Regulation of Pyruvate Dehydrogenase Kinase 4 (PDK4) by CCAAT/Enhancer-binding Protein β (C/EBPβ)

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 ␤ (C/EBP␤). C/EBP␤ modulates the expression of multiple hepatic genes including those involved in metabolism, development, and inflammation. We found that C/EBP␤ induced Pdk4 gene expression and decreased PDC activity. This transcriptional induction was mediated through two C/EBP␤ binding sites in the Pdk4 promoter. C/EBP␤ 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/EBP␤ in the T 3 regulation of Pdk4. T 3 increased C/EBP␤ abundance in primary rat hepatocytes. Knockdown of C/EBP␤ 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/EBP␤ stimulates Pdk4 expression and participates in the T 3 induction of the Cpt1a and Pdk4 genes.

CK2 inhibition induced PDK4-AMPK axis regulates metabolic adaptation and survival responses in glioma

“…CK2 negatively regulates CREB functions in response to DNA damage [31], and CCAAT-enhancer-binding proteins (C/EBP) binding on PDK4 promoter induces its expression [32]. Based on these findings, we studied the effect of CK2 inhibition on CREB and CREBbinding protein (CBP) expression.…”

Role of Sirtuin 1 in the Regulation of Hepatic Gene Expression by Thyroid Hormone

“…SIRT1 and T 3 stimulate many common hepatic gene targets. In addition, PGC-1␣ is activated by SIRT1 and PGC-1␣ participates in the T 3 induction of several genes in the liver (19,30). In light of this potential relationship, we examined the role of SIRT1 in the T 3 induction of cpt1a, pdk4, and pepck.…”

Fatty acid elongase-5 (Elovl5) regulates hepatic triglyceride catabolism in obese C57BL/6J mice

“…The HFD had no signifi cant effect on the expression of enzymes involved in fatty acyl carnitine metabolism [carnitine palmitoyl transferase (CPT) 1a and CPT2], mitochondrial ␤ -oxidation [long-chain acyl-CoA dehydrogenase (LCAD), medium-chain acyl-CoA dehydrogenase (MCAD), and shortchain acyl-CoA dehydrogenase (SCAD)], or sirtuin 3 (SIRT3), an NAD + -regulated deacetylase implicated in the control of FAO ( 25,(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47) ( Fig. 3B ).…”