TY - JOUR
T1 - Estrogen-related receptors stimulate pyruvate dehydrogenase kinase isoform 4 gene expression
AU - Zhang, Yi
AU - Ma, Ke
AU - Sadana, Prabodh
AU - Chowdhury, Farhana
AU - Gaillard, Stephanie
AU - Wang, Fang
AU - McDonnell, Donald P.
AU - Unterman, Terry G.
AU - Elam, Marshall B.
AU - Park, Edwards A.
PY - 2006/12/29
Y1 - 2006/12/29
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M608657200
DO - 10.1074/jbc.M608657200
M3 - Article
C2 - 17079227
AN - SCOPUS:33845973409
SN - 0021-9258
VL - 281
SP - 39897
EP - 39906
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 52
ER -