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)

Short-term and long-term regulation of hepatic carbohydrate metabolism by insulinlike growth factor-I was studied in primary cultures of adult rat hepatocytes and compared with the metabolic potency of insulin. Insulinlike growth factor-I stimulated the formation of [14C]lactate from [14C]glucose up to three-fold with a half-maximally effective concentration of approximately 50 nmol/L. Basal glycogenolysis was inhibited by about 20%, and glucagon-activated glycogenolysis was blocked completely by insulinlike growth factor-I with half-maximally effective concentrations of about 1.5 to 2 nmol/L. The activity of the key glycolytic enzymes glucokinase and pyruvate kinase were induced twofold. The glucagon-dependent induction of phosphoenolpyruvate carboxykinase--the key gluconeogenic enzyme--was antagonized with a half-maximally effective concentration of about 5 nmol/L. This inhibition of the glucagon-dependent induction of the enzyme was accompanied by a similar reduction of the increase in phosphoenolpyruvate carboxykinase-mRNA level as assessed by Northern blot analysis. The potency of insulinlike growth factor-I at half-maximally effective concentrations was approximately 2% to 4% that of insulin. Because binding studies demonstrated a comparably low affinity of insulinlike growth factor-I to the insulin receptor, it is suggested that in adult liver--in contrast to fetal and regenerating liver--insulinlike growth factor-I could exert short-term and long-term metabolic effects on parenchymal cells only through interaction with the insulin receptor.
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PMID:Metabolic actions of insulin-like growth factor-I in cultured hepatocytes from adult rats. 222 11

Birth represents a dramatic change of nutrition from a fetal diet rich in carbohydrates and poor in fat to a neonatal diet rich in fat and poor in carbohydrates. Gluconeogenesis and ketogenesis are absent or very low in the fetal liver when the mother is correctly fed, and these metabolic pathways emerge after birth to reach adult values after 24 h. Gluconeogenesis increases rapidly in the liver of the newborn in parallel with the appearance of phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme of this metabolic pathway. The rise in plasma glucagon, the fall in plasma insulin and the resulting increase in liver cAMP which occur immediately after birth are the factors which induce the activation of liver PEPCK gene transcription. The appearance of ketogenesis is also controlled by the changes of plasma insulin and glucagon that increase the capacity for liver fatty acid oxidation by decreasing lipogenesis and malonyl-CoA concentration, by reducing the sensitivity of carnitine palmitoyl-CoA I to the inhibitory influence of malonyl-CoA, and by activating hydroxymethylglutaryl-CoA synthase by desuccinylation. Once liver PEPCK has reached adult value, i.e. 12 h after birth, other factors are involved in the regulation of hepatic gluconeogenesis. Indeed, the supply of gluconeogenic substrates and of free fatty acid is of crucial importance to support a high rate of gluconeogenesis and to maintain normoglycemia in the newborn. In the liver, fatty acid oxidation provides essential co-factors (acetyl-CoA, NADH and ATP) to support gluconeogenesis, and in peripheral tissue fatty acid oxidation inhibits glucose oxidation and stimulates the production of gluconeogenic precursors (lactate, pyruvate and alanine). Similar mechanisms are operative in human newborn. A defective hepatic fatty acid oxidation is likely to explain the frequent hypoglycemia observed in small-for-date neonates. Administration of oral triglycerides is an efficient mean to prevent hypoglycemia in these newborns.
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PMID:Metabolic adaptations to change of nutrition at birth. 226 17

Regulation of gene transcription is a major action of insulin. Most of the greater than 20 examples of this effect involve the stimulation of transcription, but a few involve an inhibition. The inhibition of transcription of the phosphoenolpyruvate carboxykinase (PEPCK) gene has been studied in detail. Most of this effect is exerted at the level of transcription initiation. Hormone effects on transcription are thought to be mediated through cis-acting DNA sequences located in the 5'-flanking sequence adjacent to the transcription initiation site. The techniques of transient and stable transfection of fusion genes containing various segments of the PEPCK-gene promoter are being used to locate the insulin-responsive sequences.
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PMID:PEPCK gene as model of inhibitory effects of insulin on gene transcription. 240 80

Transcription of the gene for the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK) from the rat is acutely regulated by a number of hormones, including glucagon (acting via cAMP), glucocorticoids, and insulin. In this study we demonstrate by DNase I footprinting that a region of the PEPCK promoter, extending from -460 to +73, contained eight protein binding domains. Two nuclear proteins protected adjacent sites from -121 to -99 and -96 to -77, which have been previously shown to be involved in maintaining the level of basal gene transcription and conferring cAMP responsiveness, respectively. Oligonucleotide competition studies suggested that the protein(s) binding to the cAMP-responsive element (CRE) occupies a second site at -147 to -130, which has a high degree of sequence homology to the CRE, and also binds to two other elements that show partial sequence homologies. The protein(s) which bound to these four elements copurified through oligonucleotide affinity chromatography, suggesting that the PEPCK promoter has four binding sites for the CRE-binding protein(s). Potential tissue-specific elements in the PEPCK promoter were identified by footprinting with nuclear extracts prepared from rat liver, kidney, brain, and spleen. The multiple protein-binding sites in this promoter-regulatory region reflect the complex transcriptional regulation that is characteristic of this gene.
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PMID:Identification of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase (GTP) gene. 254 17

Hepatocytes isolated from adult fasted rats and cultured in the presence of thyroid hormones, glucocorticoids, and in a serum-free medium conserve the essentials of their differentiated function and hormonal sensitivity for at least 1 week. In these cells, the gene for L-type pyruvate kinase is expressed only when glucose and insulin are present together, each of them being inactive by itself. Inhibition of the expression of the L-type pyruvate kinase gene which occurs when glucose and/or insulin are removed from the culture medium is not associated with accumulation of the phosphoenolpyruvate carboxykinase mRNA, which argues against the involvement of intracellular cyclic AMP in this phenomenon. Rather, a transcriptional activator, derived from carbohydrate metabolism and accumulating in the presence of insulin, seems to be needed to support the expression of the L-type pyruvate kinase gene. Glucagon, in vitro as in vivo, inhibits production of the L-type pyruvate kinase mRNAs. In addition to their roles on the production of these mRNAs, glucose and insulin on the one hand and glucagon on the other have profound effects on the stability of the L-type pyruvate kinase messengers: the half-life of the mRNA whose production has been blocked by actinomycin D is 1 h in the presence of glucagon and 24 h in the presence of glucose and insulin. Glucagon and glucose/insulin partially antagonize each other's effect on mRNA stability.
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PMID:Regulation of the expression of the L-type pyruvate kinase gene in adult rat hepatocytes in primary culture. 254 75

Using the well differentiated rat hepatoma Fao we have studied the regulation of phosphoenolpyruvate carboxykinase (PEPCK) mRNA by insulin and glucose and compared these results to glucose production as estimated by glucose release into the medium. Fao cells possess an active gluconeogenic pathway and, when grown in glucose-free medium, release glucose for over 8 h. Addition of the cAMP analog, 8-(4-chlorophenyl-thio) cAMP (8-CTP-cAMP) or increasing the concentration of dihydroxyacetone and oxaloacetate results in an increase in glucose release which can be suppressed by insulin at concentrations between 1 and 100 nM. These effect of cAMP and insulin are associated with parallel changes in the level of mRNAPEPCK. Insulin treatment reduces mRNAPEPCK levels in these cells by 80%; this effect is transient reaching a maximum at 2-4 h. Addition of glucose to cells grown in glucose-free (G-) medium produces a decrease in mRNAPEPCK which is similar in magnitude and kinetics to that produced by insulin. Conversely, when cells grown in normal medium are placed in G- medium mRNAPEPCK levels triple over a period of 8 h, then return toward the basal value. Cells grown in G- medium or in G- medium plus 10nM insulin for 1 yr exhibit only slightly increased levels of mRNAPEPCK and respond to both 8-CTP-cAMP, and insulin, although the response to 8-CTP-cAMP is slightly blunted. These data indicate that glucose and insulin can play independent roles in regulation of PEPCK gene expression, and that these regulatory effects are usually transient.
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PMID:Acute and chronic regulation of phosphoenolpyruvate carboxykinase mRNA by insulin and glucose. 254 57

We used indirect end labeling to identify a series of five hypersensitive (HS) sites in the phosphoenolpyruvate carboxykinase (PEPCK) gene in H4IIE rat hepatoma cells. These sites were found at -4800 base pairs (bp) (site A), at -1300 bp (site B), over a broad domain between -400 and -30 bp (site C), at +4650 bp (site D), and at +6200 bp (site E). Sites A to D were detected only in cells capable of expressing the PEPCK gene, whereas site E was present in all of the cells examined thus far. The HS sites were present in H4IIE cells even when transcriptional activity was reduced to a minimum by treatment with insulin. Stimulation of transcription by a cyclic AMP analog to a 40-fold increase over the insulin-repressed level did not affect the main features of the HS sites. Furthermore, increased transcription did not disrupt the nucleosomal arrangement of the coding region of the gene, nor did it affect the immediate 5' region (site C), which is always nucleosome-free. In HTC cells, a rat hepatoma line that is hormonally responsive but unable to synthesize PEPCK mRNA, the four expression-specific HS sites were totally absent. Our experimental results also showed that, although there is a general correlation between lack of DNA methylation and transcriptional competence of the PEPCK gene, the role, if any, of methylation in the regulation of PEPCK gene activity is likely to be exerted at very specific sites.
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PMID:Hormonal regulation of phosphoenolpyruvate carboxykinase gene expression is mediated through modulation of an already disrupted chromatin structure. 265 89

The acinar activity pattern of phosphoenolpyruvate carboxykinase (PEPCK) was investigated in livers of streptozotocin diabetic male and female rats and in addition in livers of diabetic males, which had undergone estrogen treatment. In all diabetic animals blood glucose levels were supranormal and liver PEPCK activity was increased. This increase in activity was greatest in estrogen treated diabetic males and lowest in diabetic females. Plasma insulin levels were reduced after the application of streptozotocin to otherwise normal male and female rats. Yet, in males treated in addition with estrogens the plasma insulin levels reached the normal range again. The PEPCK activity showed a heterotopic distribution along the acinus. The periportal to perivenous gradient was steeper in males compared to females in the untreated as well as in the diabetic state. The application of estrogens to males resulted in a further steepening of the gradient.
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PMID:Phosphoenolpyruvate carboxykinase activity patterns in the liver acinus of diabetic and diabetic and estrogen treated rats. 269 16

The mRNA for the important gluconeogenic enzyme phosphoenolpyruvate carboxykinase (GTP) (PEPCK; EC 4.1.1.32) is expressed in liver and kidney. In the kidney, acidosis is a unique and potent stimulus, whereas insulin, the major counterregulatory hormone of gluconeogenesis, has no effect. In this study, we find that oral glucose administration to rats rapidly decreases the abundance of renal PEPCK mRNA by 50-72%. This reduction takes place in normal euglycemic, in insulin-induced hypoglycemic, and in streptozotocin-induced hyperglycemic diabetic animals. The effect of glucose is not seen in the presence of metabolic acidosis, whether induced by NH4Cl or by prolonged fasting. Therefore, it appears that oral glucose loading is a physiological suppressor of renal PEPCK message abundance, although not in acidosis.
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PMID:Induction of renal phosphoenolpyruvate carboxykinase mRNA: suppressive effect of glucose. 275 Sep 19

The multihormonal regulation of phosphoenolpyruvate carboxykinase (PEPCK) was studied using chimeric genes composed of various regions of the PEPCK gene promoter region fused to the coding sequence of the chloramphenicol acetyltransferase (CAT) gene. These constructions, transfected into H4IIE hepatoma cells, are regulated like the endogenous PEPCK gene: dexamethasone and cAMP both stimulate PEPCK-CAT gene expression and their effects are additive; insulin inhibits the individual or combined effects of these stimulatory agents; and insulin inhibits dexamethasone-stimulated PEPCK-CAT fusion gene expression in a concentration-dependent fashion that is half-maximal at 10(-11) M. The induction by dexamethasone and the inhibition by insulin is specific for the DNA sequences that flank the 5' end of the PEPCK gene because similar effects were not observed for a plasmid in which the promoter and enhancer sequences of simian virus 40 (SV40) are fused to CAT. These results imply that the DNA adjacent to the transcription start site of the PEPCK gene contains the cis-acting hormone response elements responsible for the multihormonal regulation of this gene, including the insulin response.
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PMID:Multihormonal regulation of phosphoenolpyruvate carboxykinase-chloramphenicol acetyltransferase fusion genes. Insulin's effects oppose those of cAMP and dexamethasone. 282 6


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