The DOI matches its Crossref record; 132 of the 132 references it cites were found in a registry or an index.
Liver zonation: Novel aspects of its regulation and its impact on homeostasis
Open accessAbstract
Liver zonation, the spatial separation of the immense spectrum of different metabolic pathways along the liver sinusoids, is fundamental for proper functioning of this organ. Recent progress in elucidating localization and interactions of different metabolic pathways by using "omics" techniques and novel approaches to couple them with refined spatial resolution and in characterizing novel master regulators of zonation by using transgenic mice has created the basis for a deeper understanding of core mechanisms of zonation and their impact on liver physiology, pathology and metabolic diseases. This review summarizes the fascinating technical achievements for investigating liver zonation and the elucidation of an emerging network of master regulators of zonation that keep the plethora of interrelated and sometimes opposing functions of the liver in balance with nutritional supply and specific requirements of the entire body. In addition, a brief overview is given on newly described zonated functions and novel details on how diverse the segmentation of metabolic zonation may be. From these facts and developments a few fundamental principles are inferred which seem to rule zonation of liver parenchyma. In addition, we identify important questions that still need to be answered as well as interesting fields of research such as the connection of zonation with circadian rhythm and gender dimorphism which need to be pushed further, in order to improve our understanding of metabolic zonation. Finally, an outlook is given on how disturbance of liver zonation and its regulation may impact on liver pathology and the development of metabolic diseases.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In vivo, hepatocytes are situated in a highly organized lobular architecture and dynamically interact with a complex extracellular matrix (ECM) of collagens, laminins and fibronectin [14].”
From The Hepatocyte Expansion Paradox: A Review of In Vitro Challenges and Advances (2026) · cites this paper as [14]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“The absence of paracrine and juxtacrine connections in monoculture systems exacerbates hepatocyte survival and growth potential [14].”
From The Hepatocyte Expansion Paradox: A Review of In Vitro Challenges and Advances (2026) · cites this paper as [14]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“The failure to recapitulate the complexity of the hepatic environment is a major contributor to hepatocyte dedifferentiation.”
From The Hepatocyte Expansion Paradox: A Review of In Vitro Challenges and Advances (2026) · cites this paper as [14]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“When hepatocytes are maintained in vitro, however, this environment is simplified by using conventional culture substrates, leading to dysregulated integrin signaling and accelerated functional decline [14].”
From The Hepatocyte Expansion Paradox: A Review of In Vitro Challenges and Advances (2026) · cites this paper as [14]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Two new Later Stone Age sites from the Final Pleistocene in the Falémé Valley, eastern Senegal
Ndiaye, M., Lespez, L., Tribolo, C., Rassé, M., Hadjas, I., Davidoux, S., Huysecom, É., & Douze, K. (2024) · Monash University Research Portal (Monash University) · doi:10.3929/ethz-b-000667478 · Cited by 24,214
Mitochondria, Oxidants, and Aging
Balaban, R. S., Nemoto, S., & Finkel, T. (2005) · Cell · doi:10.1016/j.cell.2005.02.001 · Cited by 4,388
Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis
Inagaki, T., Choi, M., Moschetta, A., Peng, L., Cummins, C. L., McDonald, J. G., Luo, G., Jones, S. A., Goodwin, B., Richardson, J. A., et al. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.09.001 · Cited by 1,865
In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration
Huch, M., Dorrell, C., Boj, S. F., van Es, J. H., Li, V. S. W., van de Wetering, M., Sato, T., Hamer, K., Sasaki, N., Finegold, M. J., et al. (2013) · Nature · doi:10.1038/nature11826 · Cited by 1,555
Michalopoulos, G. K. (2007) · Journal of Cellular Physiology · doi:10.1002/jcp.21172 · Cited by 1,384
Hedgehog: functions and mechanisms
Varjosalo, M., & Taipale, J. (2008) · Genes & Development · doi:10.1101/gad.1693608 · Cited by 1,217
Identification of a fibroblast-derived epithelial morphogen as hepatocyte growth factor
Montesano, R., Matsumoto, K., Nakamura, T., & Orci, L. (1991) · Cell · doi:10.1016/0092-8674(91)90363-4 · Cited by 1,147
Nakamura, T., Nawa, K., & Ichihara, A. (1984) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(84)91253-1 · Cited by 1,134
In situ sequencing for RNA analysis in preserved tissue and cells
Ke, R., Mignardi, M., Pacureanu, A., Svedlund, J., Botling, J., Wählby, C., & Nilsson, M. (2013) · Nature Methods · doi:10.1038/nmeth.2563 · Cited by 934
Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes
Waxman, D. J., & Holloway, M. G. (2009) · Molecular Pharmacology · doi:10.1124/mol.109.056705 · Cited by 815
Cited by
Sorted by citations
Items 201–275 of 275
Recapitulating the liver niche in vitro
Yap, K. K., & Mitchell, G. M. (2022) · Advances in stem cells and their niches · doi:10.1016/bs.asn.2021.10.002 · Cited by 3
Rong, R., Wei, Y., Li, L., Wang, T., Zhu, H., Xiao, G., & Wang, Y. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2023.104698 · Cited by 4
Tietze, L., Christ, M., Yu, J., Stock, P., Nickel, S., Schulze, A., Bartels, M. J., Tautenhahn, H., & Christ, B. (2024) · Cells · doi:10.3390/cells13060529 · Cited by 4
Tiya, S. Y., Sewani-Rusike, C. R., & Taderera, T. (2019) · Journal of Biologically Active Products from Nature · doi:10.1080/22311866.2019.1694434 · Cited by 4
Mechanisms of liver disease in AATD
Piccolo, P., Attanasio, S., & Brunetti‐Pierri, N. (2019) · European Respiratory Society eBooks · doi:10.1183/2312508x.10032818 · Cited by 4
Rodimova, S. A., Kuznetsova, D. S., Bobrov, N., Gulin, A. A., Vasin, A. A., Gubina, M. V., Shcheslavskiy, V. I., Elagin, V. V., Karabut, M. M., Загайнов, В. Е., et al. (2021) · Современные технологии в медицине · doi:10.17691/stm2021.13.2.02 · Cited by 4
Morrison, J. K., DeRossi, C., Alter, I. L., Nayar, S., Giri, M., Zhang, C., Cho, J. H., & Chu, J. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.08.06.455422 · Cited by 4
Tambay, V., Raymond, V., Turcotte, S., & Bilodeau, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26199653 · Cited by 3
Future Challenges in the Generation of Hepatocyte-Like Cells From Human Pluripotent Stem Cells
Siller, R., Greenhough, S., Mathapati, S., Si‐Tayeb, K., & Sullivan, G. J. (2017) · Current Pathobiology Reports · doi:10.1007/s40139-017-0150-x · Cited by 3
Davydova, Y. A., Нестеркова, Д. В., & Mukhacheva, S. V. (2023) · Environmental Monitoring and Assessment · doi:10.1007/s10661-022-10810-5 · Cited by 3
Illuminating HBV with multi-scale modeling
Means, S., Ali, M. A., & Ho, H. (2023) · Frontiers in Systems Biology · doi:10.3389/fsysb.2023.1045754 · Cited by 3
Goossens, C., Tambay, V., Raymond, V., Rousseau, L., Turcotte, S., & Bilodeau, M. (2024) · PLoS ONE · doi:10.1371/journal.pone.0304405 · Cited by 3
Abdelhadi, S., Rink, J. S., Froelich, M. F., Șandra-Petrescu, F., El-Ahmar, M., Oweira, H., Rahbari, N. N., Reißfelder, C., & Birgin, E. (2025) · Langenbeck s Archives of Surgery · doi:10.1007/s00423-024-03565-9 · Cited by 3
Cell- and Stem Cell-Based Therapies for Liver Defects: Recent Advances and Future Strategies
Najimi, M. (2021) · Springer eBooks · doi:10.1007/978-3-030-77052-5_11 · Cited by 3
Nonalcoholic Fatty Liver Disease
Fitzpatrick, E. (2015) · Springer eBooks · doi:10.1007/978-3-319-17169-2_66 · Cited by 3
Nanoengineered Biomaterials for the treatment of liver diseases
Ortega‐Ribera, M., Yeste, J., Villa, R., & Gracia‐Sancho, J. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-813355-2.00018-1 · Cited by 4
Nonalcoholic Fatty Liver Disease
Fitzpatrick, E. (2022) · In clinical practice · doi:10.1007/978-3-030-98808-1_10 · Cited by 3
Intrabiliary infusion of naked DNA vectors targets periportal hepatocytes in mice
Deplazes, S., Schlegel, A. A., Song, Z., Allegri, G., Rimann, N., Scherer, T., Willimann, M., Opitz, L., Cunningham, S. C., Alexander, I. E., et al. (2022) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2022.10.006 · Cited by 3
Barton, R. (2020) · Springer eBooks · doi:10.1007/978-3-030-30730-1_16 · Cited by 3
Teperino, R., Adamová, M., Aljabali, S. M., Pai, S. S., Gerlini, R., Paez-Perez, I., Matz‐Soja, M., Heyne, S., Lempradl, A. M., Basilicata, M. F., et al. (2026) · Molecular Metabolism · doi:10.1016/j.molmet.2026.102339 · Cited by 2
Self-citationLeading-Edge Approaches for In Vitro Hepatotoxicity Evaluation
LeCluyse, E. L., Norona, L. M., Akingbasote, J. A., Howell, L. S., Woodhead, J. L., Cross, M. J., Roth, A. B., & Goldring, C. E. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.64267-8 · Cited by 2
Strategic Replication of the Hepatic Zonation In Vitro Employing a Biomimetic Approach
Sasikumar, S., Chameettachal, S., Vijayasankar, K. N., Kingshott, P., Cromer, B. A., & Pati, F. (2023) · ACS Applied Bio Materials · doi:10.1021/acsabm.3c00481 · Cited by 2
Davydova, Y. A., Нестеркова, Д. В., Mukhacheva, S. V., Владимирович, Ч. М., & Викторовна, С. Н. (2017) · Zoomorphology · doi:10.1007/s00435-017-0368-5 · Cited by 2
Hedgehog Signaling and Liver Lipid Metabolism
Matz‐Soja, M. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-811297-7.00015-9 · Cited by 2
Proteomics informed investigation of human hepatocytes and liver tissue
Handin, N. (2021) · Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy · doi:10.33063/diva-446954 · Cited by 3
Chen, J., Wu, J., Bai, Y., Yang, C., & Wang, J. (2024) · Current Opinion in Toxicology · doi:10.1016/j.cotox.2024.100462 · Cited by 4
Andersen, M. E., Barutcu, A. R., Black, M. B., & Harrill, J. (2024) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2024.116956 · Cited by 5
The Hepatic Central Vein: Anatomical and Molecular Links to Perivenous Liver Biology
Mak, K. M. (2019) · Journal of Gastroenterology and Hepatology Research · doi:10.17554/j.issn.2224-3992.2019.08.834 · Cited by 2
Andersen, M. E., Barutcu, A. R., Black, M. B., & Harrill, J. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.02.583130 · Cited by 2
Nurul, S. A. S., Nurul, S. A. S., Hamzah, H. B., Rosly, S. M., Mohd, F. H. R., Abdullahi, A., Shanmugavelu, S., Mustapha, N. M., Mazlan, M., Azlan, A., et al. (2022) · The Thai Journal of Veterinary Medicine · doi:10.56808/2985-1130.3211 · Cited by 1
Delgado, T. C., Heras, J. D. L., & Martínez‐Chantar, M. L. (2025) · Neuromethods · doi:10.1007/978-1-0716-4354-9_13 · Cited by 1
Sharifi, F., Firoozabadi, B., Saidi, M. S., & Firoozbakhsh, K. K. (2018) · Scientia Iranica · doi:10.24200/sci.2018.4065.0 · Cited by 1
Fetal Origins of Adult Disease
Friedman, J., & Baker, P. R. (2016) · Elsevier eBooks · doi:10.1016/b978-0-323-35214-7.00015-9 · Cited by 1
Liver—Structure and Microanatomy
LeCluyse, E. L., Norona, L. M., & Presnell, S. C. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.05123-0 · Cited by 2
Elsayed, H. R. H., Nashar, E. M. E., & Abd-Elmonem, M. M. (2019) · Ultrastructural Pathology · doi:10.1080/01913123.2019.1696906 · Cited by 1
Trefts, E. (2019) · Cited by 1
Shafqat, F., Rehman, S. U., Khan, M. S., & Niaz, K. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-824315-2.00138-x · Cited by 1
NEW INSIGHTS INTO THE HEPATIC IRON PHENOTYPE OF BMP6 KNOCKOUT MICEPreprint
Besson‐Fournier, C., Willemetz, A., Latour, C., Robert, L., Coppin, H., Roth, M., & Canonne‐Hergaux, F. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.09.28.559941 · Cited by 2
The Hepatocyte Expansion Paradox: A Review of In Vitro Challenges and Advances
Kolahdouzmohammadi, M., Tjandra, N., Wu, K., Nikoumaram, R., & Oldani, G. (2026) · Cells · doi:10.3390/cells15161465
“The absence of paracrine and juxtacrine connections in monoculture systems exacerbates hepatocyte survival and growth potential [14].”
InfluentialKoral, K. (2016) · D-Scholarship@Pitt (University of Pittsburgh)
Transcriptional programs during mammalian cell prolifération
Rib, L. (2016) · IRIS
Obesity-induced hepatic changes during pregnancy
Grilo, L. F. (2019) · Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT)
Liver fibrosis causes periportalization of lobular zonation
Seddek, A. (2019) · EXCLI journal · doi:10.17179/excli2019-2078
Smith, A. A., Kennedy, R., Petersen, B. K., Ropella, G. E. P., & Hunt, C. A. (2021) · doi:10.1002/9781119772767.ch11
Structural and Thermal Patterning in 3D Bioprinted Hydrogels for Tissue Engineering
Corbett, D. C. (2020) · ResearchWorks at the University of Washington (University of Washington)
van der Reest, J., Stopka, S. A., Abdelmoula, W. M., Ruiz, D. F., Joshi, S., Ringel, A. E., Haigis, M. C., & Agar, N. Y. R. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.12.13.472421
Bergasa, N. V. (2021) · Springer eBooks · doi:10.1007/978-1-4471-4715-2_1
Editorial: Computational Modeling for Liver Surgery and Interventions
Christ, B., Dahmen, U., Radde, N. E., & Ricken, T. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.859522
A spatial atlas of Wnt and Frizzled receptor expression in adult mouse liverPreprint
Gayden, J. D., Hu, S., Joseph, P., Delgado, E. R., Liu, S., Bell, A. W., Puig, S., Monga, S. P., & Freyberg, Z. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.09.23.509269
Wang, Y., Rong, R., Wei, Y., Wang, T., Xiao, G., & Zhu, H. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.10.12.511979
Extracellular Vesicles-Based Cell-Free Therapy for Liver Regeneration
Najimi, M., & Haider, K. H. (2022) · Springer eBooks · doi:10.1007/978-981-19-2655-6_9
Najimi, M. (2023) · Springer eBooks · doi:10.1007/978-3-031-25378-2_11
Application of multiphoton microscopy for studying liver fibrosis
Zhang, X., Yu, X., Zhang, Z., Chen, J., Bai, Y., & Li, L. (2023) · doi:10.1117/12.2687112
Biomimetic injectable hydrogels of gelatin and hyaluronic acid for hepatic cell culture
Rodríguez-Fernández, J. (2024) · RiuNet (Universitat Politècnica de València) · doi:10.4995/thesis/10251/207128
Überblick zu den pädiatrischen Stoffwechselstörungen
Baghdasaryan, A., & Zöggeler, T. (2025) · Pädiatrie & Pädologie · doi:10.1007/s00608-025-01301-0
Sánchez-Guerrero, G., Chavez, D. K., Jaeschke, H., & Ramachandran, A. (2025) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.70448
Mesenchymal stem cell transplantation
Najimi, M., de Bodt, G., Jannone, G., & Sokal, E. M. (2025) · Elsevier eBooks · doi:10.1016/b978-0-12-823524-9.00013-7
Poluektova, D. V., Kshnyasev, I. A., & Davydova, Y. A. (2025) · Zoomorphology · doi:10.1007/s00435-025-00755-x
Pädiatrische Stoffwechselstörungen
Baghdasaryan, A., & Zöggeler, T. (2025) · Pädiatrie & Pädologie · doi:10.1007/s00608-025-01315-8
The plastic cellular states of liver cells
Huch, M. (2016) · VUBIR (Vrije Universiteit Brussel)
Tsuchiya, Y., Sotomaru, Y., Kanai, A., Maeda, S., & Kamata, H. (2026) · Cells · doi:10.3390/cells15060546
Preclinical studies on an extracorporeal bioartificial liver
Pasqua, M. (2020) · theses.fr (ABES) · doi:10.70675/80737894z778az43e7zba8bzdc445e5d436f
Feng, X., Feng, Y., Raza, S. H. A., Ma, Y. P., & Deng, H. (2026) · Frontiers in Genetics · doi:10.3389/fgene.2026.1781941 · Cited by 1
Gavlock, D. C., Castiglione, M. W., Wang, A., Varmazyad, M., Vernetti, L. A., Schurdak, M. E., Taylor, D. L., Brown, J. A., & Miedel, M. T. (2026) · Experimental Biology and Medicine · doi:10.3389/ebm.2026.11038
Guchhait, B., Tiwari, V., Yadav, R., Pal, S., Roy, S., & Tripathi, D. M. (2026) · Journal of Controlled Release · doi:10.1016/j.jconrel.2026.115080
Liver-on-a-chip: Applications for clinical modeling of liver disease using microscale systems
Brooks, N. M., Peczak, A., & Schwartz, R. E. (2026) · Hepatology · doi:10.1097/hep.0000000000001829
Histological manifestations of vitamin A toxicity in the liver
Cazzaniga, G., Lietz, G., & TINIAKOS, D. G. (2026) · Histopathology · doi:10.1111/his.70271
Zonated cholesterol sensing by SIRT2 drives MASLD-HCC
Zhang, Y., 龙喜带, Fu, Y., Tang, X., Luo, H., Zou, Z., He, W., Han, L., Li, Y., Luo, J., et al. (2026) · Cell Metabolism · doi:10.1016/j.cmet.2026.08.015
Metadata
- Authors
- Gebhardt, R.
- Affiliations
- Leipzig University (DE)
- Corresponding author
- Gebhardt, Rolf
- Venue
- World Journal of Gastroenterology
- Publisher
- Baishideng Publishing Group Inc.
- Published
- 2014
- Volume
- 20
- Issue
- 26
- Pages
- 8491
- ISSN
- 1007-9327 (ISSN-L)
- PMC
- PMC4093700
- OpenAlex
- W2013232839
- Cited by
- 275
- References
- 132
- Citations by year
- 2026: 9 · 2025: 18 · 2024: 19 · 2023: 25 · 2022: 30 · 2021: 29 · 2020: 24 · 2019: 40 · 2018: 28 · 2017: 23 · 2016: 18 · 2015: 11 · 2014: 1
- FWCI
- 2.35
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- World Journal of Gastroenterology (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Keywords
- liver zonation, metabolic zonation, liver parenchyma, liver homeostasis, hepatic metabolism, metabolic disorders, liver pathology, circadian rhythm, sex differences, transgenic mice
- MeSH terms
- Animals, Biotransformation, Energy Metabolism, Homeostasis, Humans, Liver, Liver Diseases, Signal Transduction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
