Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth.
The Hippo pathway and its nuclear effector Yap regulate organ size and cancer formation. While many modulators of Hippo activity have been identified, little is known about the Yap target genes that mediate these growth effects. Here, we show that yap -/- mutant zebrafish exhibit defects in hepatic progenitor potential and liver growth due to impaired glucose transport and nucleotide biosynthesis. Transcriptomic and metabolomic analyses reveal that Yap regulates expression of glucose transporter glut1, causing decreased glucose uptake and use for nucleotide biosynthesis in yap -/- mutants, and impaired glucose tolerance in adults. Nucleotide supplementation improves Yap deficiency phenotypes, indicating functional importance of glucose-fueled nucleotide biosynthesis. Yap-regulated glut1 expression and glucose uptake are conserved in mammals, suggesting that stimulation of anabolic glucose metabolism is an evolutionarily conserved mechanism by which the Hippo pathway controls organ growth. Together, our results reveal a central role for Hippo signaling in glucose metabolic homeostasis.
['Cox|Andrew G|AG|0000-0003-4189-9422', 'Tsomides|Allison|A|', 'Yimlamai|Dean|D|', 'Hwang|Katie L|KL|', 'Miesfeld|Joel|J|', 'Galli|Giorgio G|GG|', 'Fowl|Brendan H|BH|', 'Fort|Michael|M|0000-0002-3314-6706', 'Ma|Kimberly Y|KY|', 'Sullivan|Mark R|MR|', 'Hosios|Aaron M|AM|', 'Snay|Erin|E|', 'Yuan|Min|M|', 'Brown|Kristin K|KK|', 'Lien|Evan C|EC|', 'Chhangawala|Sagar|S|', 'Steinhauser|Matthew L|ML|', 'Asara|John M|JM|', 'Houvras|Yariv|Y|', 'Link|Brian|B|', 'Vander Heiden|Matthew G|MG|0000-0002-6702-4192', 'Camargo|Fernando D|FD|0000-0002-5630-5909', 'Goessling|Wolfram|W|0000-0001-9972-1569']
D000818:Animals D005947:Glucose D051272:Glucose Transporter Type 1 D008099:Liver D051379:Mice D009711:Nucleotides D017346:Protein Serine-Threonine Kinases D000090742:Serine-Threonine Kinase 3 D015398:Signal Transduction D015534:Trans-Activators D000091102:YAP-Signaling Proteins D015027:Zebrafish D029961:Zebrafish Proteins
Yap Hippo pathway glut1 glucose metabolism liver development