Journal articles: 'Rat pyruvate dehydrogenase'

1

Mistry, S. C., D. A. Priestman, A. L. Kerbey, and P. J. Randle. "Evidence that rat liver pyruvate dehydrogenase kinase activator protein is a pyruvate dehydrogenase kinase." Biochemical Journal 275, no. 3 (May 1, 1991): 775–79. http://dx.doi.org/10.1042/bj2750775.

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It is shown here that rat liver pyruvate dehydrogenase (PDH) kinase activator protein (KAP) catalyses ATP-dependent inactivation and [32P]phosphorylation of pig heart PDHE1 and of yeast (Saccharomyces cerevisiae) PDH complex devoid of PDH kinase activity, that fluorosulphonylbenzoyladenosine inactivates rat liver KAP and the intrinsic PDH kinase of rat liver PDH complex, and that KAP, like PDH kinase, is inactivated by thiol-reactive reagents. It is concluded that KAP is a free PDH kinase.

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2

JOHNSON, Sam A., and Richard M. DENTON. "Insulin stimulation of pyruvate dehydrogenase in adipocytes involves two distinct signalling pathways." Biochemical Journal 369, no. 2 (January 15, 2003): 351–56. http://dx.doi.org/10.1042/bj20020920.

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In isolated rat adipocytes, the insulin stimulation of pyruvate dehydrogenase can be partially inhibited by inhibitors of PI3K (phosphoinositide 3-kinase) and MEK1/2 (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase). In combination, U0126 and wortmannin completely block the insulin stimulation of pyruvate dehydrogenase. It is concluded that the effect of insulin on pyruvate dehydrogenase in rat adipocytes involves two distinct signalling pathways: one is sensitive to wortmannin and the other to U0126. The synthetic phosphoinositolglycan PIG41 can activate pyruvate dehydrogenase but the activation is only approx. 30% of the maximal effect of insulin. This modest activation can be completely blocked by wortmannin alone, suggesting that PIG41 acts through only one of the pathways leading to the activation of pyruvate dehydrogenase.

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3

Carter, Tonia C., and Haldane G. Coore. "Effects of pyruvate on pyruvate dehydrogenase kinase of rat heart." Molecular and Cellular Biochemistry 149-150, no. 1 (August 1995): 71–75. http://dx.doi.org/10.1007/bf01076565.

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Curi, R., P. Newsholme, and E. A. Newsholme. "Metabolism of pyruvate by isolated rat mesenteric lymphocytes, lymphocyte mitochondria and isolated mouse macrophages." Biochemical Journal 250, no. 2 (March 1, 1988): 383–88. http://dx.doi.org/10.1042/bj2500383.

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1. The activities of pyruvate dehydrogenase in rat lymphocytes and mouse macrophages are much lower than those of the key enzymes of glycolysis and glutaminolysis. However, the rates of utilization of pyruvate (at 2 mM), from the incubation medium, are not markedly lower than the rate of utilization of glucose by incubated lymphocytes or that of glutamine by incubated macrophages. This suggests that the low rate of oxidation of pyruvate produced from either glucose or glutamine in these cells is due to the high capacity of lactate dehydrogenase, which competes with pyruvate dehydrogenase for pyruvate. 2. Incubation of either macrophages or lymphocytes with dichloroacetate had no effect on the activity of subsequently isolated pyruvate dehydrogenase; incubation of mitochondria isolated from lymphocytes with dichloroacetate had no effect on the rate of conversion of [1-14C]pyruvate into 14CO2, and the double-reciprocal plot of [1-14C]pyruvate concentration against rate of 14CO2 production was linear. In contrast, ADP or an uncoupling agent increased the rate of 14CO2 production from [1-14C]pyruvate by isolated lymphocyte mitochondria. These data suggest either that pyruvate dehydrogenase is primarily in the a form or that pyruvate dehydrogenase in these cells is not controlled by an interconversion cycle, but by end-product inhibition by NADH and/or acetyl-CoA. 3. The rate of conversion of [3-14C]pyruvate into CO2 was about 15% of that from [1-14C]pyruvate in isolated lymphocytes, but was only 1% in isolated lymphocyte mitochondria. The inhibitor of mitochondrial pyruvate transport, alpha-cyano-4-hydroxycinnamate, inhibited both [1-14C]- and [3-14C]-pyruvate conversion into 14CO2 to the same extent, and by more than 80%. 4. Incubations of rat lymphocytes with concanavalin A had no effect on the rate of conversion of [1-14C]pyruvate into 14CO2, but increased the rate of conversion of [3-14C]pyruvate into 14CO2 by about 50%. This suggests that this mitogen causes a stimulation of the activity of pyruvate carboxylase.

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5

Katz, L. A., A. P. Koretsky, and R. S. Balaban. "Activation of dehydrogenase activity and cardiac respiration: a 31P-NMR study." American Journal of Physiology-Heart and Circulatory Physiology 255, no. 1 (July 1, 1988): H185—H188. http://dx.doi.org/10.1152/ajpheart.1988.255.1.h185.

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31P-NMR studies were performed to determine the tissue phosphate and oxygen consumption effects of known maneuvers on the activation of pyruvate dehydrogenase during work jumps in the perfused rat heart. In control studies of the glucose-perfused heart, work jumps, with pacing, resulted in a 32% increase in oxygen consumption (QO2) from 1.72 +/- 0.09 to 2.29 +/- 0.12 mmol O2.h-1.g dry wt-1. During this transition no significant change in the high energy phosphates were detected. In contrast, work jumps did cause changes in the phosphates when the activation of pyruvate dehydrogenase was blocked with 2.5 micrograms of ruthenium red per milliliter or maximally stimulated with 11 mM pyruvate before the increase in work. The observed increase in QO2 and inorganic phosphate and calculated increase in ADP are consistent with these phosphates controlling mitochondrial respiration under these conditions. These results suggest that the activation of pyruvate dehydrogenase and/or other dehydrogenases may be an important step in the orchestration of work and QO2.

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Kilgour, E., and R. G. Vernon. "Catecholamine activation of pyruvate dehydrogenase in white adipose tissue of the rat in vivo." Biochemical Journal 241, no. 2 (January 15, 1987): 415–19. http://dx.doi.org/10.1042/bj2410415.

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Intraperitoneal injections of noradrenaline or adrenaline into rats increased the proportion of pyruvate dehydrogenase in the active state in white adipose tissue; this effect of catecholamines was also apparent in streptozotocin-diabetic rats, showing that it was not due to an increase in serum insulin concentration. The catecholamine-induced increase in pyruvate dehydrogenase of white adipose tissue in vivo was completely blocked by prior injection of either the beta-antagonist propranolol or the alpha 1-antagonist prazosin. Cervical dislocation of conscious rats increased pyruvate dehydrogenase activity of white adipose tissue, which was prevented by prior injection of propranolol. Adrenaline (30 nM) activated pyruvate dehydrogenase in white adipocytes in vitro; the maximum effect of adrenaline required activation of both alpha 1- and beta-receptors. The results show that catecholamines activate pyruvate dehydrogenase of white adipose tissue both in vivo and in vitro and that this effect is mediated by a combination of alpha 1- and beta-adrenergic receptors.

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7

McCormack, J. G., E. A. Longo, and B. E. Corkey. "Glucose-induced activation of pyruvate dehydrogenase in isolated rat pancreatic islets." Biochemical Journal 267, no. 2 (April 15, 1990): 527–30. http://dx.doi.org/10.1042/bj2670527.

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1. Rat pancreatic islets were isolated and then maintained in culture for 2-4 days before being incubated in groups of 100 in the presence of different glucose (0-20 mM) or CaCl2 (1.2-4.2 mM) concentrations, or with uncoupler. 2. Increases in extracellular glucose concentration resulted in increases in the amount of active, non-phosphorylated, pyruvate dehydrogenase in the islets, with half-maximal effects around 5-6 mM-glucose. Increasing extracellular glucose from 3 to 20 mM resulted in a 4-6-fold activation of pyruvate dehydrogenase within 2 min. 3. The total enzyme activity was unchanged, and averaged 0.4 m-unit/100 islets at 37 degrees C. 4. These changes in active pyruvate dehydrogenase were broadly similar to changes in insulin secretion by the islets. 5. Increasing extracellular Ca2+ or adding uncoupler also activated pyruvate dehydrogenase to a similar degree, but only the former was associated with increased insulin secretion.

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8

De Marcucci, O. L., A. Hunter, and J. G. Lindsay. "Low immunogenicity of the common lipoamide dehydrogenase subunit (E3) of mammalian pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase multienzyme complexes." Biochemical Journal 226, no. 2 (March 1, 1985): 509–17. http://dx.doi.org/10.1042/bj2260509.

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The production of high-titre monospecific polyclonal antibodies against the purified pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase multienzyme complexes from ox heart is described. The specificity of these antisera and their precise reactivities with the individual components of the complexes were examined by immunoblotting techniques. All the subunits of the pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase complexes were strongly antigenic, with the exception of the common lipoamide dehydrogenase component (E3). The titre of antibodies raised against E3 was, in both cases, less than 2% of that of the other subunits. Specific immunoprecipitation of the dissociated N-[3H]ethylmaleimide-labelled enzymes also revealed that E3 alone was absent from the final immune complexes. Strong cross-reactivity with the enzyme present in rat liver (BRL) and ox kidney (NBL-1) cell lines was observed when the antibody against ox heart pyruvate dehydrogenase was utilized to challenge crude subcellular extracts. The immunoblotting patterns again lacked the lipoamide dehydrogenase band, also revealing differences in the apparent Mr of the lipoate acetyltransferase subunit (E2) from ox kidney and rat liver. The additional 50 000-Mr polypeptide, previously found to be associated with the pyruvate dehydrogenase complex, was apparently not a proteolytic fragment of E2 or E3, since it could be detected as a normal component in boiled sodium dodecyl sulphate extracts of whole cells. The low immunogenicity of the lipoamide dehydrogenase polypeptide may be attributed to a high degree of conservation of its primary sequence and hence tertiary structure during evolution.

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9

Priestman, David A., Sharad C. Mistry, Alan L. Kerbey, and Philip J. Randle. "Purification and partial characterization of rat liver pyruvate dehydrogenase kinase activator protein (free pyruvate dehydrogenase kinase)." FEBS Letters 308, no. 1 (August 10, 1992): 83–86. http://dx.doi.org/10.1016/0014-5793(92)81056-r.

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10

Schadewaldt, P., E. Lammers, and W. Staib. "Influence of insulin and glucose on pyruvate catabolism in perfused rat hindlimbs." Biochemical Journal 227, no. 1 (April 1, 1985): 177–82. http://dx.doi.org/10.1042/bj2270177.

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The effects of insulin and glucose on the oxidative decarboxylation of pyruvate in isolated rat hindlimbs was studied in non-recirculating perfusion with [1-14C]pyruvate. Insulin increased the calculated pyruvate decarboxylation rate in a concentration-dependent manner. At supramaximal insulin concentrations, the calculated pyruvate decarboxylation rate was increased by about 40% in perfusions with 0.15-1.5 mM-pyruvate. Glucose up to 20 mM had no effect. In the presence of insulin and low physiological pyruvate concentrations (0.15 mM), glucose increased the calculated pyruvate oxidation. This effect was abolished by high concentrations of pyruvate (1 mM). The data provide evidence that in resting perfused rat skeletal muscle insulin primarily increased the activity of the pyruvate dehydrogenase complex. The effect of glucose was due to increased intracellular pyruvate supply.

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11

Russell, R. R., and H. Taegtmeyer. "Pyruvate carboxylation prevents the decline in contractile function of rat hearts oxidizing acetoacetate." American Journal of Physiology-Heart and Circulatory Physiology 261, no. 6 (December 1, 1991): H1756—H1762. http://dx.doi.org/10.1152/ajpheart.1991.261.6.h1756.

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Acetoacetate, when present as the only fuel for respiration in rat hearts, causes an impairment in contractile function that is reversible with the addition of substrates that can contribute to anaplerosis. To determine the importance of pyruvate carboxylation via NADP(+)-dependent malic enzyme on metabolism and function in hearts oxidizing acetoacetate, isolated working rat hearts were perfused with [1-14C]pyruvate and acetoacetate. While the cardiac power output after 60 min of perfusion in hearts utilizing acetoacetate alone had fallen to 44% of the initial value, the addition of pyruvate resulted in a stable performance with no fall in the work output. When hydroxymalonate, an inhibitor of NADP(+)-dependent malic enzyme and malate dehydrogenase, was added to the two substrates, function at 60 min was similar to the value for hearts oxidizing acetoacetate alone. Measurements of the specific activities of malate, aspartate, and citrate confirm inhibition of both pyruvate carboxylation and malate oxidation. The findings are consistent with a mechanism in which the enrichment of malate by pyruvate improves function by increasing the production of reducing equivalents by the malate dehydrogenase and the isocitrate dehydrogenase reactions increase flux through the span of the tricarboxylic acid cycle from malate to 2-oxoglutarate. The present study demonstrates the physiological importance of anaplerotic pathways in maintaining contractile function in the heart.

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12

VALENTI, Daniela, Lidia de BARI, Anna ATLANTE, and Salvatore PASSARELLA. "l-Lactate transport into rat heart mitochondria and reconstruction of the l-lactate/pyruvate shuttle." Biochemical Journal 364, no. 1 (May 8, 2002): 101–4. http://dx.doi.org/10.1042/bj3640101.

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In vitro reconstruction of the l-lactate/pyruvate shuttle has been performed, which allows NADH oxidation outside rat heart mitochondria. Such a shuttle occurs due to the combined action of the novel mitochondrial l-lactate/pyruvate antiporter, which differs from the monocarboxylate carrier, and the mitochondrial l-lactate dehydrogenase. The rate of l-lactate/pyruvate antiport proved to regulate the shuttle in vitro.

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13

Sheu, Kwan-Fu Rex, James C. K. Lai, Young Tai Kim, Gary Dorante, and Jennifer Bagg. "Immunochemical Characterization of Pyruvate Dehydrogenase Complex in Rat Brain." Journal of Neurochemistry 44, no. 2 (February 1985): 593–99. http://dx.doi.org/10.1111/j.1471-4159.1985.tb05453.x.

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14

Kandiko, Charles T., Daniel Smith, and Bryan K. Yamamoto. "Inhibition of rat brain pyruvate dehydrogenase by thiamine analogs." Biochemical Pharmacology 37, no. 22 (November 1988): 4375–80. http://dx.doi.org/10.1016/0006-2952(88)90620-x.

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15

Thomas, A. P., T. A. Diggle, and R. M. Denton. "Sensitivity of pyruvate dehydrogenase phosphate phosphatase to magnesium ions. Similar effects of spermine and insulin." Biochemical Journal 238, no. 1 (August 15, 1986): 83–91. http://dx.doi.org/10.1042/bj2380083.

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The effects of Mg2+ on the activity of pyruvate dehydrogenase phosphate phosphatase within intact mitochondria prepared from control and insulin-treated rat epididymal adipose tissue was explored by incubating the mitochondria in medium containing the ionophore A23187. The apparent Ka for Mg2+ was approximately halved in the mitochondria derived from insulin-treated tissue in both the absence and the presence of Ca2+. In this system, the major effect of Ca2+ was also to decrease the apparent Ka for Mg2+, rather than to change the Vmax. of the phosphatase. Damuni, Humphreys & Reed [(1984) Biochem. Biophys. Res. Commun. 124, 95-99] have reported that spermine activates ox kidney pyruvate dehydrogenase phosphate phosphatase. Studies were carried out on phosphatase from pig heart and rat epididymal adipose tissue which confirm and extend this observation. The major effect of spermine is shown to be a decrease in the Ka for Mg2+, which is apparent in both the presence and the absence of Ca2+. Spermine did not affect the sensitivity of the phosphatase to Ca2+ at saturating concentrations of Mg2+. Other polyamines tested were not as effective as spermine. No alteration in the maximum activity or Mg2+-sensitivity of pyruvate dehydrogenase phosphate phosphatase was apparent in extracts of mitochondria from insulin-treated tissue. The close similarity of the effects of spermine and the changes in kinetic properties of pyruvate dehydrogenase phosphate phosphatase within mitochondria from insulin-treated adipose tissue suggests that insulin may activate pyruvate dehydrogenase by increasing the concentration of spermine within the mitochondria. However, it is concluded that insulin is more likely to alter the interaction of the pyruvate dehydrogenase system with some other polybasic intramitochondrial component whose action can be mimicked by spermine.

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16

McCormack, J. G. "Characterization of the effects of Ca2+ on the intramitochondrial Ca2+-sensitive enzymes from rat liver and within intact rat liver mitochondria." Biochemical Journal 231, no. 3 (November 1, 1985): 581–95. http://dx.doi.org/10.1042/bj2310581.

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The regulatory properties of the Ca2+-sensitive intramitochondrial enzymes (pyruvate dehydrogenase phosphate phosphatase, NAD+-isocitrate dehydrogenase and 2-oxoglutarate dehydrogenase) in extracts of rat liver mitochondria appeared to be essentially similar to those described previously for other mammalian tissues. In particular, the enzymes were activated severalfold by Ca2+, with half-maximal effects at about 1 microM-Ca2+ (K0.5 value). In intact rat liver mitochondria incubated in a KCl-based medium containing 2-oxoglutarate and malate, the amount of active, non-phosphorylated, pyruvate dehydrogenase could be increased severalfold by increasing extramitochondrial [Ca2+], provided that some degree of inhibition of pyruvate dehydrogenase kinase (e.g. by pyruvate) was achieved. The rates of 14CO2 production from 2-oxo-[1-14C]glutarate at non-saturating, but not at saturating, concentrations of 2-oxoglutarate by the liver mitochondria (incubated without ADP) were similarly enhanced by increasing extramitochondrial [Ca2+]. The rates and extents of NAD(P)H formation in the liver mitochondria induced by non-saturating concentrations of 2-oxoglutarate, glutamate, threo-DS-isocitrate or citrate were also increased in a similar manner by Ca2+ under several different incubation conditions, including an apparent ‘State 3.5’ respiration condition. Ca2+ had no effect on NAD(P)H formation induced by β-hydroxybutyrate or malate. In intact, fully coupled, rat liver mitochondria incubated with 10 mM-NaCl and 1 mM-MgCl2, the apparent K0.5 values for extramitochondrial Ca2+ were about 0.5 microM, and the effective concentrations were within the expected physiological range, 0.05-5 microM. In the absence of Na+, Mg2+ or both, the K0.5 values were about 400, 200 and 100 nM respectively. These effects of increasing extramitochondrial [Ca2+] were all inhibited by Ruthenium Red. When extramitochondrial [Ca2+] was increased above the effective ranges for the enzymes, a time-dependent deterioration of mitochondrial function and ATP content was observed. The implications of these results on the role of the Ca2+-transport system of the liver mitochondrial inner membrane are discussed.

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Holness, M. J., T. N. Palmer, E. B. Worrall, and M. C. Sugden. "Hepatic carbon flux after re-feeding in the glycogen-storage-disease (gsd/gsd) rat." Biochemical Journal 248, no. 3 (December 15, 1987): 969–72. http://dx.doi.org/10.1042/bj2480969.

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In this study we utilized the phosphorylase b kinase-deficient (gsd/gsd) rat as a model of hepatic substrate utilization where there is a constraint on glycogenesis imposed by the maintenance of high glycogen concentrations. Glucose re-feeding of 48 h-starved gsd/gsd rats led to suppression of hepatic glucose output. In contrast with the situation in normal rats, activation of the pyruvate dehydrogenase complex and lipogenesis was observed. It is suggested that impeding glycogenic flux may divert substrate into lipogenesis, possibly via activation of the pyruvate dehydrogenase complex.

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Paxton, R., P. W. Scislowski, E. J. Davis, and R. A. Harris. "Role of branched-chain 2-oxo acid dehydrogenase and pyruvate dehydrogenase in 2-oxobutyrate metabolism." Biochemical Journal 234, no. 2 (March 1, 1986): 295–303. http://dx.doi.org/10.1042/bj2340295.

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Purified branched-chain 2-oxo acid dehydrogenase (BCODH) and pyruvate dehydrogenase (PDH) had apparent Km values (microM) for 2-oxobutyrate of 26 and 114, with a relative Vmax. (% of Vmax. for 3-methyl-2-oxobutyrate and pyruvate) of 38 and 45% respectively. The phosphorylation state of both complexes in extracts of mitochondria from rat liver, kidney, heart and skeletal muscle was shown to influence oxidative decarboxylation of 2-oxobutyrate. Inhibitory antibodies to BCODH and an inhibitor of PDH (3-fluoropyruvate) were used with mitochondrial extracts to determine the relative contribution of both complexes to oxidative decarboxylation of 2-oxobutyrate. Calculated rates of 2-oxobutyrate decarboxylation in mitochondrial extracts, based on the kinetic constants given above and the activities of both complexes, were the same as the measured rates. Hydroxyapatite chromatography of extracts of mitochondria from rat liver revealed only two peaks of oxidative decarboxylation of 2-oxobutyrate, with one peak associated with PDH and the other with BCODH. Competition studies with various 2-oxo acids revealed a different inhibition pattern with mitochondrial extracts from liver compared with those from heart or skeletal muscle. We conclude that both intramitochondrial complexes are responsible for oxidative decarboxylation of 2-oxobutyrate. However, the BCODH is probably the more important complex, particularly in liver, on the basis of kinetic analyses, activity or phosphorylation state of both complexes, competition studies, and the apparent physiological concentration of pyruvate, 2-oxobutyrate and the branched-chain 2-oxo acids.

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Park, O. J., D. Cesar, D. Faix, K. Wu, C. H. L. Shackleton, and M. K. Hellerstein. "Mechanisms of fructose-induced hypertriglyceridaemia in the rat. Activation of hepatic pyruvate dehydrogenase through inhibition of pyruvate dehydrogenase kinase." Biochemical Journal 282, no. 3 (March 15, 1992): 753–57. http://dx.doi.org/10.1042/bj2820753.

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1. The effects of purified diets containing 70% glucose or 70% fructose on the activation state of hepatic pyruvate dehydrogenase (PDHa), activity of mitochondrial PDH kinase, plasma triacylglycerols (TG) and hepatic lipogenesis de novo in rats were measured. 2. Plasma TG were significantly increased in the fructose-fed compared with the glucose-fed group (125 +/- 45 mg/dl versus 57 +/- 19 mg/dl; P less than 0.002) after 3-5 weeks on the diet despite less daily food intake. 3. Hepatic PDHa in fructose-fed rats was 144% of the value in glucose-fed rats (15.4 +/- 1.2% versus 10.7 +/- 0.5%; P less than 0.002), whereas cardiac muscle PDHa was not different (45.5 +/- 6.6% versus 41.0 +/- 7.8%). 4. Intrinsic hepatic PDH kinase activity was decreased to 34% of glucose-fed values by fructose feeding (-k = 3.56 +/- 0.39 versus 10.41 +/- 1.85 min-1; P less than 0.005). 5. The fractional contribution to very-low-density-lipoprotein palmitate from hepatic lipogenesis de novo, measured by a stable-isotope mass-spectrometric method, was 10.49 +/- 2.42% (n = 8) in fructose-fed rats versus 5.55 +/- 1.38% (n = 9) in glucose-fed rats (P less than 0.05), and 2.66 +/- 2.39% (n = 3) in chow-fed rats (P less than 0.05 versus fructose-fed group). The absolute contribution to circulating TG from lipogenesis de novo was also significantly higher in the fructose-fed than in the glucose-fed group (14.9 +/- 5.1 mg/dl versus 2.9 +/- 0.6 mg/dl; P less than 0.05) 6. Portal insulin concentrations were significantly higher in the fructose-fed rats (206 +/- 49 mu-units/ml versus 81 +/- 15 mu-units/ml; P less than 0.05). 7. In conclusion, dietary fructose appears to have a specific activating effect on hepatic PDH, mediated at least in part by inhibition of PDH kinase. These results are consistent with increased flux through hepatic PDH and synthesis of new fat, not just increased re-esterification of non-esterified fatty acids.

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Maury, J., A. L. Kerbey, D. A. Priestman, M. S. Patel, J. Girard, and P. Ferre. "Pretranslational regulation of pyruvate dehydrogenase complex subunits in white adipose tissue during the suckling-weaning transition in the rat." Biochemical Journal 311, no. 2 (October 15, 1995): 531–35. http://dx.doi.org/10.1042/bj3110531.

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Total pyruvate dehydrogenase complex activity is low in white adipose tissue during the suckling period and increases markedly at weaning on to a high-carbohydrate diet. This is concomitant with an increase in the E1 alpha, E1 beta and E2 subunit protein concentration and their respective mRNAs, suggesting a pretranslational control of this phenomenon. The most marked change is seen for the E1 alpha subunit (17-fold increase in protein concentration). The changes in pyruvate dehydrogenase complex activity and subunit abundance induced by weaning on to a high-carbohydrate diet are precluded if the animals are weaned on to a high-fat diet, suggesting that the nutritional and/or related hormonal changes rather than a developmental stage are responsible for the observed adipose-tissue pyruvate dehydrogenase complex pattern.

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Nagase, H., G. A. Bray, and D. A. York. "Pyruvate and hepatic pyruvate dehydrogenase levels in rat strains sensitive and resistant to dietary obesity." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 270, no. 3 (March 1, 1996): R489—R495. http://dx.doi.org/10.1152/ajpregu.1996.270.3.r489.

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This study compared the effects of exogenous pyruvate and lactate on the serum levels of pyruvate, lactate, glucose, alanine, and insulin, as well as the activity of hepatic pyruvate dehydrogenase (PDH) in strains of rat that were either sensitive [Osborne-Mendel (OM)] or resistant (S5B/Pl) to high-fat diet-induced obesity. Serum pyruvate and lactate were significantly higher and glucose lower in ad libitum-fed OM rats, but these differences disappeared after an 18-h fast. The increase in pyruvate and lactate after exogenous pyruvate administration was significantly greater in S5B/Pl rats than OM rats. There were no differences in serum alanine with strain or diet. The total PDH activity was similar across strains and diets but the proportion of PDH in its activated form (PDHa) was decreased in ad libitum-fed S5B/Pl rats. Pyruvate injection increased insulin and hepatic PDHa activity in OM rats fed both high- and low-fat diets, but these responses were greatly attenuated or absent in S5B/Pl rats. The data are consistent with the hypothesis that modulation of carbohydrate oxidation by PDH may be related to susceptibility to obesity when rats are fed a high-fat diet.

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Wüst, Rob C. I., and Ger J. M. Stienen. "Successive contractile periods activate mitochondria at the onset of contractions in intact rat cardiac trabeculae." Journal of Applied Physiology 124, no. 4 (April 1, 2018): 1003–11. http://dx.doi.org/10.1152/japplphysiol.01010.2017.

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The rate of oxidative phosphorylation depends on the contractile activity of the heart. Cardiac mitochondrial oxidative phosphorylation is determined by free ADP concentration, mitochondrial Ca2+ accumulation, mitochondrial enzyme activities, and Krebs cycle intermediates. The purpose of the present study was to examine the factors that limit oxidative phosphorylation upon rapid changes in contractile activity in cardiac muscle. We tested the hypotheses that prior contractile performance enhances the changes in NAD(P)H and FAD concentration upon an increase in contractile activity and that this mitochondrial “priming” depends on pyruvate dehydrogenase activity. Intact rat cardiac trabeculae were electrically stimulated at 0.5 Hz for at least 30 min. Thereafter, two equal bouts at elevated stimulation frequency of 1, 2, or 3 Hz were applied for 3 min with 3 min of 0.5-Hz stimulation in between. No discernible time delay was observed in the changes in NAD(P)H and FAD fluorescence upon rapid changes in contractile activity. The amplitudes of the rapid changes in fluorescence upon an increase in stimulation frequency (the on-transients) were smaller than upon a decrease in stimulation frequency (the off-transients). A first bout in glucose-containing superfusion solution resulted, during the second bout, in an increase in the amplitudes of the on-transients, but the off-transients remained the same. No such priming effect was observed after addition of 10 mM pyruvate. These results indicate that mitochondrial priming can be observed in cardiac muscle in situ and that pyruvate dehydrogenase activity is critically involved in the mitochondrial adaptation to increases in contractile performance. NEW & NOTEWORTHY Mitochondrial respiration increases with increased cardiac contractile activity. Similar to mitochondrial “priming” in skeletal muscle, we hypothesized that cardiac mitochondrial activity is altered upon successive bouts of contractions and depends on pyruvate dehydrogenase activity. We found altered bioenergetics upon repeated contractile periods, indicative of mitochondrial priming in rat myocardium. No effect was seen when pyruvate was added to the perfusate. As such, pyruvate dehydrogenase activity is involved in the mitochondrial adaptation to increased contractile performance.

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Sargent, C. A., S. Dzwonczyk, P. Sleph, M. Wilde, and G. J. Grover. "Pyruvate increases threshold for preconditioning in globally ischemic rat hearts." American Journal of Physiology-Heart and Circulatory Physiology 267, no. 4 (October 1, 1994): H1403—H1409. http://dx.doi.org/10.1152/ajpheart.1994.267.4.h1403.

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Isolated rat hearts can be protected by preconditioning, although this has not been found when they are perfused with pyruvate. We addressed the question of whether pyruvate could increase the threshold for preconditioning in isolated rat hearts and whether this could be overcome with increased durations of ischemia. A protocol of four periods of 5 min of ischemic preconditioning (4 x 5 min) protected hearts (improved recovery of function, reduced lactate dehydrogenase release) not perfused with pyruvate from a subsequent 30-min period of global ischemia, but did not protect pyruvate-perfused hearts. Pilot studies indicated that hearts perfused in the presence of pyruvate must be ischemic for approximately 40% longer to produce equivalent ischemic damage in nonpyruvate-treated hearts. Thus the preconditioning period of 5 min was increased by approximately 40% to 7 min to produce equivalent degrees of preconditioning. Hearts preconditioned with the 4 x 7 min protocol with pyruvate were significantly protected against a subsequent severe global ischemia (enhanced recovery of function, reduced lactate dehydrogenase release). High-energy phosphates were measured at the end of the preconditioning protocol (before final global ischemia) to determine whether there was a correlation between cardioprotection and high-energy phosphate levels. There was no correlation between ATP, ADP, or AMP levels and the efficacy of preconditioning. However, an increase in creatine phosphate was associated with cardioprotection, although the importance of this in mediating preconditioning is doubtful. Thus the ability to precondition rat hearts is somewhat dependent on their energy source, but this appears to be due to changes in the severity of the ischemic preconditioning event.

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Ma, Ke, Yi Zhang, Marshall B. Elam, George A. Cook, and Edwards A. Park. "Cloning of the Rat Pyruvate Dehydrogenase Kinase 4 Gene Promoter." Journal of Biological Chemistry 280, no. 33 (June 20, 2005): 29525–32. http://dx.doi.org/10.1074/jbc.m502236200.

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KILGOUR, ELAINE, and RICHARD G. VERNON. "Pyruvate dehydrogenase activity during pregnancy and lactation in the rat." Biochemical Society Transactions 13, no. 5 (October 1, 1985): 881–82. http://dx.doi.org/10.1042/bst0130881.

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STERNICZUK, Anna, Stan HRENIUK, Russell C. SCADUTO, and Kathryn F. LaNOUE. "Effect of phenylephrine on pyruvate dehydrogenase in fasting rat livers." European Journal of Biochemistry 196, no. 1 (February 1991): 151–57. http://dx.doi.org/10.1111/j.1432-1033.1991.tb15798.x.

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Matuda, Sadayuki, Kyoko Nakano, Izumi Tabata, Seiji Matuo, and Takeyori Saheki. "Properties of component X of rat heart pyruvate dehydrogenase complex." Biochemical and Biophysical Research Communications 150, no. 2 (January 1988): 816–21. http://dx.doi.org/10.1016/0006-291x(88)90464-0.

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28

Cockburn, Brian N., and Haldane G. Coore. "Starvation reduces pyruvate dehydrogenase phosphate phosphatase activity in rat kidney." Molecular and Cellular Biochemistry 149-150, no. 1 (August 1995): 131–36. http://dx.doi.org/10.1007/bf01076571.

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29

Paxton, R., R. Harris, A. Sener, and W. Malaisse. "Branched Chain α-Ketoacid Dehydrogenase and Pyruvate Dehydrogenase Activity in Isolated Rat Pancreatic Islets." Hormone and Metabolic Research 20, no. 06 (June 1988): 317–22. http://dx.doi.org/10.1055/s-2007-1010826.

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30

WU, Pengfei, Juichi SATO, Yu ZHAO, Jerzy JASKIEWICZ, M. Kirill POPOV, and A. Robert HARRIS. "Starvation and diabetes increase the amount of pyruvate dehydrogenase kinase isoenzyme 4 in rat heart." Biochemical Journal 329, no. 1 (January 1, 1998): 197–201. http://dx.doi.org/10.1042/bj3290197.

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This study investigated whether conditions known to alter the activity and phosphorylation state of the pyruvate dehydrogenase complex have specific effects on the levels of isoenzymes of pyruvate dehydrogenase kinase (PDK) in rat heart. Immunoblot analysis revealed a remarkable increase in the amount of PDK4 in the hearts of rats that had been starved or rendered diabetic with streptozotocin. Re-feeding of starved rats and insulin treatment of diabetic rats very effectively reversed the increase in PDK4 protein and restored PDK enzyme activity to levels of chow-fed control rats. Starvation and diabetes also markedly increased the abundance of PDK4 mRNA, and re-feeding and insulin treatment reduced levels of the message to that of controls. In contrast with the findings for PDK4, little or no changes in the amounts of PDK1 and PDK2 protein and the abundance of their messages occurred in response to starvation and diabetes. The observed shift in the relative abundance of PDK isoenzymes probably explains previous studies of the effects of starvation and diabetes on heart PDK activity. The results indicate that control of the amount of PDK4 is important in long-term regulation of the activity of the pyruvate dehydrogenase complex in rat heart.

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31

Borle, A. B., and R. T. Stanko. "Pyruvate reduces anoxic injury and free radical formation in perfused rat hepatocytes." American Journal of Physiology-Gastrointestinal and Liver Physiology 270, no. 3 (March 1, 1996): G535—G540. http://dx.doi.org/10.1152/ajpgi.1996.270.3.g535.

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The effects of 5 mM pyruvate on anoxic injury, superoxide (O2-.) and hydrogen peroxide (H2O2) generation, and lactate dehydrogenase (LDH) release during reoxygenation after 2.5 h anoxia were studied in perfused rat hepatocytes. When pyruvate was present during anoxia and reoxygenation, there was little anoxic injury, and the generation of free radicals and LDH release during reoxygenation were reduced 50-60%. When Pyruvate was added during reoxygenation, there was no decrease in O2-. or LDH release, although H2O2 formation was depressed. Free radical formation and anoxic/reperfusion injury were significantly reduced when pyruvate was added during the anoxic period only. Pyruvate reduced the deleterious effects of 10 microM antimycin A by preventing the increase in O2-. formation and LDH release evoked by the inhibitor. These results indicate that pyruvate protected hepatocytes against anoxic injury and that its protective action occurred principally during anoxia and not during reoxygenation. Pyruvate appeared to act at a mitochondrial site, since it reduced the deleterious effects of antimycin A.

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32

Cipres, G., E. Urcelay, N. Butta, M. S. Ayuso, R. Parrilla, and A. Martin-Requero. "Loss of fatty acid control of gluconeogenesis and PDH complex flux in adrenalectomized rats." American Journal of Physiology-Endocrinology and Metabolism 267, no. 4 (October 1, 1994): E528—E536. http://dx.doi.org/10.1152/ajpendo.1994.267.4.e528.

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This work aimed to determine the role played by the adrenal gland in the fatty acid control of gluconeogenesis in isolated perfused rat livers. The gluconeogenic substrate concentration responses were not altered in adrenalectomized (ADX) rats. This observation indicates that glucocorticoids are not essential to maintain normal basal gluconeogenic rates. In contrast, fatty acid failed to stimulate gluconeogenesis from lactate and elicited attenuated stimulation with pyruvate as substrate in livers from ADX rats. Fatty acid-induced stimulation of respiration and ketone body production were similar in control and ADX rats. Thus the diminished responsiveness of the gluconeogenic pathway to fatty acid cannot be the result of different rates of energy production and/or generation of reducing power. Fatty acids did not inhibit pyruvate decarboxylation in livers from ADX rats. Even though mitochondria isolated from livers of ADX rats showed normal basal rates of pyruvate metabolism, fatty acids failed to inhibit pyruvate decarboxylation and the activity of the pyruvate dehydrogenase complex. This novel observation of the glucocorticoid effect in controlling the pyruvate dehydrogenase complex responsiveness indicates that the mitochondrial partitioning of pyruvate between carboxylation and decarboxylation reactions may be altered in livers from ADX rats. We propose that the diminished effect of fatty acid in stimulating gluconeogenesis in livers from ADX rats is the result of a limited pyruvate availability for the carboxylase reaction due to a lack of inhibition of flux through the pyruvate dehydrogenase complex.

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33

Dumortier, Olivier, Gaia Fabris, Didier F. Pisani, Virginie Casamento, Nadine Gautier, Charlotte Hinault, Patricia Lebrun, et al. "microRNA-375 regulates glucose metabolism-related signaling for insulin secretion." Journal of Endocrinology 244, no. 1 (January 2020): 189–200. http://dx.doi.org/10.1530/joe-19-0180.

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Enhanced beta cell glycolytic and oxidative metabolism are necessary for glucose-induced insulin secretion. While several microRNAs modulate beta cell homeostasis, miR-375 stands out as it is highly expressed in beta cells where it regulates beta cell function, proliferation and differentiation. As glucose metabolism is central in all aspects of beta cell functioning, we investigated the role of miR-375 in this process using human and rat islets; the latter being an appropriate model for in-depth investigation. We used forced expression and repression of mR-375 in rat and human primary islet cells followed by analysis of insulin secretion and metabolism. Additionally, miR-375 expression and glucose-induced insulin secretion were compared in islets from rats at different developmental ages. We found that overexpressing of miR-375 in rat and human islet cells blunted insulin secretion in response to glucose but not to α-ketoisocaproate or KCl. Further, miR-375 reduced O2 consumption related to glycolysis and pyruvate metabolism, but not in response to α-ketoisocaproate. Concomitantly, lactate production was augmented suggesting that glucose-derived pyruvate is shifted away from mitochondria. Forced miR-375 expression in rat or human islets increased mRNA levels of pyruvate dehydrogenase kinase-4, but decreased those of pyruvate carboxylase and malate dehydrogenase1. Finally, reduced miR-375 expression was associated with maturation of fetal rat beta cells and acquisition of glucose-induced insulin secretion function. Altogether our findings identify miR-375 as an efficacious regulator of beta cell glucose metabolism and of insulin secretion, and could be determinant to functional beta cell developmental maturation.

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34

Midgley, P. J., G. A. Rutter, A. P. Thomas, and R. M. Denton. "Effects of Ca2+ and Mg2+ on the activity of pyruvate dehydrogenase phosphate phosphatase within toluene-permeabilized mitochondria." Biochemical Journal 241, no. 2 (January 15, 1987): 371–77. http://dx.doi.org/10.1042/bj2410371.

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Mitochondria from rat epididymal white adipose tissue were made permeable to small molecules by toluene treatment and were used to investigate the effects of Mg2+ and Ca2+ on the re-activation of pyruvate dehydrogenase phosphate by endogenous phosphatase. Re-activation of fully phosphorylated enzyme after addition of 0.18 mM-Mg2+ showed a marked lag of 5-10 min before a maximum rate of reactivation was achieved. Increasing the Mg2+ concentration to 1.8 mM (near saturating) or the addition of 100 microM-Ca2+ resulted in loss of the lag phase, which was also greatly diminished if pyruvate dehydrogenase was not fully phosphorylated. It is concluded that, within intact mitochondria, phosphatase activity is highly sensitive to the degree of phosphorylation of pyruvate dehydrogenase and that the major effect of Ca2+ may be to overcome the inhibitory effects of sites 2 and 3 on the dephosphorylation of site 1. Apparent K0.5 values for Mg2+ and Ca2+ were determined from the increases in pyruvate dehydrogenase activity observed after 5 min. The K0.5 for Mg2+ was diminished from 0.60 mM at less than 1 nM-Ca2+ to 0.32 mM at 100 microM-Ca2+; at 0.18 mM-Mg2+, the K0.5 for Ca2+ was 0.40 microM. Ca2+ had little or no effect at saturating Mg2+ concentrations. Since effects of Ca2+ are readily observed in intact coupled mitochondria, it follows that Mg2+ concentrations within mitochondria are sub-saturating for pyruvate dehydrogenase phosphate phosphatase and hence less than 0.5 mM.

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35

Moule, S. K., N. J. Edgell, G. I. Welsh, T. A. Diggle, E. J. Foulstone, K. J. Heesom, C. G. Proud, and R. M. Denton. "Multiple signalling pathways involved in the stimulation of fatty acid and glycogen synthesis by insulin in rat epididymal fat cells." Biochemical Journal 311, no. 2 (October 15, 1995): 595–601. http://dx.doi.org/10.1042/bj3110595.

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We have investigated the signalling pathways involved in the stimulation of glycogen and fatty acid synthesis by insulin in rat fat cells using wortmannin, an inhibitor of phosphatidylinositol 3-kinase, and rapamycin, which blocks activation of p70 ribosomal S6 protein kinase (p70S6K). Insulin produced a decrease in the activity of glycogen synthase kinase-3 which is likely to be important in the observed stimulation of glycogen synthase. Both of these actions were found to be sensitive to inhibition by wortmannin. Activation of three processes is involved in the stimulation of fatty acid synthesis from glucose by insulin, namely glucose uptake, acetyl-CoA carboxylase and pyruvate dehydrogenase. Whereas wortmannin largely abolished the effects of insulin on glucose utilization and acetyl-CoA carboxylase activity, it was without effect on the stimulation of pyruvate dehydrogenase. Although epidermal growth factor stimulated mitogen-activated protein kinase to a greater extent than insulin, it was unable to mimic the effect of insulin on glycogen synthase, glycogen synthase kinase-3, glucose utilization, acetyl-CoA carboxylase or pyruvate dehydrogenase. Rapamycin also failed to have any appreciable effect on stimulation of these parameters by insulin, although it did block the effect of insulin on p70S6K. We conclude that the activity of phosphatidylinositol 3-kinase is required for the effects of insulin on glycogen synthesis, glucose uptake and acetyl-Co-AN carboxylase, but is not involved in signalling to pyruvate dehydrogenase. Activation of mitogen-activated protein kinase or p70S6K, however, does not appear to be sufficient to bring about the stimulation of fatty acid or glycogen synthesis. Altogether is seems likely that at least four distinct signalling pathways are involved in the effects of insulin on rat fat cells.

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36

Macaulay, S. L., and R. G. Larkins. "Isolation of insulin-sensitive phosphatidylinositol-glycan from rat adipocytes. Its impaired breakdown in the streptozotocin-diabetic rat." Biochemical Journal 271, no. 2 (October 15, 1990): 427–35. http://dx.doi.org/10.1042/bj2710427.

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In this study an insulin-sensitive glycophospholipid from rat adipocytes was isolated and partially characterized. A material that activated pyruvate dehydrogenase was extracted from rat adipocyte membrane supernatants. Its release was stimulated by insulin and phosphatidylinositol-specific-phospholipase C and its activity was destroyed by nitrous acid deamination. These findings suggested that insulin might stimulate breakdown of a glycophospholipid containing inositol and glucosamine, as previously reported for some other cell types [Low & Saltiel (1988) Science 239, 268-275]. A lipid that incorporated [3H]glucosamine, [3H]galactose, [3H]inositol, and [3H]myristate and whose turnover was stimulated by insulin was subsequently isolated from intact adipocytes by sequential t.l.c. using an acidic solvent system followed by a basic solvent system. The effects of insulin on turnover of the lipid in these cells were transient, with maximal effects at 1 min, and there was a typical concentration-response curve to insulin (0.07 nM-7 nM), with effects being detected over the physiological range of insulin concentrations. In contrast with studies in other cells, there was appreciable turnover of the sugar labels. The majority of the [3H]glucosamine and [3H]galactose labels were cycled through to triacylglycerol in the adipocyte. However, of that recovered in the glycophospholipid band, a major proportion (less than 40%) was recovered as the native label. Digestion of the purified molecule with phosphatidylinositol-specific phospholipase C generated a material that activated both pyruvate dehydrogenase and low-Km cyclic AMP phosphodiesterase. Impairment in insulin-stimulated breakdown of the molecule in adipocytes of streptozotocin-diabetic rats was found, consistent with the impaired insulin activation of pyruvate dehydrogenase and glucose utilization seen in this model. These findings suggest that insulin stimulates breakdown of this glycophospholipid by stimulating an insulin-sensitive phospholipase in adipocytes. This compound may serve a function as a precursor for intracellular insulin mediators.

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37

Patel, T. B. "Effects of tolbutamide on gluconeogenesis and glycolysis in isolated perfused rat liver." American Journal of Physiology-Endocrinology and Metabolism 250, no. 1 (January 1, 1986): E82—E86. http://dx.doi.org/10.1152/ajpendo.1986.250.1.e82.

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In isolated perfused livers of 24-h fasted rats, perfused with lactate (2 mM), pyruvate (0.5 mM), or dihydroxyacetone (1 mM), infusion of tolbutamide (0.5 mM) very rapidly (within 3 min) inhibited the rate of gluconeogenesis. However, gluconeogenesis from fructose (1 mM) and glycerol (1 mM) was not affected by tolbutamide. Tolbutamide also inhibited by 30% the rate of 14CO2 production from livers perfused with [1-14C]pyruvate, without altering the rate of 14CO2 production from [2-14C]pyruvate. The rate of hepatic glycolysis from fructose, glycerol, and dihydroxyacetone was also stimulated by 250, 40, and 100%, respectively, during tolbutamide infusion into perfused livers. Tolbutamide also inhibited the endogenous rate of hepatic ketogenesis by 30%. All of the tolbutamide-mediated alterations in hepatic metabolism were reversed upon withdrawal of tolbutamide from the perfusion medium. Decreased hepatic gluconeogenesis from lactate and pyruvate in the presence of tolbutamide was not a consequence of increased pyruvate oxidation via the pyruvate dehydrogenase complex or the tricarboxylic acid cycle.

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38

Samigzhonov, A. A., M. Zh Ergasheva, and T. S. Saatov. "The effects of coordination zinc compound on glucose uptake and the activity of tissue pyruvate dehydrogenase in rats with experimental diabetes mellitus." Problems of Endocrinology 48, no. 6 (December 15, 2002): 48–50. http://dx.doi.org/10.14341/probl11730.

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Zinc compounds were examined for their effects on the transport of glucose through the membrane and on the activity of pyruvate dehydrogenase of mitochondria of the hearts and skeletal muscles from rats with experimental diabetes mellitus. The objects of the investigations were the rat diaphragm, cardiac and skeletal muscle mitochondria. The aim of the investigation was to study the effect of the coordination zinc compound piracine on the transport of glucose in the diaphragm and on the activity of pyruvate dehydrogenase of the hearts and skeletal muscles from rats with experimental diabetes mellitus. Experimental diabetes mellitus was induced by intraperitoneal alloxan hydrate during fasting. The investigation established that piracine exerted a stimulating effect on glucose transport in experimental diabetes. With the coordination zinc compound, there was an increase in the activity of pyruvate dehydrogenase, which is lowered in diabetes. The findings provide again evidence for the role of zinc ions in glucose transport and oxidation.

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39

Cardell, Monika, Tohru Koide, and Tadeusz Wieloch. "Pyruvate Dehydrogenase Activity in the Rat Cerebral Cortex following Cerebral Ischemia." Journal of Cerebral Blood Flow & Metabolism 9, no. 3 (June 1989): 350–57. http://dx.doi.org/10.1038/jcbfm.1989.53.

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The effect of cerebral ischemia on the activity of pyruvate dehydrogenase (PDH) enzyme complex (PDHC) was investigated in homogenates of frozen rat cerebral cortex following 15 min of bilateral common carotid occlusion ischemia and following 15 min, 60 min, and 6 h of recirculation after 15 min of ischemia. In frozen cortical tissue from the same animals, the levels of labile phosphate compounds, glucose, glycogen, lactate, and pyruvate were determined. In cortex from control animals, the rate of [1-14C]pyruvate decarboxylation was 9.6 ± 0.5 nmol CO2/(min-mg protein) or 40% of the total PDHC activity. This fraction increased to 89% at the end of 15 min of ischemia. At 15 min of recirculation following 15 min of ischemia, the PDHC activity decreased to 50% of control levels and was depressed for up to 6 h post ischemia. This decrease in activity was not due to a decrease in total PDHC activity. Apart from a reduction in ATP levels, the acute changes in the levels of energy metabolites were essentially normalized at 6 h of recovery. Dichloroacetate (DCA), an inhibitor of PDH kinase, given to rats at 250 mg/kg i.p. four times over 2 h, significantly decreased blood glucose levels from 7.4 ± 0.6 to 5.1 ± 0.3 mmol/L and fully activated PDHC. In animals in which the plasma glucose level was maintained at control levels of 8.3 ± 0.5 μmol/g by intravenous infusion of glucose, the active portion of PDHC increased to 95 ± 4%. In contrast, the depressed PDHC activity at 15 min following ischemia was not affected by the DCA treatment. In both DCA + glucose-treated control and recovery groups, the pyruvate levels decreased by 50%. No significant difference in the lactate levels was seen. We conclude that the depressed postischemic PDHC activity is not due to loss of enzyme protein nor to an increased PDH kinase activity, but is probably due to a decreased activity of PDH phosphatase. This could in turn be secondary to a change in the cellular levels of PDH phosphatase regulators, most probably a decreased intramitochondrial concentration of calcium. The postischemic decrease in PDH activity may be related to the postischemic metabolic depression.

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40

Bais, Renze, Allan M. Rofe, and Robert A. J. Conyers. "Inhibition of endogenous oxalate production: biochemical considerations of the roles of glycollate oxidase and lactate dehydrogenase." Clinical Science 76, no. 3 (March 1, 1989): 303–9. http://dx.doi.org/10.1042/cs0760303.

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1. Both the peroxisomal, flavin-linked glycollate oxidase [(S)-2-hydroxy-acid oxidase; EC 1.1.3.15] and the cytosolic, nicotinamide–adenine dinucleotide (NAD)-linked lactate dehydrogenase (l-lactate dehydrogenase; EC 1.1.1.27) are thought to contribute to the formation of oxalate from its immediate precursors, glycollate and glyoxylate, but the relative contributions of each enzyme to endogenous oxalate production is not known. 2. In rat liver homogenates, [14C]oxalate production from labelled glycollate is halved and that from labelled glyoxylate is increased fourfold by the addition of either NAD or NADH. 3. In isolated rat hepatocytes, the 3-hydroxy-1H-pyrrole-2,5-dione derivatives of glycollate, which are specific inhibitors of glycollate oxidase, have a greater effect on glycollate metabolism than on glyoxylate metabolism. 4. These findings are consistent with an important role for lactate dehydrogenase in oxalate formation from glyoxylate. 5. With human and rat liver homogenates and with purified human liver glycollate oxidase and rabbit muscle lactate dehydrogenase, dl-phenyl-lactate (2 mmol/l) completely inhibits glycollate oxidase but has no effect on lactate dehydrogenase. On the other hand, the reduced form of a chemically synthesized, NAD–pyruvate adduct (1 mmol/l) almost completely inhibited lactate dehydrogenase but had no effect on glycollate oxidase. 6. Either alone or in combination, dl-phenyl-lactate and reduced NAD–pyruvate adduct reduce oxalate production from glycollate and glyoxylate in isolated rat hepatocytes, but do not abolish it completely. 7. These findings support a role for another enzyme, probably glycollate dehydrogenase (EC 1.1.99.14), in oxalate production in integrated cell metabolism. 8. In relation to renal oxalate stone disease, these results suggest that the therapeutic inhibition of glycollate oxidase or lactate dehydrogenase would not completely prevent the endogenous formation of oxalate.

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Thomas, A. P., and R. M. Denton. "Use of toluene-permeabilized mitochondria to study the regulation of adipose tissue pyruvate dehydrogenase in situ. Further evidence that insulin acts through stimulation of pyruvate dehydrogenase phosphate phosphatase." Biochemical Journal 238, no. 1 (August 15, 1986): 93–101. http://dx.doi.org/10.1042/bj2380093.

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Rat epididymal-adipose-tissue mitochondria were made selectively permeable to small molecules without the loss of matrix enzymes by treating the mitochondria with toluene under controlled conditions. With this preparation the entire pyruvate dehydrogenase system was shown to be retained within the mitochondrial matrix and to retain its normal catalytic activity. By using dilute suspensions of these permeabilized mitochondria maintained in the cuvette of a spectrophotometer, it was possible to monitor changes of pyruvate dehydrogenase activity continuously while the activities of the interconverting kinase and phosphatase could be independently manipulated. Permeabilized mitochondria were prepared from control and insulin-treated adipose tissue, and the properties of both the pyruvate dehydrogenase kinase and the phosphatase were compared in situ. No difference in kinase activity was detected, but increases in phosphatase activity were observed in permeabilized mitochondria from insulin-treated tissue. Further studies showed that the main effect of insulin treatment was a decrease in the apparent Ka of the phosphatase for Mg2+, in agreement with earlier studies with mitochondria made permeable to Mg2+ by using the ionophore A23187 [Thomas, Diggle & Denton (1986) Biochem. J. 238, 83-91]. No effects of spermine were detected, although spermine diminishes the Ka of purified phosphatase preparations for Mg2+. Since effects of insulin on pyruvate dehydrogenase phosphatase activity are not evident in mitochondrial extracts, it is concluded that insulin may act by altering some high-Mr component which interacts with the pyruvate dehydrogenase system within intact or permeabilized mitochondria, but not when the mitochondrial membranes are disrupted.

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42

Large, V., H. Brunengraber, M. Odeon, and M. Beylot. "Use of labeling pattern of liver glutamate to calculate rates of citric acid cycle and gluconeogenesis." American Journal of Physiology-Endocrinology and Metabolism 272, no. 1 (January 1, 1997): E51—E58. http://dx.doi.org/10.1152/ajpendo.1997.272.1.e51.

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The use of the labeling pattern of hepatic glutamate during infusion of L-[3-13C]- or [3-14C]lactate to calculate rates of citric acid cycle activity and gluconeogenesis has been proposed. We tested the validity of this approach by perfusing isolated rat livers (48 h starved) with pyruvate and lactate (10% enriched with [3-13C]lactate) without (control) or with infusion of glucagon (to inhibit pyruvate kinase), mercaptopicolinate (to inhibit phosphoenolpyruvate carboxykinase), or dichloroacetate (to stimulate pyruvate dehydrogenase). Compared with control experiments, glucagon increased glucose output (P < 0.05) and decreased the calculated flux through pyruvate kinase (P < 0.05). Mercaptopicolinate almost totally suppressed glucose production and dramatically reduced the calculated gluconeogenic rate and flux through phosphoenolpyruvate carboxykinase (P < 0.001). Dichloroacetate moderately increased the calculated flux through pyruvate dehydrogenase (P < 0.05). In experiments with perfused livers from fed rats, the calculated gluconeogenic rate and flux through phosphoenolpyruvate carboxykinase were very low compared with control experiments (P < 0.001), whereas the pyruvate dehydrogenase flux was increased (P < 0.05). Therefore, the expected modifications of the citric acid cycle activity and gluconeogenic rate were clearly detected using the labeling pattern of glutamate to calculate these metabolic rates. Except for the perfusions with mercaptopicolinate, the dilution by isotopic exchange in the oxaloacetate pool calculated from the model agreed with the actual dilution of enrichment between liver pyruvate and phosphoenolpyruvate. The present results support the validity of this approach to trace liver metabolism.

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43

Marchington, D. R., A. L. Kerbey, M. G. Giardina, A. E. Jones, and P. J. Randle. "Longer-term regulation of pyruvate dehydrogenase kinase in cultured rat hepatocytes." Biochemical Journal 257, no. 2 (January 15, 1989): 487–91. http://dx.doi.org/10.1042/bj2570487.

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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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44

Tullson, Peter C., and Leon Goldstein. "Effects of Acute Acid-Base Changes on Rat Renal Pyruvate Dehydrogenase." Enzyme 37, no. 3 (1987): 127–33. http://dx.doi.org/10.1159/000469249.

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45

MALLOCH, G. D. A., I. R. PHILLIPS, and J. B. CLARK. "Developmental Regulation of the Pyruvate Dehydrogenase Complex in the Rat Brain." Annals of the New York Academy of Sciences 573, no. 1 Alpha-Keto Ac (December 1989): 416. http://dx.doi.org/10.1111/j.1749-6632.1989.tb15024.x.

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46

Lundgren, Johan, Monika Cardell, Tadeusz Wieloch, and Bo K. Siesjö. "Preischemic Hyperglycemia and Postischemic Alteration of Rat Brain Pyruvate Dehydrogenase Activity." Journal of Cerebral Blood Flow & Metabolism 10, no. 4 (July 1990): 536–41. http://dx.doi.org/10.1038/jcbfm.1990.95.

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Transient cerebral ischemia in normoglycemic animals is followed by a decrease in glucose utilization, reflecting a postischemic cerebral metabolic depression and a reduction in the activity of the pyruvate dehydrogenase complex (PDHC). Preischemic hyperglycemia, which aggravates ischemic brain damage and invariably causes seizure, is known to further reduce cerebral metabolic rate. To investigate whether these effects are accompanied by changes in PDHC activity, the postischemic cerebral cortical activity of this enzyme was investigated in rats with preischemic hyperglycemia (plasma glucose 20–25 m M). The results were compared with those obtained in normoglycemic animals (plasma glucose 5–10 m M). The activated portion of PDHC and total PDHC activity were measured in neocortical samples as the rate of decarboxylation of [14C]pyruvate in crude brain mitochondrial homogenates after 5 min, 15 min, 1 h, 6 h, and 18 h of recirculation following 15 min of incomplete cerebral ischemia. In normoglycemic animals the fraction of activated PDHC, which rises abruptly during ischemia, was reduced to 19–25% during recirculation compared with 30% in sham-operated controls. In hyperglycemic rats the fraction of activated PDHC was higher during the first 15 min of recirculation. However, after 1 and 6 h of recirculation, the fraction was reduced to values similar to those measured in normoglycemic animals. Fifteen of 26 rats experienced early (1–4 h post ischemia) seizures in the recovery period. The PDHC activity appeared unchanged prior to these early postischemic seizures. We conclude that the accentuated depression of postischemic metabolic rate observed in hyperglycemic animals is not coupled to a corresponding postischemic depression of PDHC. The relative increase in the fraction of activated PDHC in the early recovery phase in hyperglycemic animals probably reflects either increased intramitochondrial calcium levels or persistent increases in the NADH/NAD and/or ADP/ATP ratios.

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47

Denyer, G. S., G. J. Cooney, L. H. Storlien, A. B. Jenkins, E. W. Kraegen, M. Kusunoki, and I. D. Caterson. "Heterogeneity of response to exercise of rat muscle pyruvate dehydrogenase complex." Pfl�gers Archiv European Journal of Physiology 419, no. 2 (September 1991): 115–20. http://dx.doi.org/10.1007/bf00372995.

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48

Moreau, Régis, Shi-Hua D. Heath, Catalin E. Doneanu, Robert A. Harris, and Tory M. Hagen. "Age-related compensatory activation of pyruvate dehydrogenase complex in rat heart." Biochemical and Biophysical Research Communications 325, no. 1 (December 2004): 48–58. http://dx.doi.org/10.1016/j.bbrc.2004.10.011.

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49

Selak, Mary A., Bayard T. Storey, Iyalla Peterside, and Rebecca A. Simmons. "Impaired oxidative phosphorylation in skeletal muscle of intrauterine growth-retarded rats." American Journal of Physiology-Endocrinology and Metabolism 285, no. 1 (July 2003): E130—E137. http://dx.doi.org/10.1152/ajpendo.00322.2002.

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Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes in later life. We have developed a model of uteroplacental insufficiency, a common cause of intrauterine growth retardation, in the rat. Early in life, the animals are insulin resistant and by 6 mo of age they develop diabetes. Glycogen content and insulin-stimulated 2-deoxyglucose uptake were significantly decreased in muscle from IUGR rats. IUGR muscle mitochondria exhibited significantly decreased rates of state 3 oxygen consumption with pyruvate, glutamate, α-ketoglutarate, and succinate. Decreased pyruvate oxidation in IUGR mitochondria was associated with decreased ATP production, decreased pyruvate dehydrogenase activity, and increased expression of pyruvate dehydrogenase kinase 4. Such a defect in IUGR mitochondria leads to a chronic reduction in the supply of ATP available from oxidative phosphorylation. Impaired ATP synthesis in muscle compromises energy-dependent GLUT4 recruitment to the cell surface, glucose transport, and glycogen synthesis, which contribute to insulin resistance and hyperglycemia of type 2 diabetes.

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50

Paxton, R., and L. M. Sievert. "An improved assay for pyruvate dehydrogenase in liver and heart." Biochemical Journal 277, no. 2 (July 15, 1991): 547–51. http://dx.doi.org/10.1042/bj2770547.

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A radiochemical assay was developed to measure pyruvate dehydrogenase complex (PDC) activity in liver and heart without interference by branched-chain 2-oxo acid dehydrogenase (BCODH). Decarboxylation of pyruvate by BCODH was eliminated by using low pyruvate concentration (0.5 mM), a preferred substrate for BCODH (3-methyl-2-oxopentanoate) that is not used by PDC, and a competitive inhibitor of BCODH, dichloroacetate. This method was validated by assaying a combination of both purified enzymes and tissue homogenates with known amounts of added BCODH. The actual percentage of active PDC decreased after 48 h starvation from 13.6 to 3.1 in liver and from 77.1 to 9.0 in heart. Total PDC activity (munits of PDC/units of citrate synthase) in starved rats was increased by 34% in liver and decreased by 23% in heart. Total PDC activity (munits/g wet wt.) in fed- and starved-rat liver was 0.8 and 1.3, and in heart was 6.6 and 5.8, respectively.

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Journal articles on the topic 'Rat pyruvate dehydrogenase'

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