CCAAT/enhancer binding protein-β is a transcriptional regulator of peroxisome-proliferator-activated receptor-γ coactivator-1α in the regenerating liver

The transcriptional coactivator peroxisome-proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) is induced in the liver in response to fasting and coordinates the activation of targets necessary for increasing energy production for gluconeogenesis and ketogenesis. After partial hepatectomy, the liver must restore its mass while maintaining metabolic homeostasis to ensure survival. Here we report that PGC-1 alpha is rapidly and dramatically induced after hepatectomy, with an amplitude of induction that exceeds the fasting response. Maximal activation of PGC-1 alpha after hepatectomy is dependent on the basic leucine zipper transcription factor, CCAAT/enhancer binding protein-beta (C/EBP beta), a critical factor in hepatocyte proliferation. We demonstrate in vivo C/EBP beta binding to C/EBP and cAMP response element sites in the PGC-1 alpha promoter and show that the C/EBP site is essential for PGC-1 alpha activation. Expression of the PGC-1 alpha target, carnitine palmitoyl transferase 1a, the rate-limiting enzyme in fatty acid beta-oxidation, and of long-chain acyl-coenzyme A dehydrogenase, an enzyme involved in beta-oxidation of long chain fatty acids, was significantly reduced in C/EBP beta(-/-) livers after hepatectomy. These findings identify C/EBP beta as a direct activator of PGC-1 alpha in the regenerating liver. The demonstration of a functional link between C/EBP beta and PGC-1 alpha activation provides a likely mechanism for how upstream signaling pathways in the regenerating liver can enable the adaptation to the changed metabolic status.