Zhang Yi, Ma Ke, Sadana Prabodh, Chowdhury Farhana, Gaillard Stephanie, Wang Fang, McDonnell Donald P, Unterman Terry G, Elam Marshall B, Park Edwards A
Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
J Biol Chem. 2006 Dec 29;281(52):39897-906. doi: 10.1074/jbc.M608657200. Epub 2006 Nov 1.
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 (ERRalpha and ERRgamma). 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-1alpha) stimulates the expression of PDK4. Here we report that ERRalpha and ERRgamma stimulate the PDK4 gene in hepatoma cells, suggesting a novel role for ERRs in controlling pyruvate metabolism. In addition, both ERR isoforms recruit PGC-1alpha to the PDK4 promoter. Insulin, which decreases the expression of the PDK4 gene, inhibits the induction of PDK4 by ERRalpha and ERRgamma. The forkhead transcription factor (FoxO1) binds the PDK4 gene and contributes to the induction of PDK4 by ERRs and PGC-1alpha. Insulin suppresses PDK4 expression in part through the dissociation of FoxO1 and PGC-1alpha from the PDK4 promoter. Our data demonstrate a key role for the ERRs in the induction of hepatic PDK4 gene expression.
丙酮酸脱氢酶复合体（PDC）在线粒体中催化丙酮酸转化为乙酰辅酶A，是葡萄糖氧化为乙酰辅酶A过程中的关键调节酶。丙酮酸脱氢酶激酶（PDK2和PDK4）使PDC磷酸化会抑制PDC活性。糖尿病时PDK基因的表达升高，导致丙酮酸氧化为乙酰辅酶A的过程减少。在这些研究中，我们调查了雌激素相关受体（ERRα和ERRγ）对PDK4基因的转录调控。ERRs是孤儿核受体，其生理作用包括诱导心脏和肌肉中的脂肪酸氧化。此前，我们发现过氧化物酶体增殖物激活受体γ共激活因子（PGC-1α）可刺激PDK4的表达。在此我们报告，ERRα和ERRγ可刺激肝癌细胞中的PDK4基因，提示ERRs在控制丙酮酸代谢方面有新作用。此外，两种ERR亚型均可将PGC-1α募集至PDK4启动子。胰岛素可降低PDK4基因的表达，抑制ERRα和ERRγ对PDK4的诱导作用。叉头转录因子（FoxO1）结合PDK4基因，并参与ERRs和PGC-1α对PDK4的诱导过程。胰岛素部分通过使FoxO1和PGC-1α从PDK4启动子上解离来抑制PDK4的表达。我们的数据表明ERRs在诱导肝脏PDK4基因表达中起关键作用。
