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

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