Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

C3H/HeJ mice were used to study the origin and nature of endotoxin-induced glucocorticoid antagonizing factor (GAF). In conventional mice GAF is believed to be responsible for a variety of effects that occur as a result of an injection of endotoxin, including the inhibition of hormonal induction of hepatic phosphoenolpyruvate carboxykinase and of glyconeogenesis. Responses in such animals are seen whether the endotoxin is extracted with phenol-water or with trichloroacetic acid. C3H/HeJ mice do not respond (or produce GAF?) after an intravenous injection of phenol-water lipopolysaccharide, but they react normally (produce GAF?) when given a trichloroacetic acid preparation. They also behave the same as conventional animals when injected with serum from poisoned normal mice, especially when the reticuloendothelial system of the donors has been activated by prior injections of Zymosan or heat-killed tubercle bacilli. The C3H/HeJ mice have been used, therefore, as assay animals to establish that peak levels of GAF appear in donor serum about 2 h after an injection of lipopolysaccharide, and it is produced intraperitoneally in C3H/HeJ mice given a mixture of endotoxin and peritoneal exudate cells derived from responder mice. GAF elutes from Sephadex G-200 along with markers of known molecular weight in the region of 100,000 to 200,000. It is inactivated by trypsin and by heating at 75 degrees C for 1 h.
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PMID:Elicitation of endotoxemic effects in C3H/HeJ mice with glucocorticoid antagonizing factor and partial characterization of the factor. 34 17

The effect of treatment of rats with bacterial endotoxin on gluconeogenesis and the flux through pyruvate kinase, phosphoenolpyruvate carboxykinase (PEPCK), pyruvate carboxylase and pyruvate dehydrogenase (PDH) was measured in isolated hepatocytes, prepared from animals starved for 18 h, incubated in the presence of 1 mM pyruvate. The lipopolysaccharide reduced gluconeogenesis by 50% and lowered the flux through pyruvate kinase, PEPCK and pyruvate carboxylase by comparable amounts. There was no effect of endotoxaemia on PDH flux, indicating that the lowered rate of gluconeogenesis is not the result of a redistribution of pyruvate metabolism between oxidation and carboxylation. The results confirm that a stimulation of pyruvate kinase activity following treatment with lipopolysaccharide is not involved in the inhibition of gluconeogenesis, but that the effect resides at the level of phosphoenolpyruvate formation. The most favoured mechanism for the inhibition of glucose synthesis is via an inhibition of PEPCK and subsequent feedback inhibition of pyruvate carboxylase, although a secondary effect at the level of the mitochondria and pyruvate carboxylase cannot be excluded.
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PMID:The effect of treatment of the rat with bacterial endotoxin on gluconeogenesis and pyruvate metabolism in subsequently isolated hepatocytes. 842 54

Gap junctions mediate the communication between adjacent cells in tissues. In the liver, connexin 32 (Cx32) subunits make up the predominating gap junctions. The expression of Cx32 gene has been observed to be down-regulated in response to inflammatory states and during liver regeneration. In the present study we attempt to elucidate the molecular mechanisms underlying the down-regulation of the Cx32 expression during acute inflammation. A decrease in the level of Cx32 mRNA in rat liver occurred between 3 and 6 h after intravenous administration of bacterial lipopolysaccharide (LPS), simultaneously with the induction of an acute inflammatory response characterized by an increase in the level for beta-fibrinogen and a reduction of phosphoenolpyruvate carboxykinase mRNA. The reduction in Cx32 steady-state mRNA levels appears to occur at the posttranscriptional level, since the rate of degradation of this message seems to be higher than the rate of transcription of the gene. Degradation of Cx32 mRNA was blocked by the administration of actinomycin D, but not by cycloheximide, prior to injection of LPS. The stabilization of Cx32 message by actinomycin D correlated with the preservation of Cx32 on the cell surface, which otherwise disappears after administration of LPS alone. These results suggest that cellular communication via gap junctions could be regulated at the level of gene expression, by a posttranscriptional mechanism, during acute inflammatory states.
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PMID:Posttranscriptional regulation of connexin 32 expression in liver during acute inflammation. 859 7

The role of nitric oxide in the alterations of liver carbohydrate metabolism during septic shock has been studied in fed and starved animals injected with bacterial lipopolysaccharide (LPS). One h after LPS injection an hyperglycemic peak was observed followed by hypoglycemia when the plasma nitric oxide concentration increased. However, in animals pharmacologically treated with nitric oxide donors only hypoglycemia was observed. In isolated hepatocytes from LPS treated rats an impairment of the gluconeogenic flux was observed accompanied by a decrease in the mRNA levels of the glucose transporter GLUT-2 and phosphoenolpyruvate carboxykinase, at the time that increased the mRNA levels of the inducible form of nitric oxide synthase. These results suggest that part of the effects observed in response to LPS challenge are due to early signaling molecules (cytokines and other factors molecules) whereas other effects can be attributed to nitric oxide synthesis which in turn has specific effects on hepatic metabolism.
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PMID:Characterization of nitric oxide dependent changes in carbohydrate hepatic metabolism during septic shock. 863 9

Treatment of cultured hepatocytes with a combination of cytokines, including tumour necrosis factor-alpha, interferon-gamma and interleukin-1 beta, plus lipopolysaccharide resulted in a time-dependent induction of nitric oxide (NO) synthase (as measured by NO2- (+) NO3- production) and inhibition of hepatic gluconeogenesis and glycogen breakdown. The inhibition of glucose release was comparable with the observed following treatment of rats with lipopolysaccharide or treatment of isolated hepatocytes with artificial NO donors. In addition, this effect was also evident with all substrates tested that enter the gluconeogenic pathway below the level of phosphoenolpyruvate carboxykinase, suggesting that this combination of cytokines may underlie the inhibition of gluconeogenesis observed in endotoxic shock. The maximal inhibition of glucose output required the presence of all the cytokines plus lipopolysaccharide, whereas the induction of NO synthase was independent of the lipopolysaccharide when the cytokines were employed. Inclusion of interferon-gamma was essential to obtain a maximal response for either parameter. Inclusion of 1 mM N(G)-monomethyl-L-arginine in the incubation abolished the increase in NO2- (+) NO3- observed with the complete cytokine mixture and various combinations; however, it failed to prevent the inhibition in glucose output, indicating that mechanisms other than NO underlie the cytokine-induced inhibition of glucose release.
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PMID:Effect of multiple cytokines plus bacterial endotoxin on glucose and nitric oxide production by cultured hepatocytes. 871 78

We studied the protective effect of anti-tumor necrosis factor-alpha (anti-TNF) polyclonal antibody on phosphoenolpyruvate carboxykinase (PEPCK) expression in lipopolysaccharide-induced endotoxemia and peritonitis sepsis induced by cecal incision. At 3 h after intraperitoneal lipopolysaccharide injection, levels of serum glucose, liver glycogen, and PEPCK expression were decreased and serum TNF was elevated. In contrast, 3 h after cecal incision, levels of serum glucose, serum TNF, and PEPCK expression were elevated. At 6 h after cecal incision (terminal sepsis), serum TNF remained elevated and levels of serum glucose, liver glycogen, and PEPCK expression were decreased. Circulating TNF was not detected in septic and endotoxemic rats pretreated with anti-TNF. Passive immunization with rat anti-TNF antibody restored PEPCK expression in early endotoxemia and sepsis (3 h), but not in terminal sepsis (6 h). Anti-TNF failed to reverse sepsis-induced hypoglycemia and hyperglycemia, suggesting that besides TNF, some other mediators are involved in glucose dyshomeostasis.
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PMID:Efficacy of anti-tumor necrosis factor polyclonal antibody on phosphoenolpyruvate carboxykinase expression in septic and endotoxemic rats. 882 86

C-reactive protein (CRP), the prototypic acute-phase reactant in humans, is synthesized in liver in response to a wide variety of inflammatory stimuli. We have generated a line of transgenic mice that express rabbit CRP from the rat phosphoenolpyruvate carboxykinase (PEPCK) promoter in response to gluconeogenic signals. Here we show that transgenic mice expressing high levels of CRP were partially protected from a lethal challenge of bacterial lipopolysaccharide compared with littermates in which CRP expression had been suppressed. Similar protection was observed with challenges from platelet-activating factor (PAF) and the combination of tumor necrosis factor alpha (TNF-alpha) plus interleukin 1beta, but not with TNF-alpha alone. We further demonstrate that although PAF was able to bind CRP, the mechanism by which CRP provides protection probably does not involve sequestration of PAF. The biologically inactive precursor of PAF, lyso-PAF, also bound CRP but did not render the transgenic mice sensitive to PAF when CRP-expressing animals were simultaneously challenged with PAF and an excess of lyso-PAF. These results suggest that CRP functions in vivo by modulating host defense systems.
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PMID:Transgenic mice expressing rabbit C-reactive protein are resistant to endotoxemia. 912 37

Sepsis or endotoxaemia inhibits gluconeogenesis from various substrates, the main effect being related to a change in the phosphoenolpyruvate carboxykinase transcription rate. In addition, sepsis has been reported to affect the oxidative phosphorylation pathway. We have studied glycerol metabolism in hepatocytes isolated from rats fasted and injected 16 h previously with lipopolysaccharide from Escherichia coli. Endotoxin inhibited glycerol metabolism and led to a very large accumulation of glycerol 3-phosphate; the cytosolic reducing state was increased. Furthermore glycerol kinase activity was increased by 33% (P<<0.01). The respiratory rate of intact cells was significantly decreased by sepsis, with glycerol or octanoate as exogenous substrates, whereas oxidative phosphorylation (ATP-to-O ratio or respirations in state 4, state 3 and the oligomycin-insensitive state as well as the uncoupled state) was unchanged in permeabilized hepatocytes. Hence the effect on energy metabolism seems to be present only in intact hepatocytes. An additional important feature was the observation of a significant increase in cellular volume in cells from endotoxic animals, which might account for the alterations induced by sepsis.
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PMID:Inhibition of glycerol metabolism in hepatocytes isolated from endotoxic rats. 923 Jan 36

Induction of nitric oxide synthase by bacterial endotoxin in vivo can be mimicked by treating cultured hepatocytes with a combination of lipopolysaccharide and cytokines (LPS/cytokines), but the role of LPS/cytokine-induced nitric oxide in hepatocyte glucose metabolism is ambiguous. In this study, intermediary metabolite effects on LPS/cytokine-induced hepatocyte nitric oxide synthesis were examined. Pyruvate, lactate, oxaloacetate, and fumarate all showed some inhibitory effects on hepatocyte nitric oxide synthesis. However, these metabolic intermediates could not improve the mitochondrial respiration of LPS/cytokine-treated hepatocytes. Phosphoenolpyruvate carboxykinase activity (or flux) relating factors, glucocorticoids and cAMP, also blocked LPS/cytokine-induced nitric oxide synthesis. Insulin was much less potent than cAMP and glucocorticoids, and phorbol ester did not show any effect on hepatocyte nitric oxide synthesis. These results suggest that LPS/cytokine-induced nitric oxide synthesis is related, at least partly, to phosphoenolpyruvate carboxykinase activity (or flux) in hepatocytes.
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PMID:Role of metabolic intermediates in lipopolysaccharide/cytokine-mediated production of nitric oxide in isolated mouse hepatocytes. 924 Apr 45

The effect of pre-existent hepatic NO synthesis on liver injury induced by lipopolysaccharide was studied in animals carrying a nitric oxide synthase-2 (NOS-2) transgene under the control of the phosphoenolpyruvate carboxykinase (PEPCK) promoter. These animals expressed NOS-2 in liver cells under fasting conditions. Lipopolysaccharide-induced liver injury in D-galactosamine-conditioned mice, which enhanced notably the effect of the endotoxin on the liver, was impaired in animals expressing NOS-2. This protection against inflammatory liver damage was dependent on NO synthesis and was caused by an inhibition of nuclear factor kB (NF-kB) activity and an impairment of the synthesis of the proinflammatory cytokines tumor necrosis factor a and interleukin 1b. These data indicate that intrahepatic synthesis of NO protects liver by inhibiting the release of cascades of proinflammatory mediators and suggest a beneficial role for local delivery of NO in the control of liver injury.
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PMID:Protection by nitric oxide against liver inflammatory injury in animals carrying a nitric oxide synthase-2 transgene. 1125 74


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