Activation of the pyruvate dehydrogenase (PDH) complex (PDHC) promotes glucose disposal, whereas inactivation conserves glucose. The PDH kinases (PDHKs) regulate glucose oxidation through inhibitory phosphorylation of PDHC. The adult rat heart contains three PDHK isoforms PDHK1, PDHK2 and PDHK4. Using Western-blot analysis, with specific antibodies raised against individual recombinant PDHK1, PDHK2 and PDHK4, the present study investigated PDHK isoform expression in the developing rat heart and adulthood. We identified clear differences in the patterns of protein expression of each of these PDHK isoforms during the first 3 weeks of post-natal development, with most marked up-regulation of isoforms PDHK1 and PDHK4. Distinctions between the three cardiac PDHK isoforms were also demonstrated with respect to post-neonatal maturational up-regulation; with greatest up-regulation of PDHK1 and least up-regulation of PDHK4 from the post-neonatal period until maturity. The study also examined the role of thyroid hormone status and lipid supply on PDHK isoform expression. We observed marked selective increases in the amount of PDHK4 protein present relative to total cardiac protein in both hyperthyroidism and high-fat feeding. Overall, our data identify PDHK isoform PDHK1 as being of more potential regulatory importance for glucose oxidation in the adult compared with the neonatal heart, and cardiac PDHK4 as a PDHK isoform whose expression is specifically responsive to changes in lipid supply, suggesting that its up-regulation during early post-natal life may be the perinatal switch to use fatty acids as the energy source. We also identify regulation of pyruvate sensitivity of cardiac PDHK as a physiological variable, a change in which requires factors in addition to a change in lipid supply.
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Research Article|
December 08 2000
Expression and regulation of pyruvate dehydrogenase kinase isoforms in the developing rat heart and in adulthood: role of thyroid hormone status and lipid supply
Mary C. SUGDEN;
Mary C. SUGDEN
*Department of Diabetes and Metabolic Medicine, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary College, University of London, Mile End Road, London E1 4NS, U.K.
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Maria L. LANGDOWN;
Maria L. LANGDOWN
*Department of Diabetes and Metabolic Medicine, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary College, University of London, Mile End Road, London E1 4NS, U.K.
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Robert A. HARRIS;
Robert A. HARRIS
†Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202-5122, U.S.A.
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Mark J. HOLNESS
Mark J. HOLNESS
1
*Department of Diabetes and Metabolic Medicine, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary College, University of London, Mile End Road, London E1 4NS, U.K.
1To whom correspondence should be addressed (e-mail m.j.holness@qmw.ac.uk).
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Publisher: Portland Press Ltd
Received:
August 17 2000
Revision Received:
September 20 2000
Accepted:
October 09 2000
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 2000
2000
Biochem J (2000) 352 (3): 731–738.
Article history
Received:
August 17 2000
Revision Received:
September 20 2000
Accepted:
October 09 2000
Citation
Mary C. SUGDEN, Maria L. LANGDOWN, Robert A. HARRIS, Mark J. HOLNESS; Expression and regulation of pyruvate dehydrogenase kinase isoforms in the developing rat heart and in adulthood: role of thyroid hormone status and lipid supply. Biochem J 15 December 2000; 352 (3): 731–738. doi: https://doi.org/10.1042/bj3520731
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