Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
J Biol Chem. 2010 Jan 22;285(4):2375-85. doi: 10.1074/jbc.M109.039081. Epub 2009 Nov 30.
PDK4 (pyruvate dehydrogenase kinase 4) regulates pyruvate oxidation through the phosphorylation and inhibition of the pyruvate dehydrogenase complex (PDC). PDC catalyzes the conversion of pyruvate to acetyl-CoA and is an important control point in glucose and pyruvate metabolism. PDK4 gene expression is stimulated by thyroid hormone (T(3)), glucocorticoids, and long chain fatty acids. The effects of T(3) on gene expression in the liver are mediated via the thyroid hormone receptor. Here, we have identified two binding sites for thyroid hormone receptor beta in the promoter of the rat PDK4 (rPDK4) gene. In addition, we have investigated the role of transcriptional coactivators and found that the PGC-1 alpha (peroxisome proliferator-activated receptor gamma coactivator) enhances the T(3) induction of rPDK4. Following T(3) administration, there is an increase in the association of PGC-1 alpha with the rPDK4 promoter. Interestingly, this increased association is with the proximal rPDK4 promoter rather than the distal region of the gene that contains the T(3) response elements. Administration of T(3) to hypothyroid rats elevated the abundance of PGC-1 alpha mRNA and protein in the liver. In addition, we observed greater association of PGC-1 alpha not only with the rPDK4 gene but also with phosphoenolpyruvate carboxykinase and CPT-1a (carnitine palmitoyltransferase 1a) genes. Knockdown of PGC-1 alpha in rat hepatocytes reduced the T(3) induction of PDK4, PEPCK, and CPT-1a genes. Our results indicate that T(3) regulates PGC-1 alpha abundance and association with hepatic genes, and in turn PGC-1 alpha is an important participant in the T(3) induction of selected genes.
PDK4（丙酮酸脱氢酶激酶 4）通过磷酸化和抑制丙酮酸脱氢酶复合物（PDC）来调节丙酮酸氧化。PDC 催化丙酮酸转化为乙酰辅酶 A，是葡萄糖和丙酮酸代谢的重要控制点。PDK4 基因表达受甲状腺激素（T3）、糖皮质激素和长链脂肪酸的刺激。T3 对肝脏基因表达的影响是通过甲状腺激素受体介导的。在这里，我们在大鼠 PDK4（rPDK4）基因的启动子中鉴定了两个甲状腺激素受体β结合位点。此外，我们还研究了转录共激活因子的作用，发现 PGC-1α（过氧化物酶体增殖物激活受体γ共激活因子）增强了 rPDK4 的 T3 诱导。在 T3 给药后，PGC-1α 与 rPDK4 启动子的结合增加。有趣的是，这种增加的结合与包含 T3 反应元件的 rPDK4 基因的近端启动子而不是远端区域有关。T3 给药可增加甲状腺功能减退大鼠肝脏中 PGC-1α mRNA 和蛋白的丰度。此外，我们不仅观察到 PGC-1α 与 rPDK4 基因的结合增加，还观察到与磷酸烯醇丙酮酸羧激酶和 CPT-1a（肉毒碱棕榈酰转移酶 1a）基因的结合增加。在大鼠肝细胞中敲低 PGC-1α 可降低 T3 诱导的 PDK4、PEPCK 和 CPT-1a 基因的表达。我们的结果表明，T3 调节 PGC-1α 的丰度和与肝脏基因的结合，反过来 PGC-1α 是 T3 诱导某些基因的重要参与者。
