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 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 mutants, and impaired glucose tolerance in adults. Nucleotide supplementation improves Yap deficiency phenotypes, indicating functional importance of glucose-fueled nucleotide biosynthesis. Yap-regulated 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.
|Year of Publication
2018 Nov 15
|PubMed Central ID
K08 DK105351 / DK / NIDDK NIH HHS / United States
T32 GM007287 / GM / NIGMS NIH HHS / United States
R24 OD017870 / OD / NIH HHS / United States
P01 CA120964 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
P30 DK034854 / DK / NIDDK NIH HHS / United States
R01 DK105198 / DK / NIDDK NIH HHS / United States
P30 CA006516 / CA / NCI NIH HHS / United States
R01 DK090311 / DK / NIDDK NIH HHS / United States