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Cited by 16Liver physiology and pathologyWnt/β-catenin signaling in development and cancerPancreatic function and diabetes

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

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Plata-Gómez, Ana Belén, de Prado-Rivas, Lucía, Sanz, Alba, Deleyto-Seldas, Nerea, García, Fernando, de la Calle Arregui, Celia, Silva, Camila, Caleiras, Eduardo +8 more·2024·Nature Communications
DOI 10.1038/s41467-024-46032-1PMC PMC10948770
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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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  • The pericentral to periportal gradient of Rspo3 expression in HSCs is likely explained not only by zonal Tgfb2 and Tgfb3 expression but also by the liver's oxygen and nutrient gradients.

    “It is likely that the pericentral to periportal gradient of Rspo3 expression in HSCs is not only explained by zonal Tgfb2 and Tgfb3 expression but also by the liver’s well-characterized oxygen and nutrient gradients9,58.”

    From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [58]

    The Introduction (page unavailable) describes a portal-to-central gradient in oxygen and nutrients, and the Discussion links those gradients to hepatocyte metabolic zonation. Neither passage says that the gradients explain Rspo3 expression in hepatic stellate cells or addresses the proposed role of zonal Tgfb2 and Tgfb3 expression. (LLM, conf=0.84)

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  1. [1]Trefts, E., Gannon, M. & Wasserman, D. H. The liver. Curr. Biol.27, R1147–R1151 (2017). PMC5897118 29112863
  2. [2]Martini, T., Naef, F. & Tchorz, J. S. Spatiotemporal Metabolic Liver Zonation and Consequences on Pathophysiology. Ann. Rev. Pathol. Mechan. Dis.1810.1146/annurev-pathmechdis-031521-024831 (2023). 36693201 · DOI · Paper page
  3. [3]Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell168, 960–976 (2017). PMC5394987 28283069
  4. [4]Valvezan AJ Manning BD Molecular logic of mTORC1 signalling as a metabolic rheostat Nat. Metab. 2019 1 321 333 10.1038/s42255-019-0038-7 32694720 PMC12569966 · DOI
  5. [5]Inoki K Li Y Xu T Guan KL Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling Genes Dev. 2003 17 1829 1834 10.1101/gad.1110003 12869586 PMC196227 · DOI · Paper page
  6. [6]Tee AR Manning BD Roux PP Cantley LC Blenis J Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb Curr. Biol. 2003 13 1259 1268 10.1016/S0960-9822(03)00506-2 12906785 · DOI
  7. [7]Long X Lin Y Ortiz-Vega S Yonezawa K Avruch J Rheb binds and regulates the mTOR kinase Curr. Biol. 2005 15 702 713 10.1016/j.cub.2005.02.053 15854902 · DOI · Paper page
  8. [8]Sancak Y The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1 Science (1979) 2008 320 1496 1501 PMC2475333 18497260
  9. [11]Sengupta S Peterson TR Laplante M Oh S Sabatini DM mTORC1 controls fasting-induced ketogenesis and its modulation by ageing Nature 2010 468 1100 1104 10.1038/nature09584 21179166 · DOI · Paper page
  10. [12]Titchenell, P. M. et al. Direct Hepatocyte Insulin Signaling Is Required for Lipogenesis but Is Dispensable for the Suppression of Glucose Production. Cell Metab. 10.1016/j.cmet.2016.04.022 (2016). PMC4909537 27238637 · DOI
  11. [13]Quinn, W. J. et al. MTORC1 stimulates phosphatidylcholine synthesis to promote triglyceride secretion. J. Clin. Investig. 10.1172/JCI96036 (2017). PMC5663357 29035283 · DOI
  12. [14]Cornu, M. et al. Hepatic mTORC1 controls locomotor activity, body temperature, and lipid metabolism through FGF21. Proc. Natl. Acad. Sci. USA10.1073/pnas.1412047111 (2014). PMC4136616 25082895
  13. [15]Menon S Chronic activation of mTOR complex 1 is sufficient to cause hepatocellular carcinoma in mice Sci. Signal 2012 5 ra24 10.1126/scisignal.2002739 22457330 PMC3743103 · DOI
  14. [16]Yecies JL Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways Cell Metab. 2011 14 21 32 10.1016/j.cmet.2011.06.002 21723501 PMC3652544 · DOI
  15. [17]de la Calle Arregui, C. et al. Limited survival and impaired hepatic fasting metabolism in mice with constitutive Rag GTPase signaling. Nat Commun. 10.1038/s41467-021-23857-8 (2021). PMC8209044 34135321 · DOI
  16. [18]Cho CS Concurrent activation of growth factor and nutrient arms of mTORC1 induces oxidative liver injury Cell Discov. 2019 5 60 10.1038/s41421-019-0131-9 31754457 PMC6868011 · DOI
  17. [19]Fingar DC Salama S Tsou C Harlow E Blenis J Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E Genes Dev. 2002 16 1472 1487 10.1101/gad.995802 12080086 PMC186342 · DOI · Paper page
  18. [20]Ersching, J. et al. Germinal center selection and affinity maturation require dynamic regulation of mTORC1 Kinase. Immunity10.1016/j.immuni.2017.06.005 (2017). PMC5526448 28636954
  19. [21]Cangelosi AL Zonated leucine sensing by Sestrin-mTORC1 in the liver controls the response to dietary leucine Science (1979) 2022 377 47 56 PMC10049859 35771919
  20. [22]Halpern, K. B. et al. Single-cell spatial reconstruction reveals global division of labour in the mammalian liver. Nature10.1038/nature21065 (2017). PMC5321580 28166538
  21. [25]Sekine S Lan BYA Bedolli M Feng S Hebrok M Liver-specific loss of β-catenin blocks glutamine synthesis pathway activity and cytochrome P450 expression in mice Hepatology 2006 43 817 825 10.1002/hep.21131 16557553 · DOI · Paper page
  22. [26]Tan X Behari J Cieply B Michalopoulos GK Monga SPS Conditional deletion of β-catenin reveals its role in liver growth and regeneration Gastroenterology 2006 131 1561 1572 10.1053/j.gastro.2006.08.042 17101329 · DOI · Paper page
  23. [27]Jungermann, K. & Kietzmann, T. Zonation of parenchymal and nonparenchymal metabolism in liver. Ann. Rev. Nutr.1610.1146/annurev.nu.16.070196.001143 (1996). 8839925 · DOI · Paper page
  24. [28]Yang J Beta-catenin signaling in murine liver zonation and regeneration: a Wnt-Wnt situation! Hepatology 2014 60 964 976 10.1002/hep.27082 24700412 PMC4139486 · DOI
  25. [29]Zeng G Wnt’er in liver: expression of Wnt and frizzled genes in mouse Hepatology 2007 45 195 204 10.1002/hep.21473 17187422 · DOI
  26. [31]Mederacke I Dapito DH Affò S Uchinami H Schwabe RF High-yield and high-purity isolation of hepatic stellate cells from normal and fibrotic mouse livers Nat. Protoc. 2015 10 305 315 10.1038/nprot.2015.017 25612230 PMC4681437 · DOI
  27. [32]Xiong X Landscape of intercellular crosstalk in healthy and nash liver revealed by single-cell secretome gene analysis Mol. Cell 2019 75 305 315 10.1016/j.molcel.2019.07.028 PMC7262680 31398325 · DOI · Paper page
  28. [35]Postic C Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase J. Biol. Chem. 1999 274 305 315 10.1074/jbc.274.1.305 9867845 · DOI · Paper page
  29. [36]Weisend CM Kundert JA Suvorova ES Prigge JR Schmidt EE Cre activity in fetal albCre mouse hepatocytes: Utility for developmental studies Genesis 2009 47 789 792 10.1002/dvg.20568 19830819 PMC2828742 · DOI
  30. [37]Lemaigre, F. P. Mechanisms of liver development: concepts for understanding liver disorders and design of novel therapies. Gastroenterology13710.1053/j.gastro.2009.03.035 (2009). 19328801 · DOI
  31. [38]Ma R Martínez-Ramírez AS Borders TL Gao F Sosa-Pineda B Metabolic and non-metabolic liver zonation is established non-synchronously and requires sinusoidal Wnts Elife 2020 9 e46206 10.7554/eLife.46206 32154783 PMC7067564 · DOI · Paper page
  32. [39]Burke ZD Spatiotemporal regulation of liver development by the Wnt/β-catenin pathway Sci. Rep. 2018 8 2735 10.1038/s41598-018-20888-y 29426940 PMC5807466 · DOI
  33. [40]Zeng H MTORC1 signaling suppresses Wnt/β-catenin signaling through DVL-dependent regulation of Wnt receptor FZD level Proc. Natl Acad. Sci. USA 2018 115 E10362 E10369 10.1073/pnas.1808575115 30297426 PMC6217415 · DOI
  34. [41]MacDonald, B. T., Tamai, K. & He, X. Wnt/β-catenin signaling: components, mechanisms, and diseases. Dev. Cell1710.1016/j.devcel.2009.06.016 (2009). PMC2861485 19619488 · DOI · Paper page
  35. [43]Jain AK Stoll B Burrin DG Holst JJ Moore DD Enteral bile acid treatment improves parenteral nutrition-related liver disease and intestinal mucosal atrophy in neonatal pigs Am. J. Physiol. Gastrointest. Liver Physiol. 2012 302 G218 G224 10.1152/ajpgi.00280.2011 22094603 PMC3341112 · DOI
  36. [44]Prentzell MT G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling Cell 2021 184 655 674.e27 10.1016/j.cell.2020.12.024 33497611 PMC7868890 · DOI
  37. [46]Edinger AL Thompson CB Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake Mol. Biol. Cell 2002 13 2276 2288 10.1091/mbc.01-12-0584 12134068 PMC117312 · DOI
  38. [47]Park Y Reyna-Neyra A Philippe L Thoreen CC mTORC1 balances cellular amino acid supply with demand for protein synthesis through post-transcriptional control of ATF4 Cell Rep. 2017 19 1083 1090 10.1016/j.celrep.2017.04.042 28494858 PMC5811220 · DOI
  39. [48]Alesi N TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism Nat. Commun. 2021 12 4245 10.1038/s41467-021-24499-6 34253722 PMC8275687 · DOI
  40. [49]Hu, S. & Monga, S. P. Wnt/β-catenin signaling and liver regeneration: Circuit, biology, and opportunities. Gene Express. J. Liver Res.2010.3727/105221621X16111780348794 (2021). PMC8201651 33472727 · DOI
  41. [50]Ang CH Lgr5+ pericentral hepatocytes are self-maintained in normal liver regeneration and susceptible to hepatocarcinogenesis Proc. Natl Acad. Sci. USA 2019 116 19530 19540 10.1073/pnas.1908099116 31488716 PMC6765306 · DOI · Paper page
  42. [51]Font-Burgada J Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer Cell 2015 162 766 779 10.1016/j.cell.2015.07.026 26276631 PMC4545590 · DOI · Paper page
  43. [52]He L Proliferation tracing reveals regional hepatocyte generation in liver homeostasis and repair Science (1979) 2021 371 eabc4346 33632818
  44. [54]Gruppuso, P. A. & Sanders, J. A. Regulation of liver development: Implications for liver biology across the lifespan. J. Mol. Endocrinol. 5610.1530/JME-15-0313 (2016). PMC4882189 26887388 · DOI
  45. [55]Giancotti, A. et al. Functions and the emerging role of the foetal liver into regenerative medicine. Cells. 810.3390/cells8080914 (2019). PMC6721721 31426422 · DOI
  46. [56]Postic, C. et al. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic β cell-specific gene knock-outs using Cre recombinase. J. Biol. Chem. 10.1074/jbc.274.1.305 (1999). 9867845 · DOI · Paper page
  47. [57]Kwiatkowski, D. J. et al. A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum. Mol. Genet. 10.1093/hmg/11.5.525 (2002). 11875047 · DOI
  48. [58]Muzumdar, M. D., Tasic, B., Miyamichi, K., Li, N. & Luo, L. A global double-fluorescent cre reporter mouse. Genesis10.1002/dvg.20335 (2007). 17868096
  49. [59]Efeyan A Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival Nature 2013 493 679 683 10.1038/nature11745 23263183 PMC4000705 · DOI
  50. [60]Thoolen, B. et al. Proliferative and nonproliferative lesions of the rat and mouse hepatobiliary system. Toxicol. Pathol. 10.1177/0192623310386499 (2010). 21191096 · DOI
  51. [61]Wieczorek, S. et al. DAPAR & ProStaR: Software to perform statistical analyses in quantitative discovery proteomics. Bioinformatics. 10.1093/bioinformatics/btw580 (2017) PMC5408771 27605098 · DOI
  52. [62]Graña O Rubio-Camarillo M Fdez-Riverola F Pisano DG Glez-Peña D Nextpresso: next generation sequencing expression analysis pipeline Curr. Bioinform. 2017 13 583 591 10.2174/1574893612666170810153850 · DOI
  53. [63]Trapnell C Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks Nat. Protoc. 2012 7 562 578 10.1038/nprot.2012.016 22383036 PMC3334321 · DOI
  54. [64]Langmead B Trapnell C Pop M Salzberg SL Ultrafast and memory-efficient alignment of short DNA sequences to the human genome Genome Biol. 2009 10 R25 10.1186/gb-2009-10-3-r25 19261174 PMC2690996 · DOI · Paper page
  55. [65]Li H The sequence Alignment/Map format and SAMtools Bioinformatics 2009 25 2078 2079 10.1093/bioinformatics/btp352 19505943 PMC2723002 · DOI · Paper page
  56. [66]Frankish A Gencode 2021 Nucleic Acids Res. 2021 49 D916 D923 10.1093/nar/gkaa1087 33270111 PMC7778937 · DOI · Paper page
  57. [67]Anders S Pyl PT Huber W HTSeq-A Python framework to work with high-throughput sequencing data Bioinformatics 2015 31 166 169 10.1093/bioinformatics/btu638 25260700 PMC4287950 · DOI · Paper page
  58. [68]Love MI Huber W Anders S Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Genome Biol. 2014 15 1 21 10.1186/s13059-014-0550-8 PMC4302049 25516281 · DOI · Paper page
  59. [69]Fustero-Torre C Beyondcell: targeting cancer therapeutic heterogeneity in single-cell RNA-seq data Genome Med. 2021 13 187 10.1186/s13073-021-01001-x 34911571 PMC8675493 · DOI
  60. [70]Dobin A STAR: ultrafast universal RNA-seq aligner Bioinformatics 2013 29 15 21 10.1093/bioinformatics/bts635 23104886 PMC3530905 · DOI · Paper page
  61. [71]Stuart T Comprehensive integration of single-cell data Cell 2019 177 1888 1902.e21 10.1016/j.cell.2019.05.031 31178118 PMC6687398 · DOI · Paper page
  62. [72]Plata-Gómez, A. B. et al. Protocol for the assessment of mTOR activity in mouse primary hepatocytes. STAR Protoc. 10.1016/j.xpro.2021.100918 (2021). PMC8564195 34755120 · DOI
  63. [73]Monelli, E. et al. Angiocrine polyamine production regulates adiposity. Nat. Metab. 10.1038/s42255-022-00544-6 (2022). 35288722 · DOI

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Authors
Plata-Gómez, A. B., de Prado-Rivas, L., Sanz, A., Deleyto-Seldas, N., García, F., de la Calle Arregui, C., Silva, C., Caleiras, E., Graña-Castro, O., Piñeiro-Yáñez, E., Krebs, J., Leiva-Vega, L., Muñoz, J., Jain, A., Sabio, G., & Efeyan, A.
Affiliations
  • Spanish National Cancer Research Centre (ES)
  • Saint Louis University (US)
  • Ikerbasque (ES)
  • Spanish National Centre for Cardiovascular Research (ES)
Corresponding author
Efeyan, Alejo
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-03-18
Volume
15
Issue
1
Pages
1878-1878
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-46032-1
PMC
PMC10948770
OpenAlex
W4392919120
Cited by
16
References
10
Citations by year
2026: 4 · 2025: 9 · 2024: 2 · 2023: 1
FWCI
3.93
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • European Molecular Biology Organization
  • Ministerio de Ciencia, Innovación y Universidades (SAF2016-81975-REDT, PID2019)
  • Ministerio de Economía y Competitividad (PID2022-136413OB-I00)
  • Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona (LCF/PR/HR21/0046)
  • Horizon 2020 Framework Programme (823839, PID2019, ERC-2014-STG)
  • European Regional Development Fund (H2020)
  • Agencia Estatal de Investigación (H2020, PID2019)
  • H2020 European Research Council (638891)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Keywords
liver zonation, mTORC1 signaling, hepatocyte maturation, nutrient signaling, insulin signaling, Wnt/β-catenin signaling, Frizzled receptors, Wnt2, paracrine signaling, endothelial cells, postnatal liver development, parenteral nutrition, piglets, hepatic metabolism
MeSH terms
Mechanistic Target of Rapamycin Complex 1, Animals, Insulin, Liver, Swine, Signal Transduction, Hepatocytes, Endothelial Cells

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