Liver lobules are typically subdivided into 3 metabolic zones: Zones 1, 2, and 3. The liver is composed of small divisions, so-called liver lobules, which consist of a portal triad, linear cords of hepatocytes that are separated by adjacent sinusoids, and a central vein.

Additionally, we revealed that the metabolic phenotypes of liver tumours were acquired during tumorigenesis, irrespective of their spatial origin. Notably, Axin2-expressing hepatocytes undergoing chronic liver injury significantly contributed to liver regeneration and possessed high neoplastic potential. However, the frequency of zone 3 hepatocyte-derived tumours varied depending on the regeneration pattern of the liver parenchyma in response to liver injury. Using this system, we found that zone 3 hepatocytes generally had high neoplastic potential, which was promoted by constitutive activation of Wnt/β-catenin signalling in the pericentral area. Cell fate analysis revealed that zone 3 hepatocytes maintained their own lineage but rarely proliferated beyond their liver zonation during homoeostasis this indicated that our protocol enabled persistent genetic labelling of zone 3 hepatocytes. We found that following tamoxifen administration at 3 weeks of age, approximately one-third of total hepatocytes that correspond to zone 3 were labelled in Axin2 tdTomato mice the tdTomato + cell distribution closely matched that of the zone 3 marker CYP2E1. We first examined changes in the zonal distribution of the Wnt target gene Axin2 over time using Axin2-Cre ERT2 Rosa26-Lox-Stop-Lox-tdTomato mice ( Axin2 tdTomato).

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