Estrogen-related receptors stimulate pyruvate dehydrogenase kinase isoform 4 gene expression

Yi Zhang, Ke Ma, Prabodh Sadana, Farhana Chowdhury, Stephanie Gaillard, Fang Wang, Donald P. McDonnell, Terry G. Unterman, Marshall Elam, Edwards Park

Research output: Contribution to journalArticle

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Abstract

The pyruvate dehydrogenase complex (PDC) catalyzes the conversion of pyruvate to acetyl-CoA in mitochondria and is a key regulatory enzyme in the oxidation of glucose to acetyl-CoA. Phosphorylation of PDC by the pyruvate dehydrogenase kinases (PDK2 and PDK4) inhibits PDC activity. Expression of the PDK genes is elevated in diabetes, leading to the decreased oxidation of pyruvate to acetyl-CoA. In these studies we have investigated the transcriptional regulation of the PDK4 gene by the estrogen-related receptors (ERRα and ERRγ). The ERRs are orphan nuclear receptors whose physiological roles include the induction of fatty acid oxidation in heart and muscle. Previously, we found that the peroxisome proliferator-activated receptor γ coactivator (PGC-1α) stimulates the expression of PDK4. Here we report that ERRα and ERRγ stimulate the PDK4 gene in hepatoma cells, suggesting a novel role for ERRs in controlling pyruvate metabolism. In addition, both ERR isoforms recruit PGC-1α to the PDK4 promoter. Insulin, which decreases the expression of the PDK4 gene, inhibits the induction of PDK4 by ERRα and ERRγ. The forkhead transcription factor (FoxO1) binds the PDK4 gene and contributes to the induction of PDK4 by ERRs and PGC-1α. Insulin suppresses PDK4 expression in part through the dissociation of FoxO1 and PGC-1α from the PDK4 promoter. Our data demonstrate a key role for the ERRs in the induction of hepatic PDK4 gene expression.

Original languageEnglish (US)
Pages (from-to)39897-39906
Number of pages10
JournalJournal of Biological Chemistry
Volume281
Issue number52
DOIs
StatePublished - Dec 29 2006

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Pyruvate Dehydrogenase Complex
Acetyl Coenzyme A
Pyruvic Acid
Gene expression
Estrogen Receptors
Estrogens
Genes
Gene Expression
Orphan Nuclear Receptors
Insulin
Forkhead Transcription Factors
Peroxisome Proliferator-Activated Receptors
Oxidation
Hepatocellular Carcinoma
Myocardium
Mitochondria
Protein Isoforms
Fatty Acids
Phosphorylation
Glucose

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Estrogen-related receptors stimulate pyruvate dehydrogenase kinase isoform 4 gene expression. / Zhang, Yi; Ma, Ke; Sadana, Prabodh; Chowdhury, Farhana; Gaillard, Stephanie; Wang, Fang; McDonnell, Donald P.; Unterman, Terry G.; Elam, Marshall; Park, Edwards.

In: Journal of Biological Chemistry, Vol. 281, No. 52, 29.12.2006, p. 39897-39906.

Research output: Contribution to journalArticle

Zhang, Y, Ma, K, Sadana, P, Chowdhury, F, Gaillard, S, Wang, F, McDonnell, DP, Unterman, TG, Elam, M & Park, E 2006, 'Estrogen-related receptors stimulate pyruvate dehydrogenase kinase isoform 4 gene expression', Journal of Biological Chemistry, vol. 281, no. 52, pp. 39897-39906. https://doi.org/10.1074/jbc.M608657200
Zhang, Yi ; Ma, Ke ; Sadana, Prabodh ; Chowdhury, Farhana ; Gaillard, Stephanie ; Wang, Fang ; McDonnell, Donald P. ; Unterman, Terry G. ; Elam, Marshall ; Park, Edwards. / Estrogen-related receptors stimulate pyruvate dehydrogenase kinase isoform 4 gene expression. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 52. pp. 39897-39906.
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