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Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver

Author

Listed:
  • Ana Belén Plata-Gómez

    (Spanish National Cancer Research Centre (CNIO))

  • Lucía Prado-Rivas

    (Spanish National Cancer Research Centre (CNIO))

  • Alba Sanz

    (Spanish National Cancer Research Centre (CNIO))

  • Nerea Deleyto-Seldas

    (Spanish National Cancer Research Centre (CNIO))

  • Fernando García

    (Proteomics Unit. Spanish National Cancer Research Centre (CNIO))

  • Celia Calle Arregui

    (Spanish National Cancer Research Centre (CNIO))

  • Camila Silva

    (Spanish National Cancer Research Centre (CNIO))

  • Eduardo Caleiras

    (Histopathology Unit. Spanish National Cancer Research Centre (CNIO))

  • Osvaldo Graña-Castro

    (Bioinformatics Unit. Spanish National Cancer Research Centre (CNIO)
    San Pablo-CEU University, CEU Universities, Boadilla del Monte)

  • Elena Piñeiro-Yáñez

    (Bioinformatics Unit. Spanish National Cancer Research Centre (CNIO))

  • Joseph Krebs

    (Saint Louis University)

  • Luis Leiva-Vega

    (Centro Nacional de Investigaciones Cardiovasculares (CNIC))

  • Javier Muñoz

    (Proteomics Unit. Spanish National Cancer Research Centre (CNIO)
    Biocruces Bizkaia Health Research Institute & Ikerbasque Basque Foundation for Science)

  • Ajay Jain

    (Saint Louis University)

  • Guadalupe Sabio

    (Centro Nacional de Investigaciones Cardiovasculares (CNIC))

  • Alejo Efeyan

    (Spanish National Cancer Research Centre (CNIO))

Abstract

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. 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.

Suggested Citation

  • Ana Belén Plata-Gómez & Lucía Prado-Rivas & Alba Sanz & Nerea Deleyto-Seldas & Fernando García & Celia Calle Arregui & Camila Silva & Eduardo Caleiras & Osvaldo Graña-Castro & Elena Piñeiro-Yáñez & Jo, 2024. "Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46032-1
    DOI: 10.1038/s41467-024-46032-1
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    References listed on IDEAS

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