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:2.7.11.2 (PDK1)
2,238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The increased activity of pyruvate dehydrogenase (PDH) kinase induced in hearts of rats by starvation for 48 h was maintained following preparation of cardiac myocytes, and it was also maintained, though at a decreased level, after 25 h of culture in medium 199. This loss of PDH kinase activity was not prevented by n-octanoate, dibutyryl cyclic AMP or glucagon. The PDH kinase activity of myocytes from fed rats was increased to that of starved rats after 25 h of culture with n-octanoate, dibutyryl cyclic AMP or both agents together.
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PMID:Longer-term regulation of pyruvate dehydrogenase kinase in cultured rat cardiac myocytes. 215 9

The activities of pyruvate dehydrogenase (PDH) kinase and of PDH kinase activator protein (KAP) were increased 2-2.4-fold during 25 h of culture of hepatocytes from fed rats with glucagon plus n-octanoate. PDH kinase activity in hepatocytes from starved rats (initially 2.2 x fed control) fell during 25 h of culture in medium 199 (to 1.5 x fed control), but was maintained by glucagon plus octanoate. Dibutyryl or 8-bromo cyclic AMP increased PDH kinase activity 2-2.2-fold in hepatocytes from fed rats, but phenylephrine and isoproterenol (isoprenaline) were without effect. Insulin blocked the action of glucagon to increase PDH kinase activity and decreased the effect of octanoate and octanoate plus glucagon. It is suggested that the effects of starvation to increase activities of PDH kinase and of KAP in liver are mediated by alterations in circulating concentrations of glucagon, fatty acids and insulin and in hepatic cyclic AMP.
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PMID:Longer-term regulation of pyruvate dehydrogenase kinase in cultured rat hepatocytes. 253 88

The activity of pyruvate dehydrogenase kinase in extracts of mitochondria from rat hepatocytes cultured for 21 h in medium 199 was increased 2.5-fold by the presence of 55 nM-glucagon and 1 mM-sodium n-octanoate in the culture medium. The change was comparable with that induced in vivo by 48 h starvation. The potential contribution of branched-chain complex to estimates of PDH-complex activity in rat liver mitochondria has been defined.
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PMID:Modulation of pyruvate dehydrogenase kinase activity in cultured hepatocytes by glucagon and n-octanoate. 370 45

Activity of the pyruvate dehydrogenase complex determines the rate of glucose oxidation in animals including man. The complex is regulated by reversible phosphorylation, phosphorylation resulting in inactivation. Activity is therefore dependent upon the activities of pyruvate dehydrogenase kinase and phosphatase. Activity of the complex is reduced in diabetes and starvation as a result of insulin deficiency. The mechanism involves activation of pyruvate dehydrogenase kinase by short-term effects of products of fatty acid oxidation and by longer term effects involving specific protein synthesis; in hepatocytes the signals may include lipid fuels and glucagon. Activity of the branched chain ketoacid dehydrogenase complex determines the rate of degradation of branched chain aminoacids which is adjusted according to dietary supply. The complex is regulated by reversible phosphorylation, phosphorylation being inactivating. In liver and kidney, but not in muscles a protein activator (free E1 component) may reactivate phosphorylated complex without dephosphorylation and facilitate hepatic oxidation of branched chain ketoacids. Metabolic adjustments induced by diet and diabetes include loss of activator protein, loss of total complex activity in liver but not muscles, and enhanced inactivation by phosphorylation in liver.
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PMID:alpha-Ketoacid dehydrogenase complexes and respiratory fuel utilisation in diabetes. 405 46

In Type 2 diabetes, glucose homeostasis is impaired due to either a decrease in insulin secretion or insulin action. In this symposium, molecular targets that could have an impact on either or both of these defects were discussed and data related to specific compounds were presented. Protein tyrosine phosphatase 1B inhibitors that relieve the negative control on insulin action and are active in cell assays, dipeptidyl peptidase IV inhibitors that raise postprandial glucagon-like peptide 1 levels in animals and humans, and pyruvate dehydrogenase kinase inhibitors that increase the levels of pyruvate dehydrogenase, which in turn improve insulin sensitivity, were all discussed. Roche presented for the first time their novel glucokinase activators and discussed both the in vitro and in vivo activity profiles of representative glucokinase activators as potential therapy for Type 2 diabetes. Second generation retinoid X receptor modulators that retain the desirable effects of full agonists, while devoid of their negative attributes, such as triglyceride accumulation, were discussed. Also, clinical efficacy results of synthetic exendin-4, Exenatide trade mark, a glucagon-like peptide 1 analogue, were presented. In the area of obesity, agonists of several central (melanocortin type 4, serotonin subtype 2C and cannabinoid receptor 1) receptors and one peripheral G-protein-coupled receptor, cholecystokinin receptor-A, all of which lead to reduced food intake in animals, were discussed.
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PMID:Metabolic diseases drug discovery world summit. July 28-29, 2003, San Diego, CA, USA. 1451 91

Coenzyme A (CoA) is the major acyl group carrier in intermediary metabolism. Hopantenate (HoPan), a competitive inhibitor of the pantothenate kinases, was used to chemically antagonize CoA biosynthesis. HoPan dramatically reduced liver CoA and mice developed severe hypoglycemia. Insulin was reduced, glucagon and corticosterone were elevated, and fasting accelerated hypoglycemia. Metabolic profiling revealed a large increase in acylcarnitines, illustrating the role of carnitine in buffering acyl groups to maintain the nonesterified CoASH level. HoPan triggered significant changes in hepatic gene expression that substantially increased the thioesterases, which liberate CoASH from acyl-CoA, and increased pyruvate dehydrogenase kinase 1, which prevents the conversion of CoASH to acetyl-CoA. These results identify the metabolic rearrangements that maintain the CoASH pool which is critical to mitochondrial functions, including gluconeogenesis, fatty acid oxidation, and the tricarboxylic acid and urea cycles.
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PMID:Chemical knockout of pantothenate kinase reveals the metabolic and genetic program responsible for hepatic coenzyme A homeostasis. 1737 44

Both glucocorticoid and insulin are known to have an anabolic effect on lipogenesis. The glycolytic pathway is a part of the lipogenic pathway in the liver, and glycolytic enzymes mediate the conversion from glucose to pyruvate, and pyruvate dehydrogenase complex (PDC) mediates the conversion from pyruvate to acetyl-CoA, the activity of which is regulated by pyruvate dehydrogenase kinases (PDKs) and phosphatases (PDPs). In this study, we surveyed the effects of glucocorticoid, insulin, and forskolin (used as a surrogate of glucagon) on the transcriptional activity of glucokinase (GK), phosphofructokinase-1 (PFK1), liver-type pyruvate kinase (LPK), and all the PDKs/PDPs isoform genes. We found that both glucocorticoid and insulin had positive effects on PFK1 and LPK, whereas on GK the two hormones showed the opposite effect. Regarding the PDKs/PDPs, glucocorticoid significantly stimulated the transcriptional activity of all PDKs, among which the effect on PDK4 was the most prominent. Insulin alone had minimal effects on PDKs, but dampened the positive effects of glucocorticoid. On PDPs, glucocorticoid and forskolin showed negative effects, whereas insulin had positive effects; insulin and glucocorticoid/forskolin antagonized each other. Altogether, our data suggest that both glucocorticoid and insulin have lipogenic effects through positive effects on PFK1 and LPK expression. However, glucocorticoid antagonizes the effect of insulin at the level of GK to maintain glucose homeostasis and that of PDKs/PDPs to facilitate gluconeogenesis. Glucagon may also enhance gluconeogenesis by inhibiting PDPs.
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PMID:Hormonal regulation of glycolytic enzyme gene and pyruvate dehydrogenase kinase/phosphatase gene transcription. 1970 89

Acute amino acid (AA) infusion increases AA oxidation rates in normal late gestation fetal sheep. Because the fetal oxygen consumption rate does not change with increased AA oxidation, we hypothesized that AA infusion would suppress glucose oxidation pathways and that the additional carbon supply from AA would activate hepatic glucose production. To test this, late gestation fetal sheep were infused intravenously for 3 h with saline or exogenous AA (AA). Glucose tracer metabolic studies were performed and skeletal muscle and liver tissues samples were collected. AA infusion increased fetal arterial plasma branched chain AA, cortisol, and glucagon concentrations. Fetal glucose utilization rates were similar between basal and AA periods, yet the fraction of glucose oxidized and the glucose oxidation rate were decreased by 40% in the AA period. AA infusion increased expression of PDK4, an inhibitor of glucose oxidation, nearly twofold in muscle and liver. In liver, AA infusion tended to increase PCK1 gluconeogenic gene and PCK1 correlated with plasma cortisol concentrations. AA infusion also increased liver mRNA expression of the lactate transporter gene (MCT1), protein expression of GLUT2 and LDHA, and phosphorylation of AMPK, 4EBP1, and S6 proteins. In isolated fetal hepatocytes, AA supplementation increased glucose production and PCK1, LDHA, and MCT1 gene expression. These results demonstrate that AA infusion into fetal sheep competitively suppresses glucose oxidation and potentiates hepatic glucose production. These metabolic patterns support flexibility in fetal metabolism in response to increased nutrient substrate supply while maintaining a relatively stable rate of oxidative metabolism.
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PMID:Exogenous amino acids suppress glucose oxidation and potentiate hepatic glucose production in late gestation fetal sheep. 2817 29

In fasting or diabetes, gluconeogenic genes are transcriptionally activated by glucagon stimulation of the cAMP-protein kinase A (PKA)-CREB signaling pathway. Previous work showed pyruvate dehydrogenase kinase (PDK) inhibition in skeletal muscle increases pyruvate oxidation, which limits the availability of gluconeogenic substrates in the liver. However, this study found upregulation of hepatic PDK4 promoted glucagon-mediated expression of gluconeogenic genes, whereas knockdown or inhibition of hepatic PDK4 caused the opposite effect on gluconeogenic gene expression and decreased hepatic glucose production. Mechanistically, PDK4 deficiency decreased ATP levels, thus increasing phosphorylated AMPK (p-AMPK), which increased p-AMPK-sensitive phosphorylation of cyclic nucleotide phosphodiesterase 4B (p-PDE4B). This reduced cAMP levels and consequently p-CREB. Metabolic flux analysis showed that the reduction in ATP was a consequence of a diminished rate of fatty acid oxidation (FAO). However, overexpression of PDK4 increased FAO and increased ATP levels, which decreased p-AMPK and p-PDE4B and allowed greater accumulation of cAMP and p-CREB. The latter were abrogated by the FAO inhibitor etomoxir, suggesting a critical role for PDK4 in FAO stimulation and the regulation of cAMP levels. This finding strengthens the possibility of PDK4 as a target against diabetes.
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PMID:PDK4 Deficiency Suppresses Hepatic Glucagon Signaling by Decreasing cAMP Levels. 3006 33

To better understand the effects of synbiotics administered at early stages of embryonic development in poultry, it is necessary to analyze direct effects (meat quality) and the molecular background. The molecular interpretation of poultry meat properties after in ovo administration of synbiotics remains to be reported. The purpose of the present study was to analyze the molecular background of meat quality based on gene expression and basic physiological parameters. Eggs were injected with (S1) Lactobacillus salivarius with galacto-oligosaccharides or (S2) Lactobacillus plantarum with raffinose family oligosaccharides. The pectoral muscle was collected at two time points (day 7 and day 42) and subjected to RNA isolation. Gene expression analysis was performed by RT-qPCR for a panel of eight genes associated with metabolism. The concentration of glucose and hormones (insulin, glucagon, and leptin (S1 p = 0.04)) was also increased. The obtained results showed that metabolic gene expression in the muscle was more differential due to synbiotic stimulation on day 7 (FST in S1 p = 0.03; PDK4 in S1 p = 0.02 and S2 p = 0.01; CEBPB in S1 p = 0.01 and S2 p = 0.008; PHKB in S1 p = 0.01; PRKAG3 in S1 p = 0.02) than on day 42 (PDK4 in S1 p = 0.04). On the basis of the results obtained, it can be concluded that in ovo stimulation with S1 triggered the most potent and favorable changes in the pectoral muscle gene expression in broiler chickens.
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PMID:Metabolic Gene Expression in the Muscle and Blood Parameters of Broiler Chickens Stimulated In Ovo with Synbiotics. 3232 87


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