depletion of GSH that reflect lipid peroxidation induced by tetracycline were also inhibited by bicyclol administration. The results indicated that the hepatoprotection of bicyclol was mostly due to the improvement on lipid oxidation and transportation as well as the inhibition of lipid peroxidation in tetracycline-intoxicated mice.
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PMID:[Protective effect of bicyclol against acute fatty liver induced by tetracycline in mice]. 1835 27

Accumulation of fat in the liver, also known as steatosis, may lead to inflammation and tissue damage. Kupffer cells (KCs) are the resident macrophages of the liver and have an important role in inflammatory reactions. The inflammatory response of isolated rat KCs to endotoxin in the presence of lipids was investigated in this study. KCs were treated with lipopolysaccharide (LPS) and triglycerides (TGs) alone or in combination. TGs had no effect on the expression of pro-inflammatory mediators, but adding TGs to LPS enhanced the induction of inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and granulocyte colony-stimulating factor (G-CSF), compared with LPS treatment alone. Increased DNA binding of NF-kappaB transcription factor was seen on simultaneous exposure of the cells to TGs and LPS, which was accompanied by decreased intracellular ROS production and increased GSH levels. The inflammation-potentiating effect of TGs on iNOS expression was abolished on NF-kappaB inhibition. This enhanced inflammatory response might indicate a contribution of lipids to the inflammatory conditions in the fatty liver by increased activation of KCs.
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PMID:Triglycerides potentiate the inflammatory response in rat Kupffer cells. 1871 Mar 23

The protective effects of single dose of garlic oil (GO) on acute ethanol-induced fatty liver were investigated. Mice were treated with ethanol (4.8 g/kg bw) to induce acute fatty liver. The liver index, the serum and hepatic triglyceride (TG) levels and the histological changes were examined to evaluate the protective effects. Hepatic malondialdehyde (MDA), glutathione (GSH) levels and superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GSH-Px), glutathione-S-transferase (GST) activities were determined for the antioxidant capacity assay. Acute ethanol exposure resulted in the enlargement of the liver index and the increase of the serum and hepatic TG levels (P<0.01), which were dramatically attenuated by GO pretreatment in a dose-dependent manner (P<0.01). GO treatment (simultaneously with ethanol exposure) exhibited similar effects to those of pretreatment, while no obviously protective effects were displayed when it was used at 2h after ethanol intake. Histological changes were paralleled to these indices. Beside this, GO dramatically prolonged the drunken time and shortened the waking time, and these effects were superior to those of silymarin and tea polyphenol. In addition, GO dose-dependently suppressed the elevation of MDA levels, restored the GSH levels and enhanced the SOD, GR and GST activities. Compared with the ethanol group, the MDA levels decreased by 14.2% (P<0.05), 29.9% and 32.8% (P<0.01) in GO groups 50, 100 and 200 mg/kg, respectively. The GST activity increased by 9.97%, 19.94% (P<0.05) and 42.12% (P<0.01) of the ethanol group in GO groups 50, 100 and 200 mg/kg, respectively, while the GR activity increased by 28.57% (P<0.05), 37.97% (P<0.01), 50.45% (P<0.01) of the ethanol group in GO groups 50, 100 and 200 mg/kg, respectively. These data indicated that single dose of GO possessed ability to prevent acute ethanol-induced fatty liver, but may lose its capacity when used after ethanol exposure. The protective effects should be associated with its antioxidative activities.
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PMID:The anti-fatty liver effects of garlic oil on acute ethanol-exposed mice. 1871 57

Nonalcoholic fatty liver is involved in the development of nonalcoholic steatohepatitis and chronic liver injury. Impairment of hepatic transsulfuration reactions is suggested to be critically linked with alcoholic liver injury, but its role in nonalcoholic fatty liver remains unknown. We examined the early changes in sulfur-amino acid metabolism and their implication in nonalcoholic fatty liver disease (NAFLD). Male rats were provided with a standard liquid diet or a high-fat liquid diet (HF) for 3 wk. An additional group of rats received the HF diet supplemented with betaine (1%). HF diet intake elevated hepatic triglyceride and serum tumor necrosis factor-alpha (TNFalpha) concentrations. Antioxidant capacity of liver cytosol against hydroxyl and peroxyl radicals was reduced significantly. Hepatic S-adenosylmethionine (SAM) and glutathione (GSH) decreased, but hypotaurine and taurine concentrations increased. Methionine adenosyltransferase (MAT) activity, not its concentration, was depressed, whereas both activity and concentration of cysteine dioxygenase and GSH S-transferase were elevated. Betaine supplementation of the HF diet inhibited hepatic fat accumulation and serum TNFalpha elevation. The decrease in cytosolic antioxidant capacity was also prevented. MAT activity and its concentration were induced significantly. Hepatic SAM and GSH increased and elevation of hypotaurine and taurine was depressed. The results indicate that the metabolism of S-containing substances is significantly disturbed by the HF diet, suggesting a causal role of impairment of hepatic transsulfuration reactions in NAFLD. Betaine supplementation protects the liver from nonalcoholic steatosis and oxidative stress most probably via its effects on the transsulfuration reactions.
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PMID:Impaired sulfur-amino acid metabolism and oxidative stress in nonalcoholic fatty liver are alleviated by betaine supplementation in rats. 1905 44

Hyperlipidemia of hamsters was induced by high-fat/cholesterol diets formulated by the addition of coconut oil (CO), butter (BU), and flaxseed oil (FX). Lower (p < 0.05) serum lipids, liver size, and hepatic cholesterol and triacylglycerol contents were observed in the FX group compared to both CO and BU groups. The liver damage indices [glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) values] in the FX group were lower (p < 0.05) than those in the CO and BU groups, which may result from higher (p < 0.05) glutathione (GSH) levels and a tendency toward lower malondialdehyde (MDA) levels in livers. Besides, lower (p < 0.05) gene expression and activity of hepatic matrix metalloproteinases-9 (MMP-9) in the FX group were lower (p > 0.05) compared to those in the CO and BU groups; however, no (p > 0.05) differences in gene expression activities of hepatic MMP-2 were observed among treatments. Those beneficial effects could explain the attenuation of FX on nonalcoholic fatty liver (NAFL) induced by a high-fat/cholesterol dietary habit.
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PMID:Flaxseed oil attenuates nonalcoholic fatty liver of hyperlipidemic hamsters. 1945 4

We have previously shown that treatment of steatotic livers with vitamin E succinate decreases liver injury and increases survival after ischemia/reperfusion (I/R). It is now understood that compromised energy status is associated with increased injury following liver ischemia in the setting of hepatic steatosis at least partially as a result of increased reactive oxygen species (ROS) and induction of mitochondrial uncoupling protein-2 (UCP2). Given the association between ROS, mitochondrial function, and UCP2, it was our goal to determine whether the protective effects of vitamin E succinate were associated with decreased ROS injury, down-regulation of UCP2, or improvement of ATP levels following I/R. To test this, leptin deficient (ob/ob) mice with steatotic livers that had received other 50 IU of vitamin E succinate supplement per day or control chow for 7 days were subjected to total hepatic ischemia (15 minutes) followed by reperfusion. We measured liver expressions of ATP, glutathione (GSH), and UCP2 as well as mitochondrial DNA damage. Vitamin E treatment decreased hepatic UCP2 expression and increased ATP and GSH levels prior to I/R. These levels were maintained at 1 hour after I/R. At 24 hours, while hepatic UCP2 expression, ATP, and GSH levels were similar to those of mice not receiving vitamin E, mitochondrial DNA damage was blocked. These results revealed that vitamin E succinate decreased hepatic UCP2 expression, reduced oxidative stress, and improved mitochondrial function in mice with steatotic livers before and after I/R, identifying mechanisms of protection in this setting.
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PMID:Vitamin E succinate enhances steatotic liver energy status and prevents oxidative damage following ischemia/reperfusion. 2000 47

Until quite recently, pentabromodiphenyl ether (PentaBDE) was most commonly used as a flame retardant. Due to the considerably long atmospheric half-life of PentaBDE and its contribution to environmental pollution, it is categorized as a persistent organic pollutant (POP). As the data on the toxicity of PentaBDE is rather scarce, its potential acute toxicity was the subject of this study. PentaBDE was administered intragastrically to female rats, in a single dose (25, 200 or 2000 mg/kg b.w.). PentaBDE administered to rats disturbed redox homeostasis, which was manifested by lower total antioxidant status (TAS) in serum and by higher liver glutathione reduced (GSH) concentration. The toxic effect of PentaBDE intensified lipid peroxidation. On histopathological examination, administration of the highest PentaBDE dose (2000 mg/kg b.w.) was seen to induce symptoms of fatty liver. PentaBDE caused an increase in relative liver mass, cytochromes P-450 (after two highest doses), a dose-dependent increase in the activity of CYP lA (12-26 fold) and CYP 2B (5-6 fold) as well as the levels of CYP lAl (16-50 fold) and CYP 4A (2-3 fold) in liver.
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PMID:The effect of short-term intoxication of rats with pentabromodiphenyl ether (in mixture mimic commercial products). 2048 50

Sustained activation of the c-Jun NH(2)-terminal kinase (JNK) signaling pathway mediates the development and progression of experimental diet-induced nonalcoholic fatty liver disease (NAFLD). Delineating the mechanism of JNK overactivation in the setting of a fatty liver is therefore essential to understanding the pathophysiology of NAFLD. Both human and experimental NAFLD are associated with oxidative stress and resultant lipid peroxidation, which have been proposed to mediate the progression of this disease from simple steatosis to steatohepatitis. The ability of oxidants and the lipid peroxidation product 4-hydroxynonenal (HNE) to activate JNK signaling suggested that these two factors may act synergistically to trigger JNK overactivation. The effect of HNE on hepatocyte injury and JNK activation was therefore examined in cells under chronic oxidant stress from overexpression of the prooxidant enzyme cytochrome P450 2E1 (CYP2E1), which occurs in NAFLD. CYP2E1-generated oxidant stress sensitized a rat hepatocyte cell line to death from normally nontoxic concentrations of HNE. CYP2E1-overexpressing cells underwent a more profound depletion of glutathione (GSH) in response to HNE secondary to decreased gamma-glutamylcysteine synthetase activity. GSH depletion led to overactivation of JNK/c-Jun signaling at the level of mitogen-activated protein kinase kinase 4 that induced cell death. Oxidant stress and the lipid peroxidation product HNE cause synergistic overactivation of the JNK/c-Jun signaling pathway in hepatocytes, demonstrating that HNE may not be just a passive biomarker of hepatic oxidant stress but rather an active mediator of hepatocellular injury through effects on JNK signaling.
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PMID:Chronic oxidative stress sensitizes hepatocytes to death from 4-hydroxynonenal by JNK/c-Jun overactivation. 2050 38


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