Liver is endowed with high regenerative activity, so that the tissue regrows in mouse after partial hepatectomy within days. We reason that this requires de novo pyrimidine synthesis to support rapid progression via the cell cycle. We find that suppression of de novo pyrimidine synthesis prevents proliferation in regenerating liver, suppressing liver regrowth. Tracing studies and spatial metabolomics reveal a metabolic shift such that ammonia, normally detoxified to urea in the periportal region under homeostasis, is redirected for generating aspartate and carbamoyl phosphate periportally, and glutamine pericentrally, and these products are utilized as precursors by the de novo pyrimidine synthesis pathway. Our research uncovers a metabolic reprogramming leading to utilization of a toxic byproduct for anabolic pathways that are essential for liver regeneration.

1st Faculty of Medicine Charles University Prague Czech Republic

CIBB Center for Innovative Biomedicine and Biotechnology University of Coimbra Coimbra Portugal

CNC UC Center for Neuroscience and Cell Biology University of Coimbra Coimbra Portugal

College of Pharmacy Natural Product Research Institute Seoul National University Seoul Korea

Faculty of Science Charles University Prague Czech Republic

Faculty of Science Palacký University Olomouc Czech Republic

General University Hospital Prague Czech Republic

Institute of Biotechnology Czech Academy of Sciences Prague West Czech Republic

Institute of Microbiology Czech Academy of Sciences Prague Czech Republic

Institute of Molecular Genetics Academy of Sciences of the Czech Republic Prague Czech Republic

Institute of Physiology Czech Academy of Sciences Prague Czech Republic

Malaghan Institute of Medical Research Kelburn Wellington New Zealand

PDBEB Doctoral Programme in Experimental Biology and Biomedicine Institute of Interdisciplinary Research University of Coimbra Coimbra Portugal

School of Pharmacy and Medical Science Griffith University Southport Qld Australia

Worcester Chan Medical School University of Massachusetts Cambridge MA USA

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