Regenerating liver uses ammonia to support de novo pyrimidine synthesis and cell proliferation
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.
Authors
- František Kolář (ORCID: https://orcid.org/0000-0002-8723-1826)
- Šárka Dvořáková (ORCID: https://orcid.org/0000-0003-4910-1008)
- Michael V. Berridge (ORCID: https://orcid.org/0000-0003-2619-7473)
- Lukáš Kučera (ORCID: https://orcid.org/0000-0002-0009-5105)
- Klára Dohnalová
- Karel Chalupský (ORCID: https://orcid.org/0000-0001-6890-6464)
- Z Krška (ORCID: https://orcid.org/0000-0002-1766-7472)
- Sunghyouk Park (ORCID: https://orcid.org/0000-0003-1981-3274)
- Jan Procházka (ORCID: https://orcid.org/0000-0003-4675-8995)
- Berwini Endaya (ORCID: https://orcid.org/0000-0002-4072-4332)
- Radislav Sedláček (ORCID: https://orcid.org/0000-0002-3352-392X)
- Petra Brisudová (ORCID: https://orcid.org/0009-0001-9751-9356)
- Kryštof Klíma (ORCID: https://orcid.org/0009-0006-3374-9060)
- Jiřı́ Neužil (ORCID: https://orcid.org/0000-0002-2478-2460)
- Pavel Martásek (ORCID: https://orcid.org/0000-0001-6165-4444)
- Vladimı́r Havlı́ček (ORCID: https://orcid.org/0000-0002-8614-7059)
- Gabriela Lopes Oliveira (ORCID: https://orcid.org/0000-0001-5258-3322)
- Dominika Luptáková (ORCID: https://orcid.org/0000-0002-3691-2584)
- Jessica B. Spinelli (ORCID: https://orcid.org/0000-0003-3657-4578)
- Dan‐Diem Thi Le (ORCID: https://orcid.org/0000-0003-3922-9315)
- Štěpána Boukalová (ORCID: https://orcid.org/0000-0002-6478-4604)
- Libor Vı́tek (ORCID: https://orcid.org/0000-0002-5318-0151)
- E. N. Biryukova (ORCID: https://orcid.org/0009-0004-7977-9586)
- Renata Zobalová (ORCID: https://orcid.org/0000-0002-9097-4700)
- Paulo J. Oliveira (ORCID: https://orcid.org/0000-0002-5201-9948)
- Klára Boháčová (ORCID: https://orcid.org/0009-0006-3939-2349)
- Arash Yarmohammadi-Barzegar
- Marta Kaliaeva (ORCID: https://orcid.org/0000-0003-2635-0669)
- Andrea Brožková (ORCID: https://orcid.org/0009-0008-6903-0861)
Institutions
- Griffith University (AU)
- Seoul National University (KR)
- University of Massachusetts Chan Medical School (US)
- Malaghan Institute of Medical Research (NZ)
- Czech Academy of Sciences (CZ)
- Charles University (CZ)
- Czech Academy of Sciences, Institute of Biotechnology (CZ)
- Czech Academy of Sciences, Institute of Sociology (CZ)
- Czech Academy of Sciences, Institute of Microbiology (CZ)
- Czech Academy of Sciences, Institute of Molecular Genetics (CZ)
- General University Hospital in Prague (CZ)
- Czech Academy of Sciences, Institute of Physiology (CZ)
- Palacký University Olomouc (CZ)
- University of Coimbra (PT)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-04
- DOI
- https://doi.org/10.1038/s41467-025-65451-2
- Primary Topic
- Biochemical and Molecular Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Univerzita Karlova v Praze
- Grantová Agentura, Univerzita Karlova
- National Research Foundation
- Ministerstvo Školství, Mládeže a Tělovýchovy
- Grantová Agentura České Republiky
- Akademie Věd České Republiky
- Health Research Council of New Zealand
- Fundação para a Ciência e a Tecnologia