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. 1998 Jan 1;329(Pt 1):197–201. doi: 10.1042/bj3290197

Starvation and diabetes increase the amount of pyruvate dehydrogenase kinase isoenzyme 4 in rat heart.

P Wu 1, J Sato 1, Y Zhao 1, J Jaskiewicz 1, K M Popov 1, R A Harris 1
PMCID: PMC1219032  PMID: 9405294

Abstract

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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Selected References

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  1. Bowker-Kinley M. M., Davis W. I., Wu P., Harris R. A., Popov K. M. Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem J. 1998 Jan 1;329(Pt 1):191–196. doi: 10.1042/bj3290191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  3. Carter T. C., Coore H. G. Effects of pyruvate on pyruvate dehydrogenase kinase of rat heart. Mol Cell Biochem. 1995 Aug-Sep;149-150:71–75. doi: 10.1007/BF01076565. [DOI] [PubMed] [Google Scholar]
  4. Chan Y. L., Olvera J., Wool I. G. The structure of rat 28S ribosomal ribonucleic acid inferred from the sequence of nucleotides in a gene. Nucleic Acids Res. 1983 Nov 25;11(22):7819–7831. doi: 10.1093/nar/11.22.7819. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Coore H. G., Denton R. M., Martin B. R., Randle P. J. Regulation of adipose tissue pyruvate dehydrogenase by insulin and other hormones. Biochem J. 1971 Nov;125(1):115–127. doi: 10.1042/bj1250115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Denyer G. S., Kerbey A. L., Randle P. J. Kinase activator protein mediates longer-term effects of starvation on activity of pyruvate dehydrogenase kinase in rat liver mitochondria. Biochem J. 1986 Oct 15;239(2):347–354. doi: 10.1042/bj2390347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Feldhoff P. W., Arnold J., Oesterling B., Vary T. C. Insulin-induced activation of pyruvate dehydrogenase complex in skeletal muscle of diabetic rats. Metabolism. 1993 May;42(5):615–623. doi: 10.1016/0026-0495(93)90221-9. [DOI] [PubMed] [Google Scholar]
  8. French T. J., Holness M. J., MacLennan P. A., Sugden M. C. Effects of nutritional status and acute variation in substrate supply on cardiac and skeletal-muscle fructose 2,6-bisphosphate concentrations. Biochem J. 1988 Mar 15;250(3):773–779. doi: 10.1042/bj2500773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fuller S. J., Randle P. J. Reversible phosphorylation of pyruvate dehydrogenase in rat skeletal-muscle mitochondria. Effects of starvation and diabetes. Biochem J. 1984 Apr 15;219(2):635–646. doi: 10.1042/bj2190635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gudi R., Bowker-Kinley M. M., Kedishvili N. Y., Zhao Y., Popov K. M. Diversity of the pyruvate dehydrogenase kinase gene family in humans. J Biol Chem. 1995 Dec 1;270(48):28989–28994. doi: 10.1074/jbc.270.48.28989. [DOI] [PubMed] [Google Scholar]
  11. Holness M. J., French T. J., Sugden M. C. Hepatic glycogen synthesis on carbohydrate re-feeding after starvation. A regulatory role for pyruvate dehydrogenase in liver and extrahepatic tissues. Biochem J. 1986 Apr 15;235(2):441–445. doi: 10.1042/bj2350441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hutson N. J., Randle P. J. Enhanced activity of pyruvate dehydrogenase kinase in rat heart mitochondria in alloxan-diabetes or starvation. FEBS Lett. 1978 Aug 1;92(1):73–76. doi: 10.1016/0014-5793(78)80724-8. [DOI] [PubMed] [Google Scholar]
  13. Jones B. S., Yeaman S. J., Sugden M. C., Holness M. J. Hepatic pyruvate dehydrogenase kinase activities during the starved-to-fed transition. Biochim Biophys Acta. 1992 Mar 16;1134(2):164–168. doi: 10.1016/0167-4889(92)90040-i. [DOI] [PubMed] [Google Scholar]
  14. Kerbey A. L., Radcliffe P. M., Randle P. J. Diabetes and the control of pyruvate dehydrogenase in rat heart mitochondria by concentration ratios of adenosine triphosphate/adenosine diphosphate, of reduced/oxidized nicotinamide-adenine dinucleotide and of acetyl-coenzyme A/coenzyme A. Biochem J. 1977 Jun 15;164(3):509–519. doi: 10.1042/bj1640509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kerbey A. L., Randle P. J., Cooper R. H., Whitehouse S., Pask H. T., Denton R. M. Regulation of pyruvate dehydrogenase in rat heart. Mechanism of regulation of proportions of dephosphorylated and phosphorylated enzyme by oxidation of fatty acids and ketone bodies and of effects of diabetes: role of coenzyme A, acetyl-coenzyme A and reduced and oxidized nicotinamide-adenine dinucleotide. Biochem J. 1976 Feb 15;154(2):327–348. doi: 10.1042/bj1540327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kerbey A. L., Randle P. J. Pyruvate dehydrogenase kinase/activator in rat heart mitochondria, Assay, effect of starvation, and effect of protein-synthesis inhibitors of starvation. Biochem J. 1982 Jul 15;206(1):103–111. doi: 10.1042/bj2060103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kerbey A. L., Randle P. J. Thermolabile factor accelerates pyruvate dehydrogenase kinase reaction in heart mitochondria of starved or alloxan-diabetic rats. FEBS Lett. 1981 May 18;127(2):188–192. doi: 10.1016/0014-5793(81)80201-3. [DOI] [PubMed] [Google Scholar]
  18. Orfali K. A., Fryer L. G., Holness M. J., Sugden M. C. Interactive effects of insulin and triiodothyronine on pyruvate dehydrogenase kinase activity in cardiac myocytes. J Mol Cell Cardiol. 1995 Mar;27(3):901–908. doi: 10.1016/0022-2828(95)90040-3. [DOI] [PubMed] [Google Scholar]
  19. Popov K. M., Kedishvili N. Y., Zhao Y., Gudi R., Harris R. A. Molecular cloning of the p45 subunit of pyruvate dehydrogenase kinase. J Biol Chem. 1994 Nov 25;269(47):29720–29724. [PubMed] [Google Scholar]
  20. Popov K. M., Kedishvili N. Y., Zhao Y., Shimomura Y., Crabb D. W., Harris R. A. Primary structure of pyruvate dehydrogenase kinase establishes a new family of eukaryotic protein kinases. J Biol Chem. 1993 Dec 15;268(35):26602–26606. [PubMed] [Google Scholar]
  21. Priestman D. A., Mistry S. C., Halsall A., Randle P. J. Role of protein synthesis and of fatty acid metabolism in the longer-term regulation of pyruvate dehydrogenase kinase. Biochem J. 1994 Jun 15;300(Pt 3):659–664. doi: 10.1042/bj3000659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Priestman D. A., Mistry S. C., Kerbey A. L., Randle P. J. Purification and partial characterization of rat liver pyruvate dehydrogenase kinase activator protein (free pyruvate dehydrogenase kinase). FEBS Lett. 1992 Aug 10;308(1):83–86. doi: 10.1016/0014-5793(92)81056-r. [DOI] [PubMed] [Google Scholar]
  23. Priestman D. A., Orfali K. A., Sugden M. C. Pyruvate inhibition of pyruvate dehydrogenase kinase. Effects of progressive starvation and hyperthyroidism in vivo, and of dibutyryl cyclic AMP and fatty acids in cultured cardiac myocytes. FEBS Lett. 1996 Sep 16;393(2-3):174–178. doi: 10.1016/0014-5793(96)00877-0. [DOI] [PubMed] [Google Scholar]
  24. Randle P. J. Fuel selection in animals. Biochem Soc Trans. 1986 Oct;14(5):799–806. doi: 10.1042/bst0140799. [DOI] [PubMed] [Google Scholar]
  25. Randle P. J., Priestman D. A., Mistry S., Halsall A. Mechanisms modifying glucose oxidation in diabetes mellitus. Diabetologia. 1994 Sep;37 (Suppl 2):S155–S161. doi: 10.1007/BF00400839. [DOI] [PubMed] [Google Scholar]
  26. Rougraff P. M., Paxton R. Purification and partial characterization of chicken liver acetyl coenzyme A: arylamine N-acetyltransferase. Comp Biochem Physiol B. 1987;86(3):601–606. doi: 10.1016/0305-0491(87)90455-x. [DOI] [PubMed] [Google Scholar]
  27. Rowles J., Scherer S. W., Xi T., Majer M., Nickle D. C., Rommens J. M., Popov K. M., Harris R. A., Riebow N. L., Xia J. Cloning and characterization of PDK4 on 7q21.3 encoding a fourth pyruvate dehydrogenase kinase isoenzyme in human. J Biol Chem. 1996 Sep 13;271(37):22376–22382. doi: 10.1074/jbc.271.37.22376. [DOI] [PubMed] [Google Scholar]
  28. Sugden M. C., Holness M. J., Palmer T. N. Fuel selection and carbon flux during the starved-to-fed transition. Biochem J. 1989 Oct 15;263(2):313–323. doi: 10.1042/bj2630313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sugden M. C., Orfali K. A., Holness M. J. The pyruvate dehydrogenase complex: nutrient control and the pathogenesis of insulin resistance. J Nutr. 1995 Jun;125(6 Suppl):1746S–1752S. doi: 10.1093/jn/125.suppl_6.1746S. [DOI] [PubMed] [Google Scholar]
  30. Wieland O. H. The mammalian pyruvate dehydrogenase complex: structure and regulation. Rev Physiol Biochem Pharmacol. 1983;96:123–170. doi: 10.1007/BFb0031008. [DOI] [PubMed] [Google Scholar]
  31. Yeaman S. J. The 2-oxo acid dehydrogenase complexes: recent advances. Biochem J. 1989 Feb 1;257(3):625–632. doi: 10.1042/bj2570625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Zhao Y., Popov K. M., Shimomura Y., Kedishvili N. Y., Jaskiewicz J., Kuntz M. J., Kain J., Zhang B., Harris R. A. Effect of dietary protein on the liver content and subunit composition of the branched-chain alpha-ketoacid dehydrogenase complex. Arch Biochem Biophys. 1994 Feb 1;308(2):446–453. doi: 10.1006/abbi.1994.1063. [DOI] [PubMed] [Google Scholar]

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