The PDC (pyruvate dehydrogenase complex) is strongly inhibited by phosphorylation during starvation to conserve substrates for gluconeogenesis. The role of PDHK4 (pyruvate dehydrogenase kinase isoenzyme 4) in regulation of PDC by this mechanism was investigated with PDHK4−/− mice (homozygous PDHK4 knockout mice). Starvation lowers blood glucose more in mice lacking PDHK4 than in wild-type mice. The activity state of PDC (percentage dephosphorylated and active) is greater in kidney, gastrocnemius muscle, diaphragm and heart but not in the liver of starved PDHK4−/− mice. Intermediates of the gluconeogenic pathway are lower in concentration in the liver of starved PDHK4−/− mice, consistent with a lower rate of gluconeogenesis due to a substrate supply limitation. The concentration of gluconeogenic substrates is lower in the blood of starved PDHK4−/− mice, consistent with reduced formation in peripheral tissues. Isolated diaphragms from starved PDHK4−/− mice accumulate less lactate and pyruvate because of a faster rate of pyruvate oxidation and a reduced rate of glycolysis. BCAAs (branched chain amino acids) are higher in the blood in starved PDHK4−/− mice, consistent with lower blood alanine levels and the importance of BCAAs as a source of amino groups for alanine formation. Non-esterified fatty acids are also elevated more in the blood of starved PDHK4−/− mice, consistent with lower rates of fatty acid oxidation due to increased rates of glucose and pyruvate oxidation due to greater PDC activity. Up-regulation of PDHK4 in tissues other than the liver is clearly important during starvation for regulation of PDC activity and glucose homoeostasis.
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Research Article|
July 13 2006
Role of pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) in glucose homoeostasis during starvation
Nam Ho Jeoung;
Nam Ho Jeoung
*Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5122, U.S.A.
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Pengfei Wu;
Pengfei Wu
*Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5122, U.S.A.
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Mandar A. Joshi;
Mandar A. Joshi
*Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5122, U.S.A.
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Jerzy Jaskiewicz;
Jerzy Jaskiewicz
1
*Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5122, U.S.A.
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Cheryl B. Bock;
Cheryl B. Bock
†Comprehensive Cancer Center, Duke University Medical Center, Durham, NC 27710, U.S.A.
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Anna A. Depaoli-Roach;
Anna A. Depaoli-Roach
*Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5122, U.S.A.
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Robert A. Harris
Robert A. Harris
2
*Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5122, U.S.A.
2To whom correspondence should be addressed, at Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Biotechnology Research and Training Center, 1345 W. 16th St., Indianapolis, IN 46202-2111, U.S.A. (email raharris@iupui.edu).
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Publisher: Portland Press Ltd
Received:
January 19 2006
Revision Received:
March 13 2006
Accepted:
April 11 2006
Accepted Manuscript online:
April 11 2006
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2006
Biochem J (2006) 397 (3): 417–425.
Article history
Received:
January 19 2006
Revision Received:
March 13 2006
Accepted:
April 11 2006
Accepted Manuscript online:
April 11 2006
Citation
Nam Ho Jeoung, Pengfei Wu, Mandar A. Joshi, Jerzy Jaskiewicz, Cheryl B. Bock, Anna A. Depaoli-Roach, Robert A. Harris; Role of pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) in glucose homoeostasis during starvation. Biochem J 1 August 2006; 397 (3): 417–425. doi: https://doi.org/10.1042/BJ20060125
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