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. The authors show that regenerating liver requires de novo pyrimidine synthesis and it uses ammonia as precursors differentially as it traverses the liver zones. Tracing studies and spatial metabolomics reveal that assimilation periportally is via the urea cycle, and pericentrally through conversion into glutamine.