Regenerating liver uses ammonia to support de novo pyrimidine synthesis and cell proliferation

Berwini B. Endaya (), Lukáš Kučera, Dan-Diem Thi Le, Jessica B. Spinelli, Andrea Brožková, Dominika Luptáková, Kryštof Klíma, Gabriela L. Oliveira, Petra Brisudová, Klára Boháčová, Štěpána Boukalová, Renata Zobalová, František Kolář, Karel Chalupsky, Klára Dohnalová, Arash Yarmohammadi-Barzegar, Šárka Dvořáková, Evgeniya Biryukova, Marta Kaliaeva, Vladimír Havlíček, Radislav Sedláček, Jan Procházka, Libor Vítek, Sunghyouk Park, Pavel Martásek, Zdeněk Krška, Paulo J. Oliveira, Michael V. Berridge and Jiří Neužil ()
Additional contact information
Berwini B. Endaya: Czech Academy of Sciences
Lukáš Kučera: Academy of Sciences of the Czech Republic
Dan-Diem Thi Le: Czech Academy of Sciences
Jessica B. Spinelli: University of Massachusetts
Andrea Brožková: Charles University
Dominika Luptáková: Czech Academy of Sciences
Kryštof Klíma: Academy of Sciences of the Czech Republic
Gabriela L. Oliveira: Czech Academy of Sciences
Petra Brisudová: Czech Academy of Sciences
Klára Boháčová: Czech Academy of Sciences
Štěpána Boukalová: Czech Academy of Sciences
Renata Zobalová: Czech Academy of Sciences
František Kolář: Czech Academy of Sciences
Karel Chalupsky: Academy of Sciences of the Czech Republic
Klára Dohnalová: Academy of Sciences of the Czech Republic
Arash Yarmohammadi-Barzegar: Charles University
Šárka Dvořáková: Czech Academy of Sciences
Evgeniya Biryukova: Academy of Sciences of the Czech Republic
Marta Kaliaeva: Academy of Sciences of the Czech Republic
Vladimír Havlíček: Czech Academy of Sciences
Radislav Sedláček: Academy of Sciences of the Czech Republic
Jan Procházka: Academy of Sciences of the Czech Republic
Libor Vítek: Charles University
Sunghyouk Park: Seoul National University
Pavel Martásek: Charles University
Zdeněk Krška: Charles University
Paulo J. Oliveira: University of Coimbra
Michael V. Berridge: Kelburn
Jiří Neužil: Czech Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-65451-2

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