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  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␣ (peroxisome proliferator-activated receptor ␥ coactivator) enhances the T 3 induction of rPDK4. Following T 3 administration, there is an increase in the association of PGC-1␣ 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␣ mRNA and protein in the liver. In addition, we observed greater association of PGC-1␣ not only with the rPDK4 gene but also with phosphoenolpyruvate carboxykinase and CPT-1a (carnitine palmitoyltransferase 1a) genes. Knockdown of PGC-1␣ in rat hepatocytes reduced the T 3 induction of PDK4, PEPCK, and CPT-1a genes. Our results indicate that T 3 regulates PGC-1␣ abundance and association with hepatic genes, and in turn PGC-1␣ is an important participant in the T 3 induction of selected genes. Thyroid hormone (T 3 )2 plays an important role in various aspects of metabolism, development, and differentiation of cells (1). T 3 mediates its effect on gene expression through binding to the thyroid hormone receptors (TR) (2). TRs belong to the superfamily of nuclear hormone receptors, which are a class of ligand-activated transcriptional regulators (3). There are two major TR isoforms encoded on separate genes, designated as TR␣ and TR (2). TR is the most abundant isoform in liver and mediates the hepatic actions of T 3 (4, 5). The TR binds to specific DNA sequences known as T 3 -response elements (TRE), which most commonly contain a direct repeat of the AGGTCA sequence separated by four nucleotides (DR4). TR can bind to these elements in the presence or absence of ligand to mediate positive or negative regulation of T 3 target genes (2, 6). Generally, TR binds to the TRE as a heterodimer with the retinoid X receptor (RXR) (7).Lipid and glucose metabolism are among the many physiological processes that are regulated by thyroid hormone (8, 9). In hepatocytes, T 3 increases the expression of a number of genes involved in hepatic lipogenesis, including spot 14, fatty acid transporter protein, and fatty-acid synthase (10, 11). Paradoxically, T 3 simultaneously induces genes involved in fatty acid oxidation especially CPT-1a (carnitine palmitoyltransferase-1a) (12). With respect to glucose metabolism, ...
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