Role of pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) in glucose homoeostasis during starvation

Nam Ho Jeoung, Pengfei Wu, Mandar A. Joshi, Jerzy Jaskiewicz, Cheryl B. Bock, Anna De Paoli-Roach, Robert Harris

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

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 knock-out 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.

Original languageEnglish
Pages (from-to)417-425
Number of pages9
JournalBiochemical Journal
Volume397
Issue number3
DOIs
StatePublished - Aug 1 2006

Fingerprint

Starvation
Isoenzymes
Pyruvate Dehydrogenase Complex
Homeostasis
Glucose
Pyruvic Acid
Branched Chain Amino Acids
Gluconeogenesis
Blood
Liver
Diaphragm
Alanine
Fatty Acids
Diaphragms
Oxidation
pyruvate dehydrogenase (acetyl-transferring) kinase
pyruvate dehydrogenase kinase 4
Substrates
Glycolysis
Tissue

Keywords

  • Branched chain amino acid
  • Fatty acid oxidation
  • Glucose homoeostasis
  • Pyruvate dehydrogenase complex
  • Pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) deficiency
  • Starvation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Role of pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) in glucose homoeostasis during starvation. / Jeoung, Nam Ho; Wu, Pengfei; Joshi, Mandar A.; Jaskiewicz, Jerzy; Bock, Cheryl B.; De Paoli-Roach, Anna; Harris, Robert.

In: Biochemical Journal, Vol. 397, No. 3, 01.08.2006, p. 417-425.

Research output: Contribution to journalArticle

Jeoung, Nam Ho ; Wu, Pengfei ; Joshi, Mandar A. ; Jaskiewicz, Jerzy ; Bock, Cheryl B. ; De Paoli-Roach, Anna ; Harris, Robert. / Role of pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) in glucose homoeostasis during starvation. In: Biochemical Journal. 2006 ; Vol. 397, No. 3. pp. 417-425.
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