Inactivation of cardiac pyruvate dehydrogenase complex (PDC) after prolonged starvation and in response to hyperthyroidism is associated with enhanced protein expression of pyruvate dehydrogenase kinase (PDK) isoform 4. The present study examined the potential role of peroxisome-proliferator-activated receptor α (PPARα) in adaptive modification of cardiac PDK4 protein expression after starvation and in hyperthyroidism. PDK4 protein expression was analysed by immunoblotting in homogenates of hearts from fed or 48h-starved rats, rats rendered hyperthyroid by subcutaneous injection of tri-iodothyronine and a subgroup of euthyroid rats maintained on a high-fat/low-carbohydrate diet, with or without treatment with the PPARα agonist WY14,643. In addition, PDK4 protein expression was analysed in hearts from fed, 24h-starved or 6h-refed wild-type or PPARα-null mice. PPARα activation by WY14,643 in vivo over the timescale of the response to starvation failed to up-regulate cardiac PDK4 protein expression in rats maintained on standard diet (WY14,643, 1.1-fold increase; starvation, 1.8-fold increase) or influence the cardiac PDK4 response to starvation. By contrast, PPARα activation by WY14,643 in vivo significantly enhanced cardiac PDK4 protein expression in rats maintained on a high-fat diet, which itself increased cardiac PDK4 protein expression. PPARα deficiency did not abolish up-regulation of cardiac PDK4 protein expression in response to starvation (2.9-fold increases in both wild-type and PPARα-null mice). Starvation and hyperthyroidism exerted additive effects on cardiac PDK4 protein expression, but PPARα activation by WY14,643 did not influence the response of cardiac PDK4 protein expression to hyperthyroidism in either the fed or starved state. Our data support the hypothesis that cardiac PDK4 protein expression is regulated, at least in part, by a fatty acid-dependent, PPARα-independent mechanism and strongly implicate a fall in insulin in either initiating or facilitating the response of cardiac PDK4 protein expression to starvation.
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June 2002
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Research Article|
June 15 2002
Evaluation of the role of peroxisome-proliferator-activated receptor α in the regulation of cardiac pyruvate dehydrogenase kinase 4 protein expression in response to starvation, high-fat feeding and hyperthyroidism
Mark J. HOLNESS;
Mark J. HOLNESS
∗Department of Diabetes and Metabolic Medicine, St Bartholomew's and the Royal London School of Medicine and Dentistry, Medical Sciences Building, Queen Mary, University of London, London E1 4NS, U.K.
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Nicholas D. SMITH;
Nicholas D. SMITH
∗Department of Diabetes and Metabolic Medicine, St Bartholomew's and the Royal London School of Medicine and Dentistry, Medical Sciences Building, Queen Mary, University of London, London E1 4NS, U.K.
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Karen BULMER;
Karen BULMER
∗Department of Diabetes and Metabolic Medicine, St Bartholomew's and the Royal London School of Medicine and Dentistry, Medical Sciences Building, Queen Mary, University of London, London E1 4NS, U.K.
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Teresa HOPKINS;
Teresa HOPKINS
†Department of Pharmacology, University of Alberta, 9-70 Medical Sciences Building, Edmonton, Canada
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Geoffrey F. GIBBONS;
Geoffrey F. GIBBONS
‡Metabolic Research Laboratory, Oxford Lipid Metabolism Group, University of Oxford, Radcliffe Infirmary, Woodstock Road, Oxford, U.K.
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Mary C. SUGDEN
Mary C. SUGDEN
1
∗Department of Diabetes and Metabolic Medicine, St Bartholomew's and the Royal London School of Medicine and Dentistry, Medical Sciences Building, Queen Mary, University of London, London E1 4NS, U.K.
1To whom correspondence should be addressed (e-mail m.c.sugden@qmul.ac.uk).
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Publisher: Portland Press Ltd
Received:
December 14 2001
Revision Received:
February 25 2002
Accepted:
April 03 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 364 (3): 687–694.
Article history
Received:
December 14 2001
Revision Received:
February 25 2002
Accepted:
April 03 2002
Citation
Mark J. HOLNESS, Nicholas D. SMITH, Karen BULMER, Teresa HOPKINS, Geoffrey F. GIBBONS, Mary C. SUGDEN; Evaluation of the role of peroxisome-proliferator-activated receptor α in the regulation of cardiac pyruvate dehydrogenase kinase 4 protein expression in response to starvation, high-fat feeding and hyperthyroidism. Biochem J 15 June 2002; 364 (3): 687–694. doi: https://doi.org/10.1042/bj20011841
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