Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.1.1.49 (phosphoenolpyruvate carboxykinase)
4,654 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The control of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2; EC 2.7.1.105/3.1.3.46) gene expression during liver regeneration was studied. The level of PFK-2/FBPase-2 mRNA decreased to about 5% of the control value 6 hr after partial hepatectomy. Thereafter the mRNA increased to a maximum at 48 hr and returned to normal levels by 96 hr. In sham-operated animals, only a small increase was observed during the first 4 hr. The mRNA was recognized by a 299-base-pair liver-specific cDNA probe but not by a muscle-specific probe. The time course of mRNA modulation was well correlated with PFK-2/FBPase-2 activity and with the amount of bifunctional enzyme protein determined by immunoblotting with an antibody raised against the N-terminal decapeptide of liver PFK-2/FBPase-2. No alteration in the degradation rate of PFK-2/FBPase-2 mRNA was noted after partial hepatectomy. The modulation of PFK-2/FBPase-2 gene expression during liver regeneration involved changes in the transcription rate. The rate decreased by 50% at 6 hr after liver resection. The rate increased thereafter to a maximum at 72 hr and then returned to control values by 96 hr. The transcription rate of albumin did not change, whereas that of phosphoenolpyruvate carboxykinase increased 12-fold at 6 hr. These results show that PFK-2/FBPase-2 gene transcription is specifically regulated and that this regulation is in part responsible for the alterations in hepatic metabolism seen in regenerating liver.
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PMID:Transcriptional and posttranscriptional regulation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase during liver regeneration. 131 37

Changes in plasma glucose, hepatic cyclic AMP, glycogen and fructose 2,6-bisphosphate (F-2,6-P2), and liver 6-phosphofructo-2-kinase (6-PF-2kinase), fructose 2,6-bisphosphatase (F-2,6-P2ase) and phosphoenolpyruvate carboxykinase (PEPCK) activities were examined in rats fed a low protein, high carbohydrate (HC) diet during 3 d of either starvation or feeding a high protein, carbohydrate-free (HP) diet. Under both HP feeding or starvation, liver cyclic AMP increased after 1 d and remained constant thereafter. Whereas plasma glucose was low during starvation, it was unaffected by HP feeding. In both experimental groups, liver glycogen fell after 1 d; thereafter it remained low on starvation, but increased progressively on HP diet reaching 70% of the HC-fed rats value on day 3. Under both experimental conditions, F-2,6-P2 fell 85% after day 1 and was unchanged thereafter. One day after the start of starvation or consumption of the HP diet, 6-PF-2kinase decreased, F-2,6-P2ase increased and 6-PF-2kinase/F-2,6-P2ase ratio decreased, but changes were significantly more important with the HP diet than with starvation. PEPCK activity increased in both experimental conditions, but the increase was greater on the HP diet than on starvation. These findings suggest that during the first 3 d the adaptative response of hepatic gluconeogenesis is higher with a HP diet than upon starvation.
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PMID:Changes in rat hepatic fructose 2,6-bisphosphate and 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase activity during three days of consumption of a high protein diet or starvation. 282 29

Pertinent hepatic metabolites and enzymes were examined in rats fed a high carbohydrate (HC) diet and during the first 24 h of either starvation or feeding a high protein (HP) diet. Consumption of the HC diet induced slight but definite 24-h oscillations in hepatic concentrations of cyclic AMP, glycogen, glucose 6-phosphate, fructose 2,6-bisphosphate, fructose 1,6-bisphosphate and phosphoenolpyruvate, as well as the activities of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase and phosphoenolpyruvate carboxykinase. The transition to starvation or the HP diet induced, within 12 h, concurrent increases in cyclic AMP and phosphoenolpyruvate and decreases in glycogen, glucose 6-phosphate, fructose 6-phosphate, fructose 2,6-bisphosphate and fructose 1,6-bisphosphate. These changes were associated with a decrease in the ratio of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase and an increase in phosphoenolpyruvate carboxykinase. These results suggest that the activity of the fructose 6-phosphate/fructose 1,6-bisphosphate cycle is similar during the first 24 h of starvation or HP consumption.
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PMID:Studies on the early changes in rat hepatic fructose 2,6-bisphosphate and enzymes in response to a high protein diet. 300 33

Incubation of fetal hepatocytes from 21-day-old rats with permeant derivatives of cyclic AMP (cAMP) or glucagon, increased the mRNA levels of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase (PFK-2/FBPase-2), L-pyruvate kinase (L-PK) and phosphoenolpyruvate carboxykinase (PEPCK). Contrary to this behavior, adult hepatocytes exhibited a decrease in the PFK-2/FBPase-2 and L-PK mRNA levels when incubated under equivalent experimental conditions. Dexamethasone also increased the PFK-2/FBPase-2 mRNA levels and costimulation of fetal hepatocytes with dexamethasone and a permeant analogue of cyclic AMP enhanced the levels of PFK-2/FBPase-2 mRNA, a situation opposite to that exhibited by adult hepatocytes. Treatment of the hepatocytes with transcriptional and translational inhibitors also produced differential responses in both types of cells. The PFK-2/FBPase-2 mRNA in fetal hepatocytes was more stable than in the adult cells. These results suggest that specific transcriptional factors and regulatory pathways differentially operate in fetal and adult hepatocytes in the control of the responses of carbohydrate metabolism to cAMP.
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PMID:Differential regulation of the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase and pyruvate kinase by cyclic adenosine 3',5'-monophosphate in fetal and adult hepatocytes. 759 43

Oral administration of tungstate for 15 days normalized glycemia in streptozotocin-induced diabetic rats. Simultaneously, the alterations in hepatic glucose metabolism due to diabetes were almost completely counteracted by this treatment. Thus, 6-phosphofructo-2-kinase, L-pyruvate kinase, and glycogen phosphorylase alpha activities reached levels similar to those observed in healthy animals. Hepatic levels of fructose 2,6-bisphosphate and glycogen also recovered. However, the recovery of glucokinase activity and hepatic levels of glucose 6-phosphate was only partial. The total activity of glycogen synthase increased, although the activation state was not recovered. Moreover, mRNA levels of hepatic glucokinase, glycogen phosphorylase, and phosphoenolpyruvate carboxykinase were also normalized. Tungstate administration in healthy animals also affected all these parameters, although to a much lesser extent. All these effects were similar to those previously reported for vanadate, suggesting a common mechanism of action in vivo.
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PMID:Insulin-like actions of tungstate in diabetic rats. Normalization of hepatic glucose metabolism. 805 Oct 90

The control of hepatic 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase gene expression by glucagon was studied. Intraperitoneal administration of glucagon rapidly decreased the fructose 2,6-bisphosphate content by phosphorylation of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase and diminution of its Vmax. Immunologic studies using a specific liver antibody showed that the amount of enzyme rapidly decreased. Northern blot analysis showed that the isozyme expressed is the adult liver form. The 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase mRNA content decreased, whereas that of phosphoenolpyruvate carboxykinase increased, and that of albumin did not change. Run-on transcription assays with isolated nuclei showed inhibition in the relative transcription rate of the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase gene and a stimulation of phosphoenolpyruvate carboxykinase gene. The regulation of mRNA stability of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase by glucagon was also studied. The half-life of mRNA decreased in the presence of glucagon, suggesting that proteins modulated by a glucagon-dependent process are regulating its stability. The time course of mRNA levels correlated with the transcription inhibition of gene and destabilization of mRNA, indicating that glucagon modulates 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase gene expression at both transcriptional and posttranscriptional levels.
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PMID:Regulation of hepatic 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase gene expression by glucagon. 822 64

The actions of the phorbol ester phorbol 12-myristate 13-acetate (PMA) on glucose metabolism, amino acid transport and enzyme inductions were studied in primary cultures of adult-rat hepatocytes and compared with the effects of insulin. PMA and insulin stimulated glycolysis 5- and 7-fold respectively. The half-maximal effective dose of PMA was 60 nM. Stimulation of glycolysis was accompanied by an insulin- or PMA-dependent and okadaic acid-sensitive activation of 6-phosphofructo-2-kinase and pyruvate kinase, as well as by an increase in fructose 2,6-bisphosphate. Glucose production from glycogen was decreased to 50% by PMA and to 15% by insulin, whereas glycogen synthesis was stimulated 2- and 7-fold respectively. PMA also increased aminoisobutyrate uptake, induced ornithine decarboxylase and counteracted the glucagon-dependent induction of phosphoenolpyruvate carboxykinase. PMA strongly antagonized the hormonal activation of glycogen synthesis, but all other insulin actions assayed were not decreased by the phorbol ester. Whereas additive effects of PMA and insulin were not detected, PMA and a simultaneous increase in the glucose concentration had additive effects on glycolysis and glycogen metabolism. Cell exposure to insulin resulted in receptor autophosphorylation and a more than 10-fold activation of the receptor tyrosine kinase. PMA did not alter these effects, and also had no effect on the receptor phosphorylation status in the absence of insulin. Long-term (15 h) pretreatment of the cells with PMA abolished all PMA effects, but not the insulin effects. It is concluded that PMA does not generally antagonize the action of insulin in differentiated adult hepatocytes, and that insulin and PMA may use related signal-transduction pathways.
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PMID:Insulin-mimetic actions of phorbol ester in cultured adult rat hepatocytes. Lack of phorbol-ester-elicited inhibition of the insulin signal. 838 Sep 98

The specific binding sites for sulfonylureas in the rat liver membrane fraction were demonstrated and characterized. [3H]Glibenclamide binding to the liver membrane was specific, time- and temperature-dependent, and reversible. Scatchard analysis showed a single class binding site. The dissociation constant (Kd) for glibenclamide was 1.1 microM and the binding capacity (Bmax) was 50 pmol/mg protein. [3H]Glibenclamide binding could be displaced by other sulfonylureas. Half-maximal inhibition of binding (IC50) for glimepiride, gliclazide, acetohexamide, tolbutamide and chlorpropamide was 4.2 microM, 74 microM, 0.33 mM, 0.60 mM, 1.2 mM, respectively. Each value is close to the reported blood concentration when a therapeutic dose of each drug is administered orally. The order of IC50 values is coincident with the order of potency of the clinical hypoglycemic effect of these drugs. We had shown that these concentrations of sulfonylureas stimulate 6-phosphofructo-2-kinase in the liver or hepatocytes and inhibit phosphoenolpyruvate carboxykinase in the hepatoma cells. The specific binding sites demonstrated here may play some roles when sulfonylureas affect carbohydrate metabolism in the liver.
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PMID:Characterization of the binding sites for [3H]glibenclamide in rat liver membranes. 854 39

Glucocorticoids exert their effects on gene transcription through ubiquitous receptors that bind to regulatory sequences present in many genes. These glucocorticoid receptors are present in all cell types, yet glucocorticoid action is controlled in a tissue-specific way. One mechanism for this control relies on tissue-specific transcriptional activators that bind in the vicinity of the glucocorticoid receptor and are required for receptor action. We now describe a gene-specific and tissue-specific inhibitory mechanism through which glucocorticoid action is repressed by a tissue-restricted transcription factor, hepatocyte nuclear factor-6 (HNF-6). HNF-6 inhibits the glucocorticoid-induced stimulation of two genes coding for enzymes of liver glucose metabolism, namely 6-phosphofructo-2-kinase and phosphoenolpyruvate carboxykinase. Binding of HNF-6 to DNA is required for inhibition of glucocorticoid receptor activity. In vitro and in vivo experiments suggest that this inhibition is mediated by a direct HNF-6/glucocorticoid receptor interaction involving the amino-terminal domain of HNF-6 and the DNA-binding domain of the receptor. Thus, in addition to its known property of stimulating transcription of liver-expressed genes, HNF-6 can antagonize glucocorticoid-stimulated gene transcription.
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PMID:Antiglucocorticoid activity of hepatocyte nuclear factor-6. 1043 Aug 78

Fructose 2,6-bisphosphate (Fru-2,6-P2) is an important metabolite that controls glycolytic and gluconeogenic pathways in several cell types. Its synthesis and degradation are catalyzed by the bifunctional enzyme 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase (PFK-2). Four genes, designated Pfkfb1-4, codify the different PFK-2 isozymes. The Pfkfb3 gene product, ubiquitous PFK-2 (uPFK-2), has the highest kinase/bisphosphatase activity ratio and is associated with proliferation and tumor metabolism. A transgenic mouse model that overexpresses uPFK-2 under the control of the phosphoenolpyruvate carboxykinase promoter was designed to promote sustained and elevated Fru-2,6-P2 levels in the liver. Our results demonstrate that in diet-induced obesity, high Fru-2,6-P2 levels in transgenic livers caused changes in hepatic gene expression profiles for key gluconeogenic and lipogenic enzymes, as well as an accumulation of lipids in periportal cells, and weight gain.
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PMID:Overexpression of ubiquitous 6-phosphofructo-2-kinase in the liver of transgenic mice results in weight gain. 1799 24


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