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

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.

Cancer Cells Tune the Signaling Pathways to Empower de Novo Synthesis of Nucleotides

“…The findings in this study are consistent with those of a recent study demonstrating that YAP1, via the induction of the glucose importer GLUT1, enhances glucose uptake and utilization to stimulate de novo nucleotide synthesis. YAP1 depletion resulted in reduced organ growth, and this phenotype was partially rescued by providing exogenous nucleosides [40]. The metabolic role of the Hippo-YAP-TAZ pathway in the regulation of nucleotide metabolism merits further attention, as the specific mechanisms involving the differential regulation of pyrimidine and purine synthesis by YAP or TAZ remains mostly unknown.…”

Extracellular Matrix Stiffness: New Areas Affecting Cell Metabolism

“…For example, The YAP-TEAD was shown to directly regulate GLUT1 ( 25 , 34 ) and GLUT3 ( 26 , 28 ) transcription, thereby promoting cellular uptake of glucose, which supplies more energy to cells and is also involved in nucleotide biosynthesis. In zebrafish, WZB117-mediated inhibition of GLUT1 and mutations in YAP were both shown to reduce glucose uptake and subsequent nucleotide synthesis leading to reduced liver volume ( 34 ). Thus, it is possible that matrix stiffness is involved in regulating liver growth and size by influencing YAP/TAZ-mediated glucose uptake.…”

Hippo signalling during development

“…For example, RhoA requires modification by the mevalonate pathway to be active (Sorrentino et al, 2014) and TSC downregulation leads to an increase in YAP/TAZ protein levels through a reduction in autophagy (Liang et al, 2014). Interestingly, YAP/TAZ transcription targets include genes important for anabolic metabolism, specifically glucose uptake (Cox et al, 2018), dNTP production (Santinon et al, 2018) and amino acid availability (Bertero et al, 2018). This highlights the importance of Yki/YAP/TAZ in linking energy and nutrient levels with the anabolic requirements of growth.…”