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EMBO J. 2018 Nov 15;37(22). pii: e100294. doi: 10.15252/embj.2018100294. Epub 2018 Oct 22.

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

Author information

1
Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA andrew.cox@petermac.org wolfram_goessling@hms.harvard.edu.
2
Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
3
Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
4
Harvard/MIT MD-PhD Program, Harvard Medical School, Boston, MA, USA.
5
Medical College of Wisconsin, Milwaukee, WI, USA.
6
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
7
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
8
Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY, USA.
9
Harvard Stem Cell Institute, Cambridge, MA, USA.
10
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
11
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
12
Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA.

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.

KEYWORDS:

Hippo pathway; Yap; glucose metabolism; glut1; liver development

PMID:
30348863
PMCID:
PMC6236334
[Available on 2019-11-15]
DOI:
10.15252/embj.2018100294

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