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

被引:136
作者
Zhang, Yi
Ma, Ke
Sadana, Prabodh
Chowdhury, Farhana
Gaillard, Stephanie
Wang, Fang
McDonnell, Donald P.
Unterman, Terry G.
Elam, Marshall B.
Park, Edwards A.
机构
[1] Univ Tennessee, Coll Med, Dept Pharmacol, Hlth Sci Ctr, Memphis, TN 38163 USA
[2] Dept Vet Affairs Med Ctr, Memphis, TN 38163 USA
[3] Duke Univ, Dept Pharmacol, Durham, NC 27710 USA
[4] Univ Illinois, Dept Med, Chicago, IL 60612 USA
[5] Jesse Brown Vet Affairs Med Ctr, Chicago, IL 60612 USA
关键词
D O I
10.1074/jbc.M608657200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 (ERR alpha and ERR gamma). 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 gamma coactivator (PGC-1 alpha) stimulates the expression of PDK4. Here we report that ERR alpha and ERR gamma stimulate the PDK4 gene in hepatoma cells, suggesting a novel role for ERRs in controlling pyruvate metabolism. In addition, both ERR isoforms recruit PGC-1 alpha to the PDK4 promoter. Insulin, which decreases the expression of the PDK4 gene, inhibits the induction of PDK4 by ERR alpha and ERR gamma. The forkhead transcription factor (FoxO1) binds the PDK4 gene and contributes to the induction of PDK4 by ERRs and PGC-1 alpha. Insulin suppresses PDK4 expression in part through the dissociation of FoxO1 and PGC-1 alpha from the PDK4 promoter. Our data demonstrate a key role for the ERRs in the induction of hepatic PDK4 gene expression.
引用
收藏
页码:39897 / 39906
页数:10
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