IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-46032-1.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-46032-1
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-46032-1?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Keren Bahar Halpern & Rom Shenhav & Orit Matcovitch-Natan & Beáta Tóth & Doron Lemze & Matan Golan & Efi E. Massasa & Shaked Baydatch & Shanie Landen & Andreas E. Moor & Alexander Brandis & Amir Gilad, 2017. "Single-cell spatial reconstruction reveals global division of labour in the mammalian liver," Nature, Nature, vol. 542(7641), pages 352-356, February.
    2. Bruce Wang & Ludan Zhao & Matt Fish & Catriona Y. Logan & Roel Nusse, 2015. "Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver," Nature, Nature, vol. 524(7564), pages 180-185, August.
    3. Alejo Efeyan & Roberto Zoncu & Steven Chang & Iwona Gumper & Harriet Snitkin & Rachel L. Wolfson & Oktay Kirak & David D. Sabatini & David M. Sabatini, 2013. "Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival," Nature, Nature, vol. 493(7434), pages 679-683, January.
    4. Celia de la Calle Arregui & Ana Belén Plata-Gómez & Nerea Deleyto-Seldas & Fernando García & Ana Ortega-Molina & Julio Abril-Garrido & Elena Rodriguez & Ivan Nemazanyy & Laura Tribouillard & Alba Mart, 2021. "Limited survival and impaired hepatic fasting metabolism in mice with constitutive Rag GTPase signaling," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    5. Shomit Sengupta & Timothy R. Peterson & Mathieu Laplante & Stephanie Oh & David M. Sabatini, 2010. "mTORC1 controls fasting-induced ketogenesis and its modulation by ageing," Nature, Nature, vol. 468(7327), pages 1100-1104, December.
    6. Keren Bahar Halpern & Rom Shenhav & Orit Matcovitch-Natan & Beáta Tóth & Doron Lemze & Matan Golan & Efi E. Massasa & Shaked Baydatch & Shanie Landen & Andreas E. Moor & Alexander Brandis & Amir Gilad, 2017. "Erratum: Single-cell spatial reconstruction reveals global division of labour in the mammalian liver," Nature, Nature, vol. 543(7647), pages 742-742, March.
    7. Nicola Alesi & Elie W. Akl & Damir Khabibullin & Heng-Jia Liu & Anna S. Nidhiry & Emma R. Garner & Harilaos Filippakis & Hilaire C. Lam & Wei Shi & Srinivas R. Viswanathan & Manrico Morroni & Shawn M., 2021. "TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    8. Constantinos Demetriades & Monika Plescher & Aurelio A. Teleman, 2016. "Lysosomal recruitment of TSC2 is a universal response to cellular stress," Nature Communications, Nature, vol. 7(1), pages 1-14, April.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Inmaculada Ruz-Maldonado & John T. Gonzalez & Hanming Zhang & Jonathan Sun & Alicia Bort & Inamul Kabir & Richard G. Kibbey & Yajaira Suárez & Daniel M. Greif & Carlos Fernández-Hernando, 2024. "Heterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    2. Franziska Hildebrandt & Alma Andersson & Sami Saarenpää & Ludvig Larsson & Noémi Van Hul & Sachie Kanatani & Jan Masek & Ewa Ellis & Antonio Barragan & Annelie Mollbrink & Emma R. Andersson & Joakim L, 2021. "Spatial Transcriptomics to define transcriptional patterns of zonation and structural components in the mouse liver," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    3. Zhiyuan Yuan & Yisi Li & Minglei Shi & Fan Yang & Juntao Gao & Jianhua Yao & Michael Q. Zhang, 2022. "SOTIP is a versatile method for microenvironment modeling with spatial omics data," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    4. Jingyang Qian & Jie Liao & Ziqi Liu & Ying Chi & Yin Fang & Yanrong Zheng & Xin Shao & Bingqi Liu & Yongjin Cui & Wenbo Guo & Yining Hu & Hudong Bao & Penghui Yang & Qian Chen & Mingxiao Li & Bing Zha, 2023. "Reconstruction of the cell pseudo-space from single-cell RNA sequencing data with scSpace," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    5. Kristina Handler & Karsten Bach & Costanza Borrelli & Salvatore Piscuoglio & Xenia Ficht & Ilhan E. Acar & Andreas E. Moor, 2023. "Fragment-sequencing unveils local tissue microenvironments at single-cell resolution," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    6. Sun Woo Sophie Kang & Rory P. Cunningham & Colin B. Miller & Lauryn A. Brown & Constance M. Cultraro & Adam Harned & Kedar Narayan & Jonathan Hernandez & Lisa M. Jenkins & Alexei Lobanov & Maggie Cam , 2024. "A spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    7. Zoe Piran & Mor Nitzan, 2024. "SiFT: uncovering hidden biological processes by probabilistic filtering of single-cell data," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    8. Jie Fang & Shivendra Singh & Changde Cheng & Sivaraman Natarajan & Heather Sheppard & Ahmed Abu-Zaid & Adam D. Durbin & Ha Won Lee & Qiong Wu & Jacob Steele & Jon P. Connelly & Hongjian Jin & Wenan Ch, 2023. "Genome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma," Nature Communications, Nature, vol. 14(1), pages 1-27, December.
    9. Manuel Neumann & Xiaocai Xu & Cezary Smaczniak & Julia Schumacher & Wenhao Yan & Nils Blüthgen & Thomas Greb & Henrik Jönsson & Jan Traas & Kerstin Kaufmann & Jose M. Muino, 2022. "A 3D gene expression atlas of the floral meristem based on spatial reconstruction of single nucleus RNA sequencing data," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    10. Urban Lendahl & Lars Muhl & Christer Betsholtz, 2022. "Identification, discrimination and heterogeneity of fibroblasts," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    11. Yuan Guan & Annika Enejder & Meiyue Wang & Zhuoqing Fang & Lu Cui & Shih-Yu Chen & Jingxiao Wang & Yalun Tan & Manhong Wu & Xinyu Chen & Patrik K. Johansson & Issra Osman & Koshi Kunimoto & Pierre Rus, 2021. "A human multi-lineage hepatic organoid model for liver fibrosis," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    12. Francesca Lazzeri-Barcelo & Nuria Oliva-Vilarnau & Marion Baniol & Barbara Leibiger & Olaf Bergmann & Volker M. Lauschke & Ingo B. Leibiger & Noah Moruzzi & Per-Olof Berggren, 2024. "Intraocular liver spheroids for non-invasive high-resolution in vivo monitoring of liver cell function," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    13. Yan Tang & David J. Kwiatkowski & Elizabeth P. Henske, 2022. "Midkine expression by stem-like tumor cells drives persistence to mTOR inhibition and an immune-suppressive microenvironment," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    14. Kaushal Asrani & Juhyung Woo & Adrianna A. Mendes & Ethan Schaffer & Thiago Vidotto & Clarence Rachel Villanueva & Kewen Feng & Lia Oliveira & Sanjana Murali & Hans B. Liu & Daniela C. Salles & Brando, 2022. "An mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    15. Gloria Ursino & Giorgio Ramadori & Anna Höfler & Soline Odouard & Pryscila D. S. Teixeira & Florian Visentin & Christelle Veyrat-Durebex & Giulia Lucibello & Raquel Firnkes & Serena Ricci & Claudia R., 2022. "Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    16. Hui Xia & Catherine R. Dufour & Younes Medkour & Charlotte Scholtes & Yonghong Chen & Christina Guluzian & Wafa B’chir & Vincent Giguère, 2023. "Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression in male mice," Nature Communications, Nature, vol. 14(1), pages 1-24, December.
    17. M. L. Richter & I. K. Deligiannis & K. Yin & A. Danese & E. Lleshi & P. Coupland & C. A. Vallejos & K. P. Matchett & N. C. Henderson & M. Colome-Tatche & C. P. Martinez-Jimenez, 2021. "Single-nucleus RNA-seq2 reveals functional crosstalk between liver zonation and ploidy," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    18. Min Yan Shi & Hwang Chan Yu & Chang Yeob Han & In Hyuk Bang & Ho Sung Park & Kyu Yun Jang & Sangkyu Lee & Jeong Bum Son & Nam Doo Kim & Byung-Hyun Park & Eun Ju Bae, 2023. "p21-activated kinase 4 suppresses fatty acid β-oxidation and ketogenesis by phosphorylating NCoR1," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    19. Xing Chen & Chunyu Yu & Xinhua Liu & Beibei Liu & Xiaodi Wu & Jiajing Wu & Dong Yan & Lulu Han & Zifan Tang & Xinyi Yuan & Jianqiu Wang & Yue Wang & Shumeng Liu & Lin Shan & Yongfeng Shang, 2022. "Intracellular galectin-3 is a lipopolysaccharide sensor that promotes glycolysis through mTORC1 activation," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    20. Yanan Wang & Mengjun Luo & Fan Wang & Yu Tong & Linfeng Li & Yu Shu & Ke Qiao & Lei Zhang & Guoquan Yan & Jing Liu & Hongbin Ji & Youhua Xie & Yonglong Zhang & Wei-Qiang Gao & Yanfeng Liu, 2022. "AMPK induces degradation of the transcriptional repressor PROX1 impairing branched amino acid metabolism and tumourigenesis," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46032-1. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.