YAP suppresses gluconeogenic gene expression through PGC1α

Cell growth and proliferation are tightly coupled to metabolism, and dissecting the signaling molecules which link these processes is an important step towards understanding development, regeneration and cancer. The transcriptional regulator Yes-associated protein 1 (YAP) is a key regulator of liver size, development and function. We now show that YAP can also suppress gluconeogenic gene expression. Yap deletion in primary hepatocytes potentiates the gluconeogenic gene response to glucagon and dexamethasone, whereas constitutively active YAP suppresses it. The effects of YAP are mediated by the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1α). YAP inhibits the ability of PGC1α to bind to and activate transcription from the promoters of its gluconeogenic targets and the effects of YAP are blunted upon knockdown of PGC1α. In vivo, constitutively active YAP lowers plasma glucose levels and increases liver size. YAP therefore appears to reprogram cellular metabolism, diverting substrates away from the energy consuming process of gluconeogenesis, and towards the anabolic process of growth.