Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin on Escherichia coli was studied using wild type E. coli B/r and K12 strains and a number of phosphoenolpyruvate phosphotransferase mutants. In vivo, the effects of insulin on the differential rate of tryptophanase synthesis, the rate of alpha-methylglucoside uptake and the rate of growth on glucose were determined in E. coli B/r. In vitro, the effect of insulin on the adenylate cyclase and the phosphotransferase activities was determined using toluenized cell preparations of E. coli B/r, E. coli K12 and phosphotransferase mutant strains. The specificity of insulin action on E. coli was determined using glucagon, vasopressin and somatropin as well as insulin antisera. Results show the specific action of insulin on E. coli, inhibiting tryptophanase induction and adenylate cyclase activity, while stimulating growth on glucose and uptake and phosphorylation of alpha-methylglucoside.
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PMID:Insulin action on Escherichia coli. Regulation of the adenylate cyclase and phosphotransferase enzymes. 35 93

Biochemical functions of human livers were studied using fetal hepatocytes in primary culture. Immunocytochemical staining showed that albumin was not expressed in any fetal hepatocytes, whereas alpha-fetoprotein was detected in almost all the cells. Tryptophan 2,3-dioxygenase (TO, EC 1.13.11.11.) activity was not induced in the presence of 10(-7) M dexamethasone and 10(-7) M glucagon, but the activity of tyrosine aminotransferase (TAT, EC 2.6.1.5.) was elevated about 35 fold under the same conditions. These results suggest that the TAT and alpha-fetoprotein genes are activated in human fetal liver at 14 to 20 weeks of gestation.
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PMID:Studies on the expression of liver-specific functions of human fetal hepatocytes in primary culture. 244 88

When hepatocytes isolated from adult rats were cultured in the presence of 10 mM nicotinamide, insulin- and epidermal growth factor-induced DNA synthesis and cell proliferation were found to be greatly stimulated, and the cells were able to be kept alive for more than one month. In the nicotinamide-treated hepatocytes, albumin and tryptophan 2,3-dioxygenase mRNAs were present at much higher levels than in the untreated control, and the inducibility of tryptophan oxygenase gene expression by dexamethasone and glucagon was also preserved. Without nicotinamide, primary cultured hepatocytes were viable for only 5-7 days and the hepatocyte-specific phenotypes were rapidly lost. The intracellular NAD level was maintained in the nicotinamide-treated hepatocytes at or above the level in intact liver but depleted in hepatocytes without nicotinamide. These results suggest that the maintenance of the intracellular NAD level is essential for the growth and functioning of hepatocytes and that nicotinamide can preserve the NAD level by blocking NAD degradation as well as by acting as a precursor for NAD synthesis.
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PMID:Nicotinamide prolongs survival of primary cultured hepatocytes without involving loss of hepatocyte-specific functions. 252 46

The quantitative importance of the individual steps of aromatic amino acid metabolism in rat liver was determined by calculation of the respective Control Coefficients (Strengths). The Control Coefficient of tryptophan 2,3-dioxygenase for tryptophan degradation was determined in a variety of physiological conditions and with a range of activities of tryptophan 2,3-dioxygenase. The Control Coefficient varied from 0.75 with basal enzyme activity to 0.25 after maximal induction of the enzyme by dexamethasone. The remainder of the control for tryptophan degradation was associated with the transport of the amino acid across the plasma membrane, with only very small contributions from kynureninase and kynurenine hydroxylase. The Control Coefficients of tyrosine aminotransferase for tyrosine degradation were approx. 0.70 and 0.20 with basal and dexamethasone-induced tyrosine aminotransferase activities respectively; the Control Coefficients of the transport of the amino acid into the cell were 0.22 and 0.58 respectively. Phenylalanine hydroxylase was found to have a Control Coefficient for the degradation of phenylalanine of approx. 0.50 under conditions of basal enzyme activity; after maximal activation by glucagon, the Control Coefficient decreased to 0.12. The transport of phenylalanine was responsible for the remaining control in the pathway. These results have important implications, directly for the regulation of aromatic amino acid metabolism in the liver, and indirectly for the regulation of neuroamine synthesis in the brain.
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PMID:Quantification of the importance of individual steps in the control of aromatic amino acid metabolism. 287 85

Epidermal growth factor (EGF) dose-dependently enhanced the induction of tyrosine aminotransferase and tryptophan oxygenase by glucocorticoids in primary cultures of adult rat hepatocytes without itself having any effect on these enzymes in the absence of glucocorticoids. The amplifications were observed even with dexamethasone at high concentrations (10(-6) M-10(-5) M) that had a maximal effect. EGF had no effect on induction of tyrosine aminotransferase by glucagon or Bt2cAMP. The effect of EGF was also observed in adrenal-ectomized and submaxillary gland-ectomized rats. These results suggest that EGF is an endogenous amplifier of the action of glucocorticoids.
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PMID:Epidermal growth factor as a new regulator of induction of tyrosine aminotransferase and tryptophan oxygenase by glucocorticoids. 288 20

Cyclic AMP-dependent protein kinases I and II, partially purified from rat liver cytosol, were inhibited 50% by 40 microM hemin and 100 microM hemin, respectively. With the purified catalytic subunit of cyclic AMP-dependent protein kinase, hemin caused non-competitive inhibition with respect to the peptide substrate and mixed inhibition with respect to ATP. Hemin also inhibited purified phosphorylase b kinase, indicating that hemin concentrations above 10 microM markedly inhibit multiple protein kinases. In isolated intact hepatocytes, hemin inhibited the glucagon-dependent activation of cyclic AMP-dependent protein kinases and the activation of glycogen phosphorylase. For both effects, high heme concentrations (40-60 microM) were required for 50% inhibition. Similar high levels of exogenous hemin inhibited total hepatocyte protein synthesis. By contrast, 5 microM hemin or less was sufficient to raise intracellular heme levels, as indicated by the relative heme-saturation of tryptophan oxygenase in hepatocytes. Hemin, 5 microM, completely repressed induction of 5-aminolevulinate synthase by dexamethasone in hepatocyte primary cultures. Such repression is unlikely to be mediated by inhibition of protein kinases.
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PMID:Effects of hemin on rat liver cyclic AMP-dependent protein kinases in cell extracts and intact hepatocytes. 299 84

Acute hormonal regulation of liver carbohydrate metabolism mainly involves changes in the cytosolic levels of cAMP and Ca2+. Epinephrine, acting through beta 2-adrenergic receptors, and glucagon activate adenylate cyclase in the liver plasma membrane through a mechanism involving a guanine nucleotide-binding protein that is stimulatory to the enzyme. The resulting accumulation of cAMP leads to activation of cAMP-dependent protein kinase, which, in turn, phosphorylates many intracellular enzymes involved in the regulation of glycogen metabolism, gluconeogenesis, and glycolysis. These are (1) phosphorylase b kinase, which is activated and, in turn, phosphorylates and activates phosphorylase, the rate-limiting enzyme for glycogen breakdown; (2) glycogen synthase, which is inactivated and is rate-controlling for glycogen synthesis; (3) pyruvate kinase, which is inactivated and is an important regulatory enzyme for glycolysis; and (4) the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase bifunctional enzyme, phosphorylation of which leads to decreased formation of fructose 2,6-P2, which is an activator of 6-phosphofructo-1-kinase and an inhibitor of fructose 1,6-bisphosphatase, both of which are important regulatory enzymes for glycolysis and gluconeogenesis. In addition to rapid effects of glucagon and beta-adrenergic agonists to increase hepatic glucose output by stimulating glycogenolysis and gluconeogenesis and inhibiting glycogen synthesis and glycolysis, these agents produce longer-term stimulatory effects on gluconeogenesis through altered synthesis of certain enzymes of gluconeogenesis/glycolysis and amino acid metabolism. For example, P-enolpyruvate carboxykinase is induced through an effect at the level of transcription mediated by cAMP-dependent protein kinase. Tyrosine amino-transferase, serine dehydratase, tryptophan oxygenase, and glucokinase are also regulated by cAMP, in part at the level of specific messenger RNA synthesis. The sympathetic nervous system and its neurohumoral agonists epinephrine and norepinephrine also rapidly alter hepatic glycogen metabolism and gluconeogenesis acting through alpha 1-adrenergic receptors. The primary response to these agonists is the phosphodiesterase-mediated breakdown of the plasma membrane polyphosphoinositide phosphatidylinositol 4,5-P2 to inositol 1,4,5-P3 and 1,2-diacylglycerol. This involves a guanine nucleotide-binding protein that is different from those involved in the regulation of adenylate cyclase. Inositol 1,4,5-P3 acts as an intracellular messenger for Ca2+ mobilization by releasing Ca2+ from the endoplasmic reticulum.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanisms of hormonal regulation of hepatic glucose metabolism. 303 41

For study of hormonal regulation of gene expression of tryptophan 2,3-dioxygenase (EC 1. 13. 11. 11, TO), a DNA clone containing a sequence complementary to TO mRNA was prepared with TO mRNA from rat liver enriched 62-fold by immunoadsorption. Primary cultures of adult rat hepatocytes were treated with dexamethasone, and the amount of TO mRNA was measured by RNA dot-blot hybridization with this TO cDNA. Dexamethasone induced this TO mRNA 7-fold, while their treatments with dexamethasone plus glucagon induced the TO mRNA 18-fold. This induction of TO mRNA by dexamethasone plus glucagon was inhibited by insulin or epinephrine. Studies on transcription in isolated nuclei showed that these hormonal changes in the level of TO mRNA were caused by changes in the rate of transcription of the TO gene. Thus, expression of TO in the liver is regulated multihormonally at the transcriptional step. There was a long lag period before stimulation of transcription of the TO gene by dexamethasone in hepatocytes cultured for 20 h: the maximal rate was attained after 6-8 h. The lag time depended on the culture time without dexamethasone and was shorter after shorter culture of the cells. This finding suggested that a transcriptional factor that was lost during culture mediated the action of glucocorticoids. Consistent with this idea, cycloheximide or puromycin almost completely blocked enhanced transcription of the TO gene by dexamethasone after a 20-h culture, but not after a 2-h culture. These findings indicate that a short-lived transcriptional protein, which is also regulated by glucocorticoids, mediates their effect on expression of the TO gene.
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PMID:Multihormonal regulation of transcription of the tryptophan 2,3-dioxygenase gene in primary cultures of adult rat hepatocytes with special reference to the presence of a transcriptional protein mediating the action of glucocorticoids. 354 92

The developmental change in gene expression of tryptophan 2,3-dioxygenase (EC 1.13.11.11) in rat liver was studied by dot-blot hybridization with cDNA of the enzyme as a probe. The mRNA of tryptophan oxygenase is not expressed in fetal liver, but is expressed very slightly 1 day after birth. Its expression increases first gradually until 12 days after birth and then rapidly, and reaches the adult level about 22 days after birth. On the other hand, mRNA of albumin in the liver, measured with its cDNA, increases rapidly in the late fetal period and reaches almost the adult level at the time of birth. Studies on in vitro transcription by the nuclear run-off technique showed that the developmental increases in the mRNAs of tryptophan oxygenase and albumin are caused by an increase in the rates of transcription of their genes. Treatment of rats with cortisol significantly increased the amount of tryptophan oxygenase mRNA in the liver from soon after birth. This treatment did not increase mRNA of albumin. It is suggested from these findings that the gene of tryptophan oxygenase is switched on as early as the first day after birth in the few differentiated hepatocytes present in the liver and that the number of these differentiated cells gradually increases during early postnatal development. Although injected glucocorticoid stimulated transcription of the gene of tryptophan oxygenase precociously during this period, presumably in vivo the activity of tryptophan oxygenase normally increases about 2 weeks after birth, because this is when the plasma concentrations of glucocorticoid and glucagon increase sufficiently to be effective.
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PMID:Developmental control of gene expression of tryptophan 2,3-dioxygenase in neonatal rat liver. 374 71

Rat parenchymal hepatocytes isolated with collagenase were cultured as monolayers in Williams medium E supplemented with calf serum. Freshly isolated cells showed very low activities of various liver functions, and they had to be cultured for 6-24 h to allow recovery of these functions. Insulin and dexamethasone greatly increased cell viability in primary. After culture for 24 h, these cells showed various liver functions as seen in vivo and responded well to various added hormones and amino acids. The concentrations of amino acids in the medium regulated synthesis of serum proteins and insulin stimulated lipogenesis, which in turn regulated synthesis of lipoproteins. Insulin also stimulated glycogen synthesis and the stimulation was parallel with the number of insulin receptors. Glucagon stimulated glycogenolysis and its stimulation involved the function of the cytoskeleton. Glucagon and dexamethasone induced various enzymes of amino acid catabolism, such as tryptophan oxygenase, tyrosine aminotransferase and serine dehydratase. These inductions were inhibited by insulin or catecholamine. The effect of catecholamine was due to its alpha-adrenergic action. The beta-action of isoproterenol was low in freshly isolated cells, but increased during culture of the cells. Acquirement of hormonal responses during neonatal development can be studied in this culture system. Mature hepatocytes in culture are usually quiescent, but when insulin and epidermal growth factor were added, DNA synthesis by the cells increased markedly and they showed density-dependent growth. In this culture system, serum could be omitted for 2 days when the dishes were coated with fibronectin without appreciable change of functions, but serum was needed for longer culture of the cells. A factor that increased cell survival was found in serum and in pituitary gland. These results show that hepatocytes in primary culture are a simple and useful system for studies of liver functions in vitro and related works were also reviewed.
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PMID:Use of hepatocytes in primary culture for biochemical studies on liver functions. 612 41


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