Regulation of pyruvate dehydrogenase kinase isoform 4 (PDK4) gene expression by glucocorticoids and insulin

Sara Connaughton, Farhana Chowdhury, Ramy R. Attia, Shulan Song, Yi Zhang, Marshall Elam, George Cook, 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 (PDK) inhibits its activity. The expression of the pyruvate dehydrogenase kinase 4 (PDK4) gene is increased in fasting and other conditions associated with the switch from the utilization of glucose to fatty acids as an energy source. Transcription of the PDK4 gene is elevated by glucocorticoids and inhibited by insulin. In this study, we have investigated the factors involved in the regulation of the PDK4 gene by these hormones. Glucocorticoids stimulate PDK4 through two glucocorticoid receptor (GR) binding sites located more than 6000 base pairs upstream of the transcriptional start site. Insulin inhibits the glucocorticoid induction in part by causing dissociation of the GR from the promoter. Previously, we found that the estrogen related receptor alpha (ERRα) stimulates the expression of PDK4. Here, we determined that one of the ERRα binding sites contributes to the insulin inhibition of PDK4. A binding site for the forkhead transcription factor (FoxO1) is adjacent to the ERRα binding sites. FoxO1 participates in the glucocorticoid induction of PDK4 and the regulation of this gene by insulin. Our data demonstrate that glucocorticoids and insulin each modulate PDK4 gene expression through complex hormone response units that contain multiple factors.

Original languageEnglish (US)
Pages (from-to)159-167
Number of pages9
JournalMolecular and Cellular Endocrinology
Volume315
Issue number1-2
DOIs
StatePublished - Feb 5 2010

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Gene expression
Glucocorticoids
Insulin
Gene Expression
Genes
Binding Sites
Pyruvate Dehydrogenase Complex
Acetyl Coenzyme A
Glucocorticoid Receptors
Hormones
Forkhead Transcription Factors
Glucose
Phosphorylation
Mitochondria
pyruvate dehydrogenase (acetyl-transferring) kinase
Transcription
Pyruvic Acid
Base Pairing
Fasting
Fatty Acids

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Cite this

Regulation of pyruvate dehydrogenase kinase isoform 4 (PDK4) gene expression by glucocorticoids and insulin. / Connaughton, Sara; Chowdhury, Farhana; Attia, Ramy R.; Song, Shulan; Zhang, Yi; Elam, Marshall; Cook, George; Park, Edwards.

In: Molecular and Cellular Endocrinology, Vol. 315, No. 1-2, 05.02.2010, p. 159-167.

Research output: Contribution to journalArticle

Connaughton, Sara ; Chowdhury, Farhana ; Attia, Ramy R. ; Song, Shulan ; Zhang, Yi ; Elam, Marshall ; Cook, George ; Park, Edwards. / Regulation of pyruvate dehydrogenase kinase isoform 4 (PDK4) gene expression by glucocorticoids and insulin. In: Molecular and Cellular Endocrinology. 2010 ; Vol. 315, No. 1-2. pp. 159-167.
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