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.
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In vivo, hepatocytes interact with a complex extracellular matrix of collagens, laminins and fibronectin that provides biochemical and biomechanical cues modulating polarity, survival, and proliferation.
“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]
The Introduction describes hepatocytes arranged between sinusoids within regular liver lobules, supporting the lobular-architecture part of the citing sentence. Our copy does not describe hepatocyte interactions with an ECM of collagens, laminins and fibronectin; searches for those terms and for ECM-related cues found no supporting passage. It also does not attribute the claimed effects on polarity, survival and proliferation to ECM. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAbsence of paracrine and juxtacrine connections from non-parenchymal cells in monoculture systems exacerbates hepatocyte survival and growth potential.
“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]
The NEW METHODS section distinguishes hepatocytes from nonparenchymal cells when discussing tissue-analysis methods, but does not assess monoculture or hepatocyte survival and growth. Searches for paracrine and juxtacrine connections, monoculture, and hepatocyte culture found no passage in our copy establishing the claimed effect. (LLM, conf=0.72)
Experimental — accuracy not yet measuredFailure to recapitulate the complexity of the hepatic environment is a major contributor to hepatocyte dedifferentiation.
“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]
The RESEARCH AREAS passage discusses partial dedifferentiation as a possible consequence of aberrant gene expression in liver zonation. It does not address whether failure to recreate the hepatic environment contributes to hepatocyte dedifferentiation, or whether that is a major contributor. Searches for hepatic-environment complexity, primary culture, and dedifferentiation found no passage establishing that causal claim. (LLM, conf=0.75)
Experimental — accuracy not yet measuredIn vitro conventional culture substrates simplify the hepatic environment, leading to dysregulated integrin signaling and accelerated functional decline.
“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]
The Introduction describes the liver’s structural and functional zonation, and NEW METHODS discusses tissue sampling, but neither addresses conventional culture substrates. Searches for integrin signaling, culture substrates, and functional decline found no passage in our copy linking them as claimed. (LLM, conf=0.73)
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- 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 › Epidemiology › 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
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