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-γ coactivator-1α (PGC-1α) 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-1α is rapidly and dramatically induced after hepatectomy, with an amplitude of induction that exceeds the fasting response. Maximal activation of PGC-1α after hepatectomy is dependent on the basic leucine zipper transcription factor, CCAAT/enhancer binding protein-β (C/EBPβ), a critical factor in hepatocyte proliferation. We demonstrate in vivo C/EBPβ binding to C/EBP and cAMP response element sites in the PGC-1α promoter and show that the C/EBP site is essential for PGC-1α activation. Expression of the PGC-1α target, carnitine palmitoyl transferase 1a, the rate-limiting enzyme in fatty acid β-oxidation, and of long-chain acyl-coenzyme A dehydrogenase, an enzyme involved in β-oxidation of long chain fatty acids, was significantly reduced in C/EBPβ−/− livers after hepatectomy. These findings identify C/EBPβ as a direct activator of PGC-1α in the regenerating liver. The demonstration of a functional link between C/EBPβ and PGC-1α activation provides a likely mechanism for how upstream signaling pathways in the regenerating liver can enable the adaptation to the changed metabolic status.