Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver
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 fluctuat...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46032-1 |
| _version_ | 1797247123947782144 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Ana Belén Plata-Gómez |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T19:53:42Z |
| format | Article |
| id | doaj.art-4772ae75e9d74a97a90d1058448dea3e |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T19:53:42Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-4772ae75e9d74a97a90d1058448dea3e2024-03-24T12:26:01ZengNature PortfolioNature Communications2041-17232024-03-0115111910.1038/s41467-024-46032-1Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liverAna Belén Plata-Gómez0Lucía de Prado-Rivas1Alba Sanz2Nerea Deleyto-Seldas3Fernando García4Celia de la Calle Arregui5Camila Silva6Eduardo Caleiras7Osvaldo Graña-Castro8Elena Piñeiro-Yáñez9Joseph Krebs10Luis Leiva-Vega11Javier Muñoz12Ajay Jain13Guadalupe Sabio14Alejo Efeyan15Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO)Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO)Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO)Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO)Proteomics Unit. Spanish National Cancer Research Centre (CNIO)Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO)Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO)Histopathology Unit. Spanish National Cancer Research Centre (CNIO)Bioinformatics Unit. Spanish National Cancer Research Centre (CNIO)Bioinformatics Unit. Spanish National Cancer Research Centre (CNIO)Department of Pediatrics, Saint Louis UniversityMyocardial Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC)Proteomics Unit. Spanish National Cancer Research Centre (CNIO)Department of Pediatrics, Saint Louis UniversityMyocardial Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC)Metabolism and Cell Signaling Laboratory, 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.https://doi.org/10.1038/s41467-024-46032-1 |
| spellingShingle | 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 Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver Nature Communications |
| title | Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver |
| title_full | Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver |
| title_fullStr | Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver |
| title_full_unstemmed | Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver |
| title_short | Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver |
| title_sort | hepatic nutrient and hormone signaling to mtorc1 instructs the postnatal metabolic zonation of the liver |
| url | https://doi.org/10.1038/s41467-024-46032-1 |
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