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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月4日

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  • 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,
  • Jiří Neužil

摘要

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.