Regulation of Pyruvate Dehydrogenase Kinase 4 (PDK4) by Thyroid Hormone

Abstract

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 (T3), glucocorticoids, and long chain fatty acids. The effects of T3 on gene expression in the liver are mediated via the thyroid hormone receptor. Here, we have identified two binding sites for thyroid hormone receptor β in the promoter of the rat PDK4 (rPDK4) gene. In addition, we have investigated the role of transcriptional coactivators and found that the PGC-1α (peroxisome proliferator-activated receptor γ coactivator) enhances the T3 induction of rPDK4. Following T3 administration, there is an increase in the association of PGC-1α 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 T3 response elements. Administration of T3 to hypothyroid rats elevated the abundance of PGC-1α mRNA and protein in the liver. In addition, we observed greater association of PGC-1α not only with the rPDK4 gene but also with phosphoenolpyruvate carboxykinase and CPT-1a (carnitine palmitoyltransferase 1a) genes. Knockdown of PGC-1α in rat hepatocytes reduced the T3 induction of PDK4, PEPCK, and CPT-1a genes. Our results indicate that T3 regulates PGC-1α abundance and association with hepatic genes, and in turn PGC-1α is an important participant in the T3 induction of selected genes.