PUBLICATION
Hyperaminoacidemia from interrupted glucagon signaling increases pancreatic acinar cell proliferation and size via mTORC1 and YAP pathways
- Authors
- Dai, C., Zhang, Y., Gong, Y., Bradley, A., Tang, Z., Sellick, K., Shrestha, S., Spears, E., Covington, B.A., Stanley, J., Jenkins, R., Richardson, T.M., Brantley, R.A., Coate, K., Saunders, D.C., Wright, J.J., Brissova, M., Dean, E.D., Powers, A.C., Chen, W.
- ID
- ZDB-PUB-250109-49
- Date
- 2024
- Source
- iScience 27: 111447111447 (Journal)
- Registered Authors
- Chen, Wenbiao
- Keywords
- Biomolecules, Cell biology, Model organism, Molecular biology
- MeSH Terms
- none
- PubMed
- 39720531 Full text @ iScience
Citation
Dai, C., Zhang, Y., Gong, Y., Bradley, A., Tang, Z., Sellick, K., Shrestha, S., Spears, E., Covington, B.A., Stanley, J., Jenkins, R., Richardson, T.M., Brantley, R.A., Coate, K., Saunders, D.C., Wright, J.J., Brissova, M., Dean, E.D., Powers, A.C., Chen, W. (2024) Hyperaminoacidemia from interrupted glucagon signaling increases pancreatic acinar cell proliferation and size via mTORC1 and YAP pathways. iScience. 27:111447111447.
Abstract
Increased blood amino acid levels (hyperaminoacidemia) stimulate pancreas expansion by unclear mechanisms. Here, by genetic and pharmacological disruption of glucagon receptor (GCGR) in mice and zebrafish, we found that the ensuing hyperaminoacidemia promotes pancreatic acinar cell proliferation and cell hypertrophy, which can be mitigated by a low protein diet in mice. In addition to mammalian target of rapamycin complex 1 (mTORC1) signaling, acinar cell proliferation required slc38a5, the most highly expressed amino acid transporter gene in both species. Transcriptomics data revealed the activation signature of yes-associated protein (YAP) in acinar cells of mice with hyperaminoacidemia, consistent with the observed increase in YAP-expressing acinar cells. Yap1 activation also occurred in acinar cells in gcgr-/- zebrafish, which was reversed by rapamycin. Knocking down yap1 in gcgr-/- zebrafish decreased mTORC1 activity and acinar cell proliferation and hypertrophy. Thus, the study discovered a previously unrecognized role of the YAP/Taz pathway in hyperaminoacidemia-induced acinar cell hypertrophy and hyperplasia.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping