Regulation of Pyruvate Dehydrogenase Kinase 4 by Thyroid Hormone / Role of Peroxisome Proliferator Activated Receptor Gamma Coactivator-1 alpha and Ccaat Enhancer Binding Protein
type: CreativeWork
description: Pyruvate dehydrogenase kinase 4 (PDK4) regulates pyruvate oxidation through the phosphorylation and inhibition of the pyruvate dehydrogenase complex (PDC). The PDC catalyzes the conversion of pyruvate to acetyl-CoA and it is an important control point in glucose and pyruvate metabolism. Previous studies had reported that PDK4 gene expression is induced by thyroid hormone (T3). These studies did not investigate the mechanisms by which T3 regulated PDK4 gene expression. I have examined the role of the thyroid hormone receptor (TR), transcriptional coactivators especially the peroxisome proliferator activated receptor gamma coactivator-1 (PGC-1α) and other transcription factors that act as accessory factors in T3 actions. Thyroid hormone receptors (TRα or TRβ) are part of the nuclear receptor family and have been implicated in the induction of many genes by T3. The nuclear receptors constitute a broad class of transcription factors that have the ability to bind to DNA and regulate the expression of the genes in a ligand dependent manner. To identify a binding site for the TRβ in the promoter of the PDK4 gene, I transfected serial deletions of this promoter ligated to the luciferase reporter gene into the human hepatoma (HepG2) cells. The TRβ binding site was characterized by gel shift mobility assays, site directed mutagenesis and in vivo and in vitro luciferase constructs transfection techniques. In addition, I have used the chromatin immunoprecipitation (ChIP) technique to confirm the binding of the TRβ to the PDK4 gene promoter. Transcription coregulators bind to nuclear receptors to facilitate or inhibit the transcription of the target genes. I have explored the role of several coregulators including the transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator-1 (PGC-1α). Previous studies demonstrated that PGC-1α could induce the PDK4 gene. Here, I found that T3 increases PGC-1α abundance and association with the PDK4 gene. In additi…
abstract: Pyruvate dehydrogenase kinase 4 (PDK4) regulates pyruvate oxidation through the phosphorylation and inhibition of the pyruvate dehydrogenase complex (PDC). The PDC catalyzes the conversion of pyruvate to acetyl-CoA and it is an important control point in glucose and pyruvate metabolism. Previous studies had reported that PDK4 gene expression is induced by thyroid hormone (T3). These studies did not investigate the mechanisms by which T3 regulated PDK4 gene expression. I have examined the role of the thyroid hormone receptor (TR), transcriptional coactivators especially the peroxisome proliferator activated receptor gamma coactivator-1 (PGC-1α) and other transcription factors that act as accessory factors in T3 actions. Thyroid hormone receptors (TRα or TRβ) are part of the nuclear receptor family and have been implicated in the induction of many genes by T3. The nuclear receptors constitute a broad class of transcription factors that have the ability to bind to DNA and regulate the expression of the genes in a ligand dependent manner. To identify a binding site for the TRβ in the promoter of the PDK4 gene, I transfected serial deletions of this promoter ligated to the luciferase reporter gene into the human hepatoma (HepG2) cells. The TRβ binding site was characterized by gel shift mobility assays, site directed mutagenesis and in vivo and in vitro luciferase constructs transfection techniques. In addition, I have used the chromatin immunoprecipitation (ChIP) technique to confirm the binding of the TRβ to the PDK4 gene promoter. Transcription coregulators bind to nuclear receptors to facilitate or inhibit the transcription of the target genes. I have explored the role of several coregulators including the transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator-1 (PGC-1α). Previous studies demonstrated that PGC-1α could induce the PDK4 gene. Here, I found that T3 increases PGC-1α abundance and association with the PDK4 gene. In additi…
author: Attia, Ramy Naguib
keywords: C/EBP beta, PGC-1 alpha, Pyruvate dehydrogenase kinase 4, Thyroid hormone, Medical Biochemistry, Medical Cell Biology, Medicine and Health Sciences
date published: 2009-05-01T07:00:00Z
date modified: 2026-07-24T05:00:02Z
provider: University of Tennessee Health Science Center
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Tennessee Health Science Center