Cloning of the rat pyruvate dehydrogenase kinase 4 gene promoter: Activation of pyruvate dehydrogenase kinase 4 by the peroxisome proliferator-activated receptor γ coactivator

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Abstract

The pyruvate dehydrogenase complex catalyzes the conversion of pyruvate to acetyl-CoA in mitochondria and is a key regulatory enzyme in the metabolism of glucose to acetyl-CoA. Phosphorylation of pyruvate dehydrogenase by the pyruvate dehydrogenase kinases (PDK) inhibits pyruvate dehydrogenase complex activity. There are four PDK isoforms, and expression of PDK4 and PDK2 genes is elevated in starvation and diabetes, allowing glucose to be conserved while fatty acid oxidation is increased. In these studies we have investigated the transcriptional mechanisms by which the expression of the PDK4 gene is increased. The peroxisome proliferator-activated receptor γ coactivator (PGC-1α) stimulates the expression of genes involved in hepatic gluconeogenesis and mitochondrial fatty acid oxidation. We have found that PGC-1α will induce the expression of both the PDK2 and PDK4 genes in primary rat hepatocytes and ventricular myocytes. We cloned the promoter for the rat PDK4 gene. Hepatic nuclear factor 4 (HNF4), which activates many genes in the liver, will induce PDK4 expression. Although HNF4 and PGC-1α interact to stimulate several genes encoding gluconeogenic enzymes, the induction of PDK4 does not involve interactions of PGC-1α with HNF4. Using the chromatin immunoprecipitation assay, we have demonstrated that HNF4 and PGC-1α are associated with the PDK4 gene in vivo. Our data suggest that by inducing PDK genes PGC-1α will direct pyruvate away from metabolism into acetyl-CoA and toward the formation of oxaloacetate and into the gluconeogenic pathway.

Original languageEnglish (US)
Pages (from-to)29525-29532
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number33
DOIs
StatePublished - Aug 19 2005

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Peroxisome Proliferator-Activated Receptors
Cloning
Transcriptional Activation
Rats
Organism Cloning
Genes
Chemical activation
Acetyl Coenzyme A
Pyruvic Acid
Liver
Pyruvate Dehydrogenase Complex
Metabolism
Hepatocyte Nuclear Factor 1
Fatty Acids
Gene Expression
Glucose
Oxaloacetic Acid
Enzyme Induction
Gluconeogenesis
Chromatin Immunoprecipitation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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title = "Cloning of the rat pyruvate dehydrogenase kinase 4 gene promoter: Activation of pyruvate dehydrogenase kinase 4 by the peroxisome proliferator-activated receptor γ coactivator",
abstract = "The pyruvate dehydrogenase complex catalyzes the conversion of pyruvate to acetyl-CoA in mitochondria and is a key regulatory enzyme in the metabolism of glucose to acetyl-CoA. Phosphorylation of pyruvate dehydrogenase by the pyruvate dehydrogenase kinases (PDK) inhibits pyruvate dehydrogenase complex activity. There are four PDK isoforms, and expression of PDK4 and PDK2 genes is elevated in starvation and diabetes, allowing glucose to be conserved while fatty acid oxidation is increased. In these studies we have investigated the transcriptional mechanisms by which the expression of the PDK4 gene is increased. The peroxisome proliferator-activated receptor γ coactivator (PGC-1α) stimulates the expression of genes involved in hepatic gluconeogenesis and mitochondrial fatty acid oxidation. We have found that PGC-1α will induce the expression of both the PDK2 and PDK4 genes in primary rat hepatocytes and ventricular myocytes. We cloned the promoter for the rat PDK4 gene. Hepatic nuclear factor 4 (HNF4), which activates many genes in the liver, will induce PDK4 expression. Although HNF4 and PGC-1α interact to stimulate several genes encoding gluconeogenic enzymes, the induction of PDK4 does not involve interactions of PGC-1α with HNF4. Using the chromatin immunoprecipitation assay, we have demonstrated that HNF4 and PGC-1α are associated with the PDK4 gene in vivo. Our data suggest that by inducing PDK genes PGC-1α will direct pyruvate away from metabolism into acetyl-CoA and toward the formation of oxaloacetate and into the gluconeogenic pathway.",
author = "Ke Ma and Yi Zhang and Marshall Elam and George Cook and Edwards Park",
year = "2005",
month = "8",
day = "19",
doi = "10.1074/jbc.M502236200",
language = "English (US)",
volume = "280",
pages = "29525--29532",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
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TY - JOUR

T1 - Cloning of the rat pyruvate dehydrogenase kinase 4 gene promoter

T2 - Activation of pyruvate dehydrogenase kinase 4 by the peroxisome proliferator-activated receptor γ coactivator

AU - Ma, Ke

AU - Zhang, Yi

AU - Elam, Marshall

AU - Cook, George

AU - Park, Edwards

PY - 2005/8/19

Y1 - 2005/8/19

N2 - The pyruvate dehydrogenase complex catalyzes the conversion of pyruvate to acetyl-CoA in mitochondria and is a key regulatory enzyme in the metabolism of glucose to acetyl-CoA. Phosphorylation of pyruvate dehydrogenase by the pyruvate dehydrogenase kinases (PDK) inhibits pyruvate dehydrogenase complex activity. There are four PDK isoforms, and expression of PDK4 and PDK2 genes is elevated in starvation and diabetes, allowing glucose to be conserved while fatty acid oxidation is increased. In these studies we have investigated the transcriptional mechanisms by which the expression of the PDK4 gene is increased. The peroxisome proliferator-activated receptor γ coactivator (PGC-1α) stimulates the expression of genes involved in hepatic gluconeogenesis and mitochondrial fatty acid oxidation. We have found that PGC-1α will induce the expression of both the PDK2 and PDK4 genes in primary rat hepatocytes and ventricular myocytes. We cloned the promoter for the rat PDK4 gene. Hepatic nuclear factor 4 (HNF4), which activates many genes in the liver, will induce PDK4 expression. Although HNF4 and PGC-1α interact to stimulate several genes encoding gluconeogenic enzymes, the induction of PDK4 does not involve interactions of PGC-1α with HNF4. Using the chromatin immunoprecipitation assay, we have demonstrated that HNF4 and PGC-1α are associated with the PDK4 gene in vivo. Our data suggest that by inducing PDK genes PGC-1α will direct pyruvate away from metabolism into acetyl-CoA and toward the formation of oxaloacetate and into the gluconeogenic pathway.

AB - The pyruvate dehydrogenase complex catalyzes the conversion of pyruvate to acetyl-CoA in mitochondria and is a key regulatory enzyme in the metabolism of glucose to acetyl-CoA. Phosphorylation of pyruvate dehydrogenase by the pyruvate dehydrogenase kinases (PDK) inhibits pyruvate dehydrogenase complex activity. There are four PDK isoforms, and expression of PDK4 and PDK2 genes is elevated in starvation and diabetes, allowing glucose to be conserved while fatty acid oxidation is increased. In these studies we have investigated the transcriptional mechanisms by which the expression of the PDK4 gene is increased. The peroxisome proliferator-activated receptor γ coactivator (PGC-1α) stimulates the expression of genes involved in hepatic gluconeogenesis and mitochondrial fatty acid oxidation. We have found that PGC-1α will induce the expression of both the PDK2 and PDK4 genes in primary rat hepatocytes and ventricular myocytes. We cloned the promoter for the rat PDK4 gene. Hepatic nuclear factor 4 (HNF4), which activates many genes in the liver, will induce PDK4 expression. Although HNF4 and PGC-1α interact to stimulate several genes encoding gluconeogenic enzymes, the induction of PDK4 does not involve interactions of PGC-1α with HNF4. Using the chromatin immunoprecipitation assay, we have demonstrated that HNF4 and PGC-1α are associated with the PDK4 gene in vivo. Our data suggest that by inducing PDK genes PGC-1α will direct pyruvate away from metabolism into acetyl-CoA and toward the formation of oxaloacetate and into the gluconeogenic pathway.

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