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Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth. EMBO J 2018 11 15;37(22)

Date

10/24/2018

Pubmed ID

30348863

Pubmed Central ID

PMC6236334

DOI

10.15252/embj.2018100294

Scopus ID

2-s2.0-85055253100   20 Citations

Abstract

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.

Author List

Cox AG, Tsomides A, Yimlamai D, Hwang KL, Miesfeld J, Galli GG, Fowl BH, Fort M, Ma KY, Sullivan MR, Hosios AM, Snay E, Yuan M, Brown KK, Lien EC, Chhangawala S, Steinhauser ML, Asara JM, Houvras Y, Link B, Vander Heiden MG, Camargo FD, Goessling W

Author

Brian A. Link PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Glucose
Glucose Transporter Type 1
Liver
Mice
Nucleotides
Protein-Serine-Threonine Kinases
Signal Transduction
Trans-Activators
Zebrafish
Zebrafish Proteins
jenkins-FCD Prod-486 e3098984f26de787f5ecab75090d0a28e7f4f7c0