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 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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Authors | Nam Ho Jeoung, Pengfei Wu, Mandar A Joshi, Jerzy Jaskiewicz, Cheryl B Bock, Anna A Depaoli-Roach, Robert A Harris |
Journal | The Biochemical journal
(Biochem J)
Vol. 397
Issue 3
Pg. 417-25
(Aug 01 2006)
ISSN: 1470-8728 [Electronic] England |
PMID | 16606348
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Fatty Acids
- Insulin
- Isoenzymes
- Pdk4 protein, mouse
- Pyruvate Dehydrogenase Acetyl-Transferring Kinase
- Lactic Acid
- Pyruvic Acid
- Protein Kinases
- pyruvate dehydrogenase kinase 4
- Protein Serine-Threonine Kinases
- Glucose
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Topics |
- Animals
- Diaphragm
(metabolism)
- Fatty Acids
(metabolism)
- Glucose
(metabolism)
- Glycolysis
- Homeostasis
- Insulin
(blood)
- Isoenzymes
(biosynthesis, genetics, physiology)
- Lactic Acid
(metabolism)
- Liver
(metabolism)
- Male
- Mice
- Mice, Knockout
- Organ Specificity
- Oxidation-Reduction
- Protein Kinases
(biosynthesis, genetics, physiology)
- Protein Serine-Threonine Kinases
- Pyruvate Dehydrogenase Acetyl-Transferring Kinase
- Pyruvic Acid
(metabolism)
- Starvation
(blood, metabolism)
- Up-Regulation
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