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)

Overgrowth of Gram-negative bacteria as a result of total parenteral nutrition (TPN) and bowel rest could be responsible for the release of a variety of hepatotoxic substances such as endotoxin or tumor necrosis factor (TNF) and the ensuing TPN-associated liver function derangements. Polymyxin B is an effective antimicrobial agent as well as a blocking agent for endotoxin (lipopolysaccharide) activity and TNF production. In the present study we compared the oral and intravenous effects of polymyxin in rats receiving TPN in an attempt to define these two possible mechanisms of action of polymyxin on TPN-associated hepatic steatosis. Both oral, as well as intravenous polymyxin B, significantly reduced total hepatic fat and triglyceride accumulation in TPN rats, more so in the intravenous group exhibiting close to control levels. Both polymyxin-treated groups exhibited significantly lower Gram-negative bacterial counts in the cecum, with the oral group exhibiting a lower count than the IV group. The spontaneous production of TNF by peritoneal macrophages was markedly increased in rats receiving TPN and very close to being undetected in both groups receiving TPN and polymyxin. We believe polymyxin B protects the liver during TPN by both its antimicrobial effect which prevents overgrowth of gut Gram-negative bacteria and the subsequent translocation of endotoxin, and by its specific antilipopolysaccharide activity which, in the present study, completely abolished hepatic steatosis and TNF production during TPN.
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PMID:Polymyxin B reduces total parenteral nutrition-associated hepatic steatosis by its antibacterial activity and by blocking deleterious effects of lipopolysaccharide. 149 9

Morphologic analysis of the changes in the internal organs after i.v. injection of 20 micrograms per mice of tumor necrosis factor (TNF) revealed the development of signs of multiorgan failure (interstitial and intraalveolar edema in the lung, acute fatty liver, tubular necrosis in kidney, brain edema) during first 24 h. The microvascular endothelial cells played a particular role in the state development. Results of investigation proved that endothelial cells were one of the major cellular targets for TNF action in vivo.
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PMID:[Cytological features of the development of multi-organ failure induced by exposure of the body to tumor necrosis factor]. 162 Dec 87

We investigated lipopolysaccharide-induced tumor necrosis factor production in vitro by peripheral blood monocytes from patients with various liver diseases. Tumor necrosis factor production was found to be significantly reduced in patients with chronic hepatitis B (n = 17; 135 +/- 30 pg tumor necrosis factor/ml; mean +/- S.E.M.) and patients with chronic non-A, non-B hepatitis (n = 15; 212 +/- 22 pg tumor necrosis factor/ml) compared with healthy control individuals (n = 47; 411 +/- 40 pg tumor necrosis factor/ml; p less than 0.0005 and p less than 0.01, respectively). This reduced tumor necrosis factor production was not only seen with an optimal stimulating concentration of lipopolysaccharide (100 ng/ml) but also with suboptimal concentrations (0.1 ng/ml). In contrast to patients with chronic viral hepatitis, monocytes from patients with alcohol-induced cirrhosis (n = 26; 444 +/- 49 pg tumor necrosis factor/ml), primary biliary cirrhosis (n = 7; 412 +/- 81 pg tumor necrosis factor/ml) and alcohol-induced fatty liver changes (n = 5; 401 +/- 62 pg tumor necrosis factor/ml) produced normal amounts of tumor necrosis factor when stimulated with an optimal concentration of lipopolysaccharide. Lipopolysaccharide (0.1 ng lipopolysaccharide/ml)-stimulated peripheral blood monocytes of patients with chronic hepatitis B (n = 15; 102 +/- 32 pg/ml) or non-A, non-B hepatitis (n = 13; 97+/- 16 pg/ml) could not be induced to produce more tumor necrosis factor either when prestimulated with gamma-interferon (170 +/- 45 pg/ml and 149 +/- 32 pg/ml, respectively), a lymphokine known to activate monocytes, or with the cyclooxygenase inhibitor indomethacin to reduce the suppressive effect of prostaglandin E2 (148 +/- 40 pg/ml and 153 +/- 45 pg/ml, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Impaired lipopolysaccharide-inducible tumor necrosis factor production in vitro by peripheral blood monocytes of patients with viral hepatitis. 212 37

The precise mechanism of the pathogenesis of alcoholic hepatitis is unknown, but immune involvement may perpetuate and exacerbate the process. Heat-shock proteins, normally protective, may be immunogenic and have been shown to induce antibody formation in some inflammatory conditions. Alcohol, cellular hypoxia and tumor necrosis factor, all involved in alcoholic hepatitis, are potent inducers of heat-shock protein. In this study, we sought 60-kD heat-shock protein in liver tissue with a murine monoclonal antibody and measured circulating antibody to 60-kD heat-shock protein on ELISA. Fourteen of 20 livers from patients with acute alcoholic hepatitis expressed 60-kD heat-shock protein in hepatocyte cytoplasm in a diffuse pattern with superimposed clusters; other cell types were occasionally positive. Twelve of these patients had high-titer IgA 60-kD heat-shock protein antibody in serum. In contrast, 60-kD heat-shock protein was identified in only 2 of the 10 patients with alcoholic cirrhosis without hepatitis (p = 0.013). These two patients had severe liver disease, and one patient in this group was seropositive for IgA 60-kD heat-shock protein antibody. Eight alcoholic patients with fatty liver alone were negative for antigen, and all but one were negative for antibody. The 10 patients without liver damage were negative for antigen and antibody. The findings that 60-kD heat-shock protein is present in liver tissue of patients with acute alcoholic liver damage and that circulating IgA 60-kD heat-shock protein antibody levels are increased may point to one pathogenetic mechanism underlying development and progression of liver damage in alcoholic hepatitis.
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PMID:Hepatic 60-kD heat-shock protein responses in alcoholic hepatitis. 851 53

Alcoholic liver disease can be associated with hepatic choline deficiency and hepatic steatosis, abnormalities also observed in rats administered choline-deficient (CD) diets. Bacterial lipopolysaccharides (LPS) have been postulated to play a key role in this choline deficiency model of liver injury, and LPS hepatotoxicity is mediated to a major extent by the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). This study addressed the following questions: Does LPS administration exacerbate an in vivo liver injury induced by choline deficiency? If so, do CD rats have increased serum TNF-alpha concentrations and does pretreatment anti-TNF-alpha IgG attenuate this injury? Rats administered choline-sufficient (CS) or CD diets for 16 days were intravenously administered either saline or LPS. One group of CD rats also received a single dose of anti-TNF-alpha IgG before LPS administration. Changes in histology and serum transaminase levels were determined. Both liver histology and serum transaminases were unchanged in the CS group treated with LPS, compared with the CS group treated with saline (control group). However, compared with this control group, transaminases were 5- to 7-fold higher in saline-treated CD rats and 30- to 50-fold higher in LPS-treated CD rats. Livers of saline-treated CD rats had massive fatty infiltration, and no necrosis but livers of LPS-treated CD rats showed both extensive fatty infiltration and large areas of necrosis. Serum TNF-alpha concentrations in CD rats (saline or LPS treated) were significantly elevated, compared with levels in corresponding CS rats. Pretreatment with the anti-TNF-alpha IgG prevented hepatonecrosis in LPS-treated CD rats and lowered their serum transaminases by one-third. Thus, LPS administration exacerbated liver injury induced by choline deficiency, and this injury was probably partially mediated by TNF-alpha and attenuated by anti-TNF-alpha IgG.
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PMID:Choline deficiency augments and antibody to tumor necrosis factor-alpha attenuates endotoxin-induced hepatic injury. 930 14

Broiler chicks were fed a diet containing 4% of either corn oil or fish oil from 3 to 14 d of age. From Days 15 to 23, half of the chicks in each dietary treatment were fed Lofrin (an experimental 5-lipoxygenase inhibitor) at 33 micrograms/kg feed. The remaining chicks within each dietary treatment were the untreated controls. At 24 d of age, half of the chicks within each diet-Lofrin treatment group were each infected with 4.6 x 10(4) sporulated Eimeria tenella oocysts, resulting in a 2 x 2 x 2 factorial arrangement of treatments. Body weight gain, feed consumption, and feed conversion efficiency were determined throughout the study. At 27 d of age, blood, liver, and ceca were sampled. Plasma tumor necrosis factor and hemopexin, hepatic fatty acid composition, and cecal inflammatory cell infiltration were determined. Liver fatty acid composition tended to reflect that of the diet. Chicks fed fish oil had livers that were enriched in (n-3) polyunsaturated fatty acids (PUFA) at the expense of (n-6) PUFA. Chicks fed fish oil gained body weight more rapidly than those fed corn oil. Infection of chicks with Eimeria decreased body weight gain of chicks fed corn oil, but not of chicks fed fish oil. The addition of Lofrin to the corn oil diets abrogated the growth-suppressing effects of infection, although there was no Lofrin effect among chicks fed fish oil. There was a diet by Lofrin interaction in which Lofrin treatment of birds fed corn oil decreased feed consumption and increased feed conversion efficiency, but had no effect on chicks fed diets containing fish oil. Plasma hemopexin was greater, but tumor necrosis factor was lower, in chicks fed fish oil than in chicks fed corn oil. Eimeria infection significantly increased cecal inflammatory cell infiltration across all dietary treatments. There were no clear relationships between growth rate or efficiency and the severity of the inflammatory response to Eimeria infection, as indicated by hemopexin levels and cecal inflammatory scores. These results indicate that Lofrin or fish oil, both of which modify eicosanoid metabolism, attenuate the growth-depressing effects of an Eimeria tenella infection.
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PMID:Dietary fish oil or lofrin, a 5-lipoxygenase inhibitor, decrease the growth-suppressing effects of coccidiosis in broiler chicks. 931 10

We investigated the potential of 16-desmethyl tirilazad mesylate, a member of 21-aminosteroids, to ameliorate alcohol-induced liver injury. Four groups (five rats/group) of male Wistar rats were studied. One group of rats was fed fish oil and ethanol (FE) for 4 weeks, and a second group received isocaloric amounts of dextrose instead of ethanol (FD). The third (FE-LAZ) and fourth (FD-LAZ) groups received the addition of 10 mg/kg/day of 16-desmethyl tirilazad mesylate (U74389) daily via intragastric tube. Liver samples were analyzed for histopathology, nonheme iron, lipid peroxidation and levels of mRNA for tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2). Concentrations of endotoxin and 8-isoprostane were measured in plasma. Membrane ATPases were measured in isolated membrane red cells. FE rats developed fatty liver, necrosis and inflammation. Treatment with the 21-aminosteroid resulted in prevention of necroinflammatory changes, but the degree of fatty liver was unchanged. The absence of necroinflammatory changes in the FE-LAZ group was accompanied by a decrease in levels of nonheme iron, lipid peroxidation, TNF-alpha mRNA and COX-2 mRNA. Ethanol administration decreased membrane Ca(++)-ATPase and calmodulin-stimulated Ca(++)-ATPase, and the decrease was reversed by 21-aminosteroid treatment. The data indicate that the improvement in the degree of necrosis and inflammation in the rats treated with the 21-aminosteroid may be explained, at least in part, by reduced levels of proinflammatory stimuli such as lipid peroxidation, TNF-alpha and COX-2. Membrane stabilization may also, by reducing lipid peroxidation, play an additional role in preventing liver injury.
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PMID:The 21-aminosteroid 16-desmethyl tirilazad mesylate prevents necroinflammatory changes in experimental alcoholic liver disease. 943 4

The role of T-cell activation in alcoholic liver disease was investigated in rats fed alcohol and subsequently exposed to concanavalin A (Con A). Following Con A injection (20 mg/kg body weight), greater increases in liver-to-body weight ratio and ALT levels were observed at 12 and 24 hr in rats fed ethanol, compared with control rats fed sucrose. Furthermore, increases in serum interleukin-6 and tumor necrosis factor-alpha levels were noted in ethanol-fed rats, with maximal levels detected at 4 hr declining thereafter, but remaining above control levels at 24 hr. Analysis of T-cell subpopulations showed an increased percentage of CD4+, CD5+, and CD8+ T cells in blood from all groups, but not in liver perfusate. In contrast, a significant increase in the percentage of activated CD25+ T cells was detected in both blood and liver perfusate from rats fed ethanol even 24 hr after Con A injection. When CD4+ and CD8+ T cells from liver perfusate were cultured in the absence or presence of Con A, an increase in interleukin-6 and tumor necrosis factor-alpha production in supernatants was observed in ethanol-fed rats. In cultures stimulated with Con A, a 2- to 8-fold increase in cytokine production was detected, with intrahepatic CD4+ T cells being the major source. Immunohistological analysis revealed infiltration of CD4+ T cells around portal vein and central vein areas associated with fatty liver and severe hepatic necrosis. The results suggest that alcohol consumption induced a dysregulated T-cell population that mediated hepatic necrosis following polyclonal activation with Con A.
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PMID:Altered T-lymphocyte responsiveness to polyclonal cell activators is responsible for liver cell necrosis in alcohol-fed rats. 962 56

Increases in monocyte/macrophage production of the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), parallel the evolution of liver injury in rats and humans with alcoholic liver disease. However, the possibility that TNF-alpha expression may be induced in other cell populations before serious liver disease develops has not been evaluated. To clarify this issue, mRNAs and/or protein levels of TNF-alpha and cytokines [interleukin (IL)-6, IL-10, transforming growth factor-beta (TGF)-beta, IL-12, and interferon-gamma] that regulate its biological activity were measured in sera, liver, and adipose tissues of rats that had developed hepatic steatosis after consuming ethanol-containing diets for 6 weeks. Cytokine expression in the ethanol-fed groups was compared with that of pair-fed controls rats that had received isocaloric amounts of a similar, ethanol-free diet for the same time period. Animals were studied both before and after a surgical stress (partial hepatectomy) that is known to provoke cytokine production. Chronic ethanol consumption led to increased serum concentrations of TNF and related cytokines, at least in part, by inducing the overproduction of these factors in the liver and peripheral adipose tissues. Despite the pair-feeding protocol that ensured similar calorie consumption in both groups, adipose tissues in ethanol-fed rats also expressed more leptin, a TNF-alpha-inducible mRNA that encodes an appetite-suppressing hormone. Thus, white adipose tissue can be an important source of cytokines in nonobese animals and may be a target for ethanol's actions. These data implicate TNF-alpha as a potential mediator of the nutritional-metabolic aberrations that often accompany chronic alcohol intake, even in the absence of advanced liver disease.
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PMID:Chronic ethanol consumption induces the production of tumor necrosis factor-alpha and related cytokines in liver and adipose tissue. 972 42

Perfluorodecanoic acid (PFDA) is a potent peroxisome proliferator that causes hepatotoxicity but lacks tumor-promoting activity in rats. We previously showed that a single dose of PFDA at 50 mg/kg (approximately LD50) causes an elevation in liver phosphocholine (PCho) and other effects related to phospholipid metabolism. In this study, we examined metabolic effects in the dose range 2-50 mg/kg in rats. At doses < or =20 mg/kg, PFDA is significantly less hepatotoxic than the LD50 as manifested by electron microscopy and measurements of daily food consumption and body weight. At 50 mg/kg rat serum tumor necrosis factor (TNF)-alpha concentration was increased 8-fold, while at 15 mg/kg there was no apparent increase in this cytokine. This lower dose, however, induces metabolic effects similar to those seen at the LD50. Liver fatty acyl-CoA oxidase activity showed a dose-dependent increase from 5-25 mg/kg PFDA. Treatments at 15 and 50 mg/kg caused a significant increase in liver phosphatidylcholine (28 and 66%) and phosphatidylethanolamine (31 and 74%). Both doses caused a significant increase in liver PCho but did not affect liver ATP levels, as manifested in 31P nuclear magnetic resonance (NMR) spectra from rat livers in vivo. These data suggest that the increase in liver [PCho] observed following PFDA exposure in rats represents a specific metabolic response, rather than a broad-range hepatotoxic effect.
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PMID:Dose-response hapatotoxicity of the peroxisome proliferator, perfluorodecanoic acid and the relationship to phospholipid metabolism in rats. 1040 36


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