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 provision of the high-fat diet (47% of calories as fat) for 28 days evoked a significant decline in cardiac PDHa activity, together with marked increases in the activity of PDH kinase measured in isolated mitochondria and freshly-prepared cardiomyocytes from adult rats. Plasma insulin concentrations in fat-fed rats were not significantly different from control, but plasma NEFA concentrations were elevated. PDH kinase activity in cardiomyocytes from fat-fed rats fell substantially in culture (25 h). This decline was prevented by the inclusion of n-octanoate and DBcAMP in combination, but not individually, in the culture medium. The results are discussed in relation to the role for fatty acids and insulin in the long-term modulation of cardiac PDH kinase activity by high-fat feeding.
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PMID:Long-term regulation of pyruvate dehydrogenase kinase by high-fat feeding. Experiments in vivo and in cultured cardiomyocytes. 828 19

The review examines the mechanisms regulating the activities of the two key enzymes determining rates of glucose and fatty acid oxidation, i.e., the pyruvate dehydrogenase (PDH) complex and the carnitine palmitoyltransferase (CPT) system. The review also evaluates the regulatory importance of gene expression in the control of tissue fuel selection within the context of substrate competition between glucose and fatty acids. It identifies a strong indirect input of nutrient-gene interactions in the control of pyruvate oxidation through the regulated provision of pyruvate as a substrate for PDH and as an inhibitor of PDH kinase. Nutrient-gene interactions are also identified in relation to the regulation of CPT I activity by malonyl-CoA (inhibitor) and by the provision of long-chain acyl-CoA (substrate/activator), the latter via the hydrolysis of plasma or tissue triacylglycerol (by lipoprotein lipase and hormone-sensitive lipase, respectively). We discuss how such regulation is reinforced by long-term modulation of PDH kinase-specific activity and CPT I maximal activity. We also explore the role of mechanisms operating at the levels of the PDH complex and the CPT system that act to promote and accelerate a switch in fuel utilization once a committed change in nutrient supply has been established. In particular, we discuss the regulatory influences exerted by altered sensitivities of PDH kinase to inhibition by pyruvate and CPT I to inhibition by malonyl-CoA, respectively.
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PMID:Interactive regulation of the pyruvate dehydrogenase complex and the carnitine palmitoyltransferase system. 829 90

Despite significant increases in circulating concentrations of lipid fuels (triacylglycerol, non-esterified fatty acids (NEFA) and ketone bodies) in late-pregnant rats sampled in the fed (absorptive) state, cardiac and skeletal muscle active pyruvate dehydrogenase (PDHa) activities remained comparable with those observed in fed, age-matched virgin controls. Cardiac PDHa activity was suppressed in response to acute (6 h) starvation in late-pregnant (as well as virgin) rats: this inactivation was opposed by inhibition of mitochondrial long-chain FA oxidation. Starvation (6 h) also led to PDH inactivation in skeletal muscles of late-pregnant, but not virgin, rats. Starvation for 24 h led to further suppression of cardiac PDHa activity and was associated with significant increases in PDH kinase activities in both virgin and late-pregnant rats. Late pregnancy did not itself influence cardiac PDH kinase activity.
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PMID:Control of muscle pyruvate oxidation during late pregnancy. 847 40

The pyruvate dehydrogenase (PDH) complex undergoes reversible phosphorylation catalyzed by a PDH kinase (inactivating) and a PDH phosphatase (activating). In skeletal muscle, a decreased proportion of active PDH (PDHa) complex limits glucose oxidation in insulin-deficient states. The time-course for reactivation of the PDH complex by insulin in skeletal muscle of diabetic rats is important to understanding the potential mode of the action of insulin in regulating glucose metabolism. A single injection of insulin (1 U/kg) completely reversed the effects of alloxan-diabetes on PDHa activity within 1 hour. The normalization of the effects of diabetes on PDHa activity by insulin was maintained for a minimum of 6 hours. The increase in PDHa activity occurred before an insulin-induced decrease in plasma free fatty acids levels, demonstrating a dissociation between the antilipolytic effects of insulin and its ability to activate the PDH complex. PDH kinase activity was not normalized to control values following a single injection of insulin. Therefore, acute (1 to 6 hours) insulin-mediated activation of the PDH complex does not result from a decrease in PDH kinase activity. However, longer-term insulin therapy (1 U/kg body weight; twice daily) restored both PDHa and PDH kinase activities. The results are consistent with the hypothesis that activation of the PDH complex immediately following insulin administration is not mediated by a decreased PDH kinase activity. However, with daily insulin therapy in diabetes, activation of the PDH complex results from decreased PDH kinase activity.
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PMID:Insulin-induced activation of pyruvate dehydrogenase complex in skeletal muscle of diabetic rats. 849 17

We studied the effects of fatty acid oxidation on insulin secretion of db/db mice and underlying molecular mechanisms of these effects. At 2-3 months of age, db/db mice were markedly obese, hyperglycemic, and hyperinsulinemic. Serum free fatty acid (FFA) levels were increased in 2-month-old (1.5 +/- 0.1 vs. 1.1 +/- 0.1 mmol/l, P < 0.05) and 3-month-old (1.9 +/- 0.1 vs. 1.2 +/- 0.1 mmol/l, P < 0.01) mice compared with the age and sex-matched db/+ mice serving as controls. Glucose-induced insulin release from db/db islets was markedly decreased compared with that from db/+ islets and was specifically ameliorated (by 54% in 2-month-old and 38% in 3-month-old mice) by exposure to a carnitine palmitoyltransferase I inhibitor, etomoxir (1 micromol/l). Etomoxir failed to affect the insulin response to alpha-ketoisocaproate. The effect of etomoxir on glucose-induced insulin release was lost after culturing db/db islets in RPMI medium containing 22 mmol/l glucose but no fatty acid. Culture of db/+ islets with 0.125 mmol/l palmitate led to a decrease in glucose-induced insulin secretion, which was partially reversible by etomoxir. Both islet glucose oxidation and the ratio of glucose oxidation to utilization were decreased in db/db islets. Etomoxir significantly enhanced glucose oxidation by 60% and also the ratio of oxidation to glucose utilization (from 27 +/- 2.5 to 37 +/-3.0%, P < 0.05). Pyruvate dehydrogenase (PDH) activity was decreased in islets of db/db mice (75 +/-4.2 vs. 91 +/- 2.9 nU/ng DNA, P < 0.01), whereas PDH kinase activity was increased (rate of PDH inactivation -0.25 +/- 0.02 vs. - 0.11 +/- 0.02/min, P < 0.0 1). These abnormalities were partly but not wholly reversed by a 2-h preexposure to etomoxir. In conclusion, elevated FFA levels in the db/db mouse diminish glucose-induced insulin secretion by a glucose-fatty acid cycle in which fatty acid oxidation inhibits glucose oxidation by decreasing PDH activity and increasing PDH kinase activities.
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PMID:A fatty acid-induced decrease in pyruvate dehydrogenase activity is an important determinant of beta-cell dysfunction in the obese diabetic db/db mouse. 862 Oct 7

Ranolazine has shown anti-anginal efficacy in humans and cardiac anti-ischaemic activity in models, but without affecting haemodynamics or baseline contraction. In isolated normoxic rat hearts, Langendorff-perfused for 30 min with 11 mM glucose, 3% albumin, and 0.4 mM or 0.8 mM palmitate, 20 microM ranolazine significantly increased active, dephosphorylated, pyruvate dehydrogenase (PDHa), but not with no palmitate or 1.2 mM palmitate. Dichloroactetate (DCA, 1 mM), a PDHa kinase inhibitor, significantly increased PDHa in hearts perfused with 0, 0.4 or 0.8 mM but not 1.2 mM palmitate. PDHa was significantly increased with 1.2 mM palmitate by DCA plus ranolazine, and additive effects were also seen at 0.8 mM palmitate. Activation of PDH by ranolazine and promotion of glucose oxidation offers a plausible means by which the drug may be anti-ischaemic nonhaemodynamically. Extensive studies with extracted enzymes and isolated rat heart mitochondria failed to demonstrate any effects of ranolazine on PDH kinase or phosphatase, or on PDH catalytic activity, whereas effects of other known effectors (such as DCA) were readily demonstrable, suggesting that ranolazine activates PDH indirectly. Further analyses of the hearts revealed that ranolazine reduced acetyl CoA content under all conditions where fatty acid was present, and +/- DCA which itself had little effect. In the absence of fatty acid, ranolazine and/or DCA raised acetyl CoA. In perfusions where octanoate (+/- albumin) replaced palmitate, ranolazine still decreased acetyl CoA, but not when acetate replaced palmitate. In octanoate-perfused hearts, the contents of the C4, C6 and C8 CoA esters were all increased by ranolazine. This is consistent with ranolazine causing an inhibition of fatty acid beta-oxidation leading to decreased acetyl CoA and activation of PDH.
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PMID:Ranolazine increases active pyruvate dehydrogenase in perfused normoxic rat hearts: evidence for an indirect mechanism. 872 66

A live-attenuated dengue 2 vaccine (strain 16681 PDK 53) developed at Mahidol University, Thailand was evaluated for safety and immunogenicity by administering 10(4) p.f.u. subcutaneously to ten flavivirus non-immune American volunteers. The vaccine was safe; there were no serious adverse reactions. Eight recipients experienced no or mild side effects. One recipient reported headaches on 7 separate days. One volunteer, who had a fracture of the humerus 1 day after vaccination requiring surgical repair, experienced generalized malaise with fever (maximum temperature = 38.9 degrees C), headache, eye pain and myalgia lasting less than 24 h. The vaccine was highly immunogenic; all recipients developed neutralizing antibody that persisted for two years.
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PMID:Testing of a dengue 2 live-attenuated vaccine (strain 16681 PDK 53) in ten American volunteers. 874 61

Fasting inhibits glucose-induced insulin secretion. We investigated the role of a glucose fatty acid cycle for such inhibition and its molecular basis in pancreatic islets from 48-h fasted rats. The fasting-impaired insulin response to 27 mM glucose was restored by 41% with a carnitine palmitoyltransferase I inhibitor, etomoxir. Etomoxir also restored (by 50%) impaired glucose oxidation in islets from fasted rats and increased the ratio of oxidation to glycolytic flux from 33 to 43%. Fasting decreased total pyruvate dehydrogenase (PDH) activity (active, unphosphorylated plus inactive, phosphorylated form) by 29%, as well as the percentage of active form (54 +/- 5 vs. 79 +/- 2% in fed rats, P < 0.001). Fasting increased islet PDH kinase activity as follows: PDH-bound activity by 36% and free (not PDH bound) PDH kinase by 70%. Fasting failed to affect PDH kinase content when assayed by an enzyme-linked immunoabsorbent assay with antibodies raised against 45 kDa PDH kinase alpha-chain. We conclude that fasting impairs B cell function to a major extent through the operation of a glucose fatty acid cycle and that decreased PDH activity resulting from increased specific activity of PDH kinase constitutes an important molecular mechanism.
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PMID:Fasting and decreased B cell sensitivity: important role for fatty acid-induced inhibition of PDH activity. 876 83

Experimental hyperthyroidism induced by the administration of tri-iodothyronine (T3; 100 micrograms/100 g body wt; 3 days) increased plasma non-esterified fatty acids in the fed state in the rat. At the same time, hepatic PDH kinase responded with a persistent (1.6-fold) increase in activity. The exposure of hepatocytes from fed euthyroid rats to T3 (100 nM) in culture for 21 h increased PDH kinase activity to an extent comparable to that observed in vivo in response to hyperthyroidism. The in vitro increase in PDH kinase activity was suppressed by insulin (100 microU/ml) and by inhibition of mitochondrial fatty acid oxidation. The results demonstrate a direct hepatic action of T3 to increase PDH kinase activity, which is mediated by intramitochondrial fatty acyl-CoA or a product of beta-oxidation, and facilitated by hepatic insulin resistance.
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PMID:Increased hepatic pyruvate dehydrogenase kinase activity in fed hyperthyroid rats: studies in vivo and with cultured hepatocytes. 880 41

The pyruvate dehydrogenase (PDH) complex undergoes reversible phosphorylation catalyzed by a PDH kinase (inactivating) and a PDH phosphatase (activating). In skeletal muscle, a decreased proportion of PDH complex in the active, nonphosphorylated form (PDHa) limits glucose oxidation and promotes the conversion of pyruvate to lactate. Increased lactate formation with the accompanying hyperlactatemia is a frequent metabolic complication of sepsis. The time course for inactivation of the PDH complex in skeletal muscle during sepsis was contrasted with changes in PDHa during sterile inflammation 3,7, or 14 days following the implantation of the foreign body nidus. Total PDH complex activity was not altered in any of the conditions examined. Sepsis, but not sterile inflammation, caused a reduction in the muscle PDHa measured 3 or 7 days following induction of sepsis. The inhibition of the muscle PDHa during sepsis was associated with a sustained hyperlactatemia. PDH kinase activity measured in extracts of mitochondria was enhanced twofold during this period. Fourteen days after induction of sepsis, there were no differences in the PDHa or plasma lactate concentrations in septic rats compared with either control or sterile inflammation. Furthermore, the PDH kinase activity was decreased to values observed in control values. The results are consistent with the hypothesis that a reduced PDHa in skeletal muscle during sepsis is responsible, in part, for the hyperlactatemia characteristic of septic hypermetabolism. Furthermore, the results provide evidence that the decrease in PDHa results from a stable stimulation of PDH kinase activity.
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PMID:Sepsis-induced alterations in pyruvate dehydrogenase complex activity in rat skeletal muscle: effects on plasma lactate. 885 41


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