YAP suppresses gluconeogenic gene expression through PGC1α

Abstract

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.

F-actin dynamics regulates mammalian organ growth and cell fate maintenance

“…Another recently reported function of YAP in the liver is the regulation of gluconeogenesis and blood glucose homeostasis [29]. Accordingly, we found decreased expression of key gluconeogenic genes in CAPZ LKO mice (Fig.…”

“…YAP/TAZ function as transcriptional coactivators together with the TEAD family of transcription factors, and their activity is regulated by upstream inputs including the Hippo cascade, centered on the LATS1/2 kinases [16,17]. In vivo, the function of YAP and of YAP-regulatory inputs has been studied with great detail in the liver tissue, where YAP activation leads to hallmark phenotypes [18][19][20][21][22][23][24][25][26][27][28][29].…”

Mechanical stimuli control liver homeostasis

“…They found reduced expression and function of pericentral genes in CAPZ knockouts. In addition, and in line with earlier work on the repressive role of YAP on gluconeogenic genes, 6 CAPZ knockout livers displayed low expression of these genes, and this was functionally related to decreased steady-state blood glucose levels. Very elegantly, Pocaterra and coworkers also demonstrated that the CAPZ knockout liver phenotype was dependent on YAP.…”

Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth

“…In the current study, we use a combination of approaches to reveal that Yap directly induces the glucose transporters to redirect glucose utilization toward anabolism. The switch to anabolic glucose metabolism is supported by the recent demonstration that Yap is able to repress gluconeogenesis via suppression of PGC1α (Hu et al , ). In addition to our studies elucidating how Yap regulates glucose transporters, recent reports demonstrate that Yap directly induces the expression of the amino acid transporters SLC38A1 and SLC7A5 to stimulate cell growth (Hansen et al , ; Park et al , ).…”