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