Biomaterial Database

SLAM-ITseq identifies that Nrf2 induces liver regeneration through the pentose phosphate pathway. 2024

Vicky W T Tan, and Talhah M Salmi, and Anthony P Karamalakis, and Andrea Gillespie, and Athena Jessica S Ong, and Jesse J Balic, and Yih-Chih Chan, and Cerys E Bladen, and Kristin K Brown, and Mark A Dawson, and Andrew G Cox

Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia.

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.