Regulation of pyruvate dehydrogenase kinase isoform 4 (PDK4) gene expression by glucocorticoids and insulin.
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 (ERRalpha) stimulates the expression of PDK4. Here, we determined that one of the ERRalpha binding sites contributes to the insulin inhibition of PDK4. A binding site for the forkhead transcription factor (FoxO1) is adjacent to the ERRalpha 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.
Connaughton
Sara
S
Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN 38163, USA.
Chowdhury
Farhana
F
Attia
Ramy R
RR
Song
Shulan
S
Zhang
Yi
Y
Elam
Marshall B
MB
Cook
George A
GA
Park
Edwards A
EA
D000818:Animals; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D017930:Genes, Reporter; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D020218:Response Elements; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000097983:ERRalpha Estrogen-Related Receptor; D000071161:Forkhead Box Protein O1
D051858:Forkhead Transcription Factors; D005938:Glucocorticoids; D007328:Insulin; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011494:Protein Kinases; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; C501429:Ppargc1a protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C403287:pyruvate dehydrogenase kinase 4
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