Hepatic Nutrient and Hormone Signaling to MTORC1 Instructs the Postnatal Metabolic Zonation of the Liver

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Mar 19

PMID 38499523

Authors

Ana Belen Plata-Gomez

Lucia de Prado-Rivas

Alba Sanz

Nerea Deleyto-Seldas

Fernando Garcia

Celia De La Calle Arregui

Camila Silva

Eduardo Caleiras

Osvaldo Grana-Castro

Elena Pineiro-Yanez

Joseph Krebs

Luis Leiva-Vega

Javier Munoz

Ajay Jain

Guadalupe Sabio

Alejo Efeyan

Affiliations

Soon will be listed here.

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.

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