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

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. Her...

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Authors: Plata-Gómez, Ana Belén, de Prado-Rivas, Lucía, Sanz, Alba, Deleyto-Seldas, Nerea, García, Fernando, de la Calle Arregui, Celia, Silva, Camila, Caleiras, Eduardo, Graña-Castro, Osvaldo, Piñeiro-Yáñez, Elena, Krebs, Joseph, Leiva-Vega, Luis, Muñoz, Javier, Jain, Ajay, Sabio, Guadalupe, Efeyan, Alejo
Format: article
Publication Date:2024
Country:España
Institution:Instituto de Salud Carlos III (ISCIII)
Repository:Repisalud
Language:English
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/20034
Online Access:http://hdl.handle.net/20.500.12105/20034
Access Level:Open access
Keyword:Endothelial Cells
Liver
Swine
Animals
Mechanistic Target of Rapamycin Complex 1
Hepatocytes
Signal Transduction
Insulin
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spelling Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver.Plata-Gómez, Ana Belénde Prado-Rivas, LucíaSanz, AlbaDeleyto-Seldas, NereaGarcía, Fernandode la Calle Arregui, CeliaSilva, CamilaCaleiras, EduardoGraña-Castro, OsvaldoPiñeiro-Yáñez, ElenaKrebs, JosephLeiva-Vega, LuisMuñoz, JavierJain, AjaySabio, GuadalupeEfeyan, AlejoEndothelial CellsLiverSwineAnimalsMechanistic Target of Rapamycin Complex 1HepatocytesSignal TransductionInsulinThe 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.Nature Publishing GroupUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)Unión Europea. Comisión Europea. European Research Council (ERC)Fundación La Caixa20242024-07-0320242024-03-1820242024-03-18journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/20034reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengEuropean Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme ERC-2014-STG-638891open accesshttp://purl.org/coar/access_right/c_abf2Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/200342026-06-12T12:43:37Z
dc.title.none.fl_str_mv Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver.
title Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver.
spellingShingle Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver.
Plata-Gómez, Ana Belén
Endothelial Cells
Liver
Swine
Animals
Mechanistic Target of Rapamycin Complex 1
Hepatocytes
Signal Transduction
Insulin
title_short 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_sort Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver.
dc.creator.none.fl_str_mv Plata-Gómez, Ana Belén
de Prado-Rivas, Lucía
Sanz, Alba
Deleyto-Seldas, Nerea
García, Fernando
de la Calle Arregui, Celia
Silva, Camila
Caleiras, Eduardo
Graña-Castro, Osvaldo
Piñeiro-Yáñez, Elena
Krebs, Joseph
Leiva-Vega, Luis
Muñoz, Javier
Jain, Ajay
Sabio, Guadalupe
Efeyan, Alejo
author Plata-Gómez, Ana Belén
author_facet Plata-Gómez, Ana Belén
de Prado-Rivas, Lucía
Sanz, Alba
Deleyto-Seldas, Nerea
García, Fernando
de la Calle Arregui, Celia
Silva, Camila
Caleiras, Eduardo
Graña-Castro, Osvaldo
Piñeiro-Yáñez, Elena
Krebs, Joseph
Leiva-Vega, Luis
Muñoz, Javier
Jain, Ajay
Sabio, Guadalupe
Efeyan, Alejo
author_role author
author2 de Prado-Rivas, Lucía
Sanz, Alba
Deleyto-Seldas, Nerea
García, Fernando
de la Calle Arregui, Celia
Silva, Camila
Caleiras, Eduardo
Graña-Castro, Osvaldo
Piñeiro-Yáñez, Elena
Krebs, Joseph
Leiva-Vega, Luis
Muñoz, Javier
Jain, Ajay
Sabio, Guadalupe
Efeyan, Alejo
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Unión Europea. Comisión Europea. European Research Council (ERC)
Fundación La Caixa
dc.subject.none.fl_str_mv Endothelial Cells
Liver
Swine
Animals
Mechanistic Target of Rapamycin Complex 1
Hepatocytes
Signal Transduction
Insulin
topic Endothelial Cells
Liver
Swine
Animals
Mechanistic Target of Rapamycin Complex 1
Hepatocytes
Signal Transduction
Insulin
description 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.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024-07-03
2024
2024-03-18
2024
2024-03-18
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/20034
url http://hdl.handle.net/20.500.12105/20034
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv European Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme ERC-2014-STG-638891
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.81155

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