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 p...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
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EMBO
2020
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| Online Access: | https://hdl.handle.net/1721.1/125162 |
| _version_ | 1811091619046227968 |
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| author | Cox, Andrew G Tsomides, Allison Yimlamai, Dean Hwang, Katie L Miesfeld, Joel Galli, Giorgio G Fowl, Brendan H Fort, Michael Ma, Kimberly Y Sullivan, Mark R Hosios, Aaron M Snay, Erin Yuan, Min Brown, Kristin K Lien, Evan C Chhangawala, Sagar Steinhauser, Matthew L Asara, John M Houvras, Yariv Link, Brian Vander Heiden, Matthew G Camargo, Fernando D Goessling, Wolfram |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Cox, Andrew G Tsomides, Allison Yimlamai, Dean Hwang, Katie L Miesfeld, Joel Galli, Giorgio G Fowl, Brendan H Fort, Michael Ma, Kimberly Y Sullivan, Mark R Hosios, Aaron M Snay, Erin Yuan, Min Brown, Kristin K Lien, Evan C Chhangawala, Sagar Steinhauser, Matthew L Asara, John M Houvras, Yariv Link, Brian Vander Heiden, Matthew G Camargo, Fernando D Goessling, Wolfram |
| author_sort | Cox, Andrew G |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T15:05:15Z |
| format | Article |
| id | mit-1721.1/125162 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T15:05:15Z |
| publishDate | 2020 |
| publisher | EMBO |
| record_format | dspace |
| spelling | mit-1721.1/1251622022-09-29T12:38:21Z Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth Cox, Andrew G Tsomides, Allison Yimlamai, Dean Hwang, Katie L Miesfeld, Joel Galli, Giorgio G Fowl, Brendan H Fort, Michael Ma, Kimberly Y Sullivan, Mark R Hosios, Aaron M Snay, Erin Yuan, Min Brown, Kristin K Lien, Evan C Chhangawala, Sagar Steinhauser, Matthew L Asara, John M Houvras, Yariv Link, Brian Vander Heiden, Matthew G Camargo, Fernando D Goessling, Wolfram Koch Institute for Integrative Cancer Research at MIT 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. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (Grant P30DK034854) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (Grant 1R01DK090311) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (Grant R24OD017870) National Institutes of Health (U.S.) (Grant P30DK034854) National Institutes of Health (U.S.) (Grant 1R01DK090311) National Institutes of Health (U.S.) (Grant 1R01DK105198) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (Grant 1R01DK105198) National Institutes of Health (U.S.) (Grant R24OD017870) National Institute of General Medical Sciences (NIGMS) (Grant T32GM007753) NHMRC (Grant 1146558) National Cancer Institute (U.S.) (Grant 5P01CA120964) National Cancer Institute (U.S.) (Grant 5P30CA006516) 2020-05-11T20:17:21Z 2020-05-11T20:17:21Z 2018-10 2018-07 2020-01-30T16:47:38Z Article http://purl.org/eprint/type/JournalArticle 1460-2075 https://hdl.handle.net/1721.1/125162 Cox, Andrew G. et al. "Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth." EMBO Journal 37 (October 2018): e100294 © 2018 The Authors en http://dx.doi.org/10.15252/EMBJ.2018100294 EMBO Journal Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf EMBO bioRxiv |
| spellingShingle | Cox, Andrew G Tsomides, Allison Yimlamai, Dean Hwang, Katie L Miesfeld, Joel Galli, Giorgio G Fowl, Brendan H Fort, Michael Ma, Kimberly Y Sullivan, Mark R Hosios, Aaron M Snay, Erin Yuan, Min Brown, Kristin K Lien, Evan C Chhangawala, Sagar Steinhauser, Matthew L Asara, John M Houvras, Yariv Link, Brian Vander Heiden, Matthew G Camargo, Fernando D Goessling, Wolfram Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth |
| title | Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth |
| title_full | Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth |
| title_fullStr | Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth |
| title_full_unstemmed | Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth |
| title_short | Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth |
| title_sort | yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth |
| url | https://hdl.handle.net/1721.1/125162 |
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