PUBLICATION
SLAM-ITseq identifies that Nrf2 induces liver regeneration through the pentose phosphate pathway
- Authors
- Tan, V.W.T., Salmi, T.M., Karamalakis, A.P., Gillespie, A., Ong, A.J.S., Balic, J.J., Chan, Y.C., Bladen, C.E., Brown, K.K., Dawson, M.A., Cox, A.G.
- ID
- ZDB-PUB-240218-11
- Date
- 2024
- Source
- Developmental Cell 59(7): 898-910.e6 (Journal)
- Registered Authors
- Cox, Andrew, Karamalakis, Anthony
- Keywords
- G6PD, NRF2, SLAM-ITseq, acute liver failure, nascent transcription, pentose phosphate pathway, regeneration, zebrafish
- Datasets
- GEO:GSE230829, GEO:GSE230831, GEO:GSE230832, GEO:GSE230830
- MeSH Terms
-
- Animals
- Pentose Phosphate Pathway*/genetics
- Zebrafish/genetics
- Zebrafish/metabolism
- NF-E2-Related Factor 2/genetics
- NF-E2-Related Factor 2/metabolism
- Liver Regeneration*/genetics
- Liver/metabolism
- PubMed
- 38366599 Full text @ Dev. Cell
Citation
Tan, V.W.T., Salmi, T.M., Karamalakis, A.P., Gillespie, A., Ong, A.J.S., Balic, J.J., Chan, Y.C., Bladen, C.E., Brown, K.K., Dawson, M.A., Cox, A.G. (2024) SLAM-ITseq identifies that Nrf2 induces liver regeneration through the pentose phosphate pathway. Developmental Cell. 59(7):898-910.e6.
Abstract
The liver exhibits a remarkable capacity to regenerate following injury. Despite this unique attribute, toxic injury is a leading cause of liver failure. The temporal processes by which the liver senses injury and initiates regeneration remain unclear. Here, we developed a transgenic zebrafish model wherein hepatocyte-specific expression of uracil phosphoribosyltransferase (UPRT) enabled the implementation of SLAM-ITseq to investigate the nascent transcriptome during initiation of liver injury and regeneration. Using this approach, we identified a rapid metabolic transition from the fed to the fasted state that was followed by induction of the nuclear erythroid 2-related factor (Nrf2) antioxidant program. We find that activation of Nrf2 in hepatocytes is required to induce the pentose phosphate pathway (PPP) and improve survival following liver injury. Mechanistically, we demonstrate that inhibition of the PPP disrupts nucleotide biosynthesis to prevent liver regeneration. Together, these studies provide fundamental insights into the mechanism by which early metabolic adaptation to injury facilitates tissue regeneration.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping