title: Regulation of pyruvate dehydrogenase kinase 4 (PDK4) by CCAAT/enhancer-binding protein beta (C/EBPbeta).
abstract: The conversion of pyruvate to acetyl-CoA in mitochondria is catalyzed by the pyruvate dehydrogenase complex (PDC). Activity of PDC is inhibited by phosphorylation via the pyruvate dehydrogenase kinases (PDKs). Here, we examined the regulation of Pdk4 gene expression by the CCAAT/enhancer-binding protein β (C/EBPβ). C/EBPβ modulates the expression of multiple hepatic genes including those involved in metabolism, development, and inflammation. We found that C/EBPβ induced Pdk4 gene expression and decreased PDC activity. This transcriptional induction was mediated through two C/EBPβ binding sites in the Pdk4 promoter. C/EBPβ participates in the hormonal regulation of gluconeogenic genes. Previously, we reported that Pdk4 was induced by thyroid hormone (T(3)). Therefore, we investigated the role of C/EBPβ in the T(3) regulation of Pdk4. T(3) increased C/EBPβ abundance in primary rat hepatocytes. Knockdown of C/EBPβ with siRNA diminished the T(3) induction of the Pdk4 and carnitine palmitoyltransferase (Cpt1a) genes. CPT1a is an initiating step in the mitochondrial oxidation of long chain fatty acids. Our results indicate that C/EBPβ stimulates Pdk4 expression and participates in the T(3) induction of the Cpt1a and Pdk4 genes.
authors.affiliation: Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Ramy R
authors.initials: RR
authors.lastname: Attia
authors.forename: Pragya
authors.initials: P
authors.lastname: Sharma
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Janssen
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Friedman
authors.forename: Xiong
authors.initials: X
authors.lastname: Deng
authors.forename: Jae Seung
authors.initials: JS
authors.lastname: Lee
authors.forename: Marshall B
authors.initials: MB
authors.lastname: Elam
authors.forename: George A
authors.initials: GA
authors.lastname: Cook
authors.forename: Edwards A
authors.initials: EA
authors.lastname: Park
mesh_terms: D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D002334:Carnitine O-Palmitoyltransferase / Q000096:biosynthesis / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D005943:Gluconeogenesis / Q000502:physiology; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D020218:Response Elements / Q000502:physiology*; D014284:Triiodothyronine / Q000235:genetics / Q000378:metabolism
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C000631432:PDK4 protein, human; C000631440:Pdk4 protein, rat; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D014284:Triiodothyronine; D002334:Carnitine O-Palmitoyltransferase; D017346:Protein Serine-Threonine Kinases