Ana Belén Plata-Gómez, Lucía de Prado-Rivas, Alba Sanz, Nerea Deleyto-Seldas, Fernando García, Celia de la Calle Arregui, Camila Silva, Eduardo Caleiras, Osvaldo Graña-Castro, Elena Piñeiro-Yáñez, Joseph Krebs, Luis Leiva-Vega, Javier Muñoz, Ajay Jain, Guadalupe Sabio & Alejo Efeyan

The metabolic functions of the liver are spatially organized in a phenomenon called zonation, linked to the differential exposure of portal and central hepatocytes to nutrient-rich blood. The mTORC1 signaling pathway controls cellular metabolism in response to nutrients and insulin fluctuations.

Liver zonation (Image: Ana Belén Plata Gómez).

Here we show that simultaneous genetic activation of nutrient and hormone signaling to mTORC1 in hepatocytes results in impaired establishment of postnatal metabolic and zonal identity of hepatocytes. Mutant hepatocytes fail to upregulate postnatally the expression of Frizzled receptors 1 and 8, and show reduced Wnt/β-catenin activation. This defect, alongside diminished paracrine Wnt2 ligand expression by endothelial cells, underlies impaired postnatal maturation. Impaired zonation is recapitulated in a model of constant supply of nutrients by parenteral nutrition to piglets.

Our work shows the role of hepatocyte sensing of fluctuations in nutrients and hormones for triggering a latent metabolic zonation program.