Spatiotemporal Metabolic Liver Zonation and Consequences on Pathophysiology
Open accessAbstract
Hepatocytes are the main workers in the hepatic factory, managing metabolism of nutrients and xenobiotics, production and recycling of proteins, and glucose and lipid homeostasis. Division of labor between hepatocytes is critical to coordinate complex complementary or opposing multistep processes, similar to distributed tasks at an assembly line. This so-called metabolic zonation has both spatial and temporal components. Spatial distribution of metabolic function in hepatocytes of different lobular zones is necessary to perform complex sequential multistep metabolic processes and to assign metabolic tasks to the right environment. Moreover, temporal control of metabolic processes is critical to align required metabolic processes to the feeding and fasting cycles. Disruption of this complex spatiotemporal hepatic organization impairs key metabolic processes with both local and systemic consequences. Many metabolic diseases, such as nonalcoholic steatohepatitis and diabetes, are associated with impaired metabolic liver zonation. Recent technological advances shed new light on the spatiotemporal gene expression networks controlling liver function and how their deregulation may be involved in a large variety of diseases. We summarize the current knowledge about spatiotemporal metabolic liver zonation and consequences on liver pathobiology.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
WNT/β-catenin emerged as a top hit in pathway analysis in HSC-depleted livers.
“Consistent with its master role in liver function and zonation9,20, WNT/β-catenin emerged as a top hit in our pathway analysis in HSC-depleted livers (Extended Data Fig. 4a).”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [9]
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 [9]
Many end-stage liver diseases are characterised by insufficient functional hepatocytes or maladaptive repair processes that can have fatal consequences.
“Many end-stage liver diseases are characterised by insufficient functional hepatocytes or maladaptive repair processes that can have fatal consequences.9”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [9]
Impaired metabolic function is associated with severe hepatic and systemic diseases.
“Impaired metabolic function is associated with severe hepatic and systemic diseases (reviewed in9).”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [9]
Hepatocyte diversity is a critical prerequisite for maintaining liver function.
“Although hepatocytes may look alike and appear similar, numerous functional and expression profiling studies have revealed their functional and anatomical diversity; this diversity of hepatocytes is a critical prerequisite for maintaining liver function (reviewed in9).”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [9]
Gluconeogenesis-regulating genes are induced in periportal hepatocytes following prolonged starvation at the end of the resting phase.
“For example, gluconeogenesis-regulating genes are induced in periportal hepatocytes following prolonged starvation at the end of the resting phase.9,26”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [9]
Midzonal hepatocytes generally express lower levels of metabolic genes, while periportal and pericentral hepatocytes express higher levels of their respective zone-specific metabolic genes.
“Given the generally lower expression of metabolic genes in midzonal hepatocytes, along with higher expression of periportal and pericentral metabolic genes in their respective zones”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [9]
Hepatocyte zonation matches function to the physiologic environment in both space and time.
“Hepatocyte zonation matches function to the physiologic environment in both space and time5.”
From Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution (2025) · cites this paper as [5]
Persistent changes in hepatocyte identity are associated with most liver diseases and are often accompanied by severe hepatic and systemic consequences.
“Unfortunately, persistent changes in hepatocyte identity are associated with most liver diseases and are often accompanied by severe hepatic and systemic consequences.9”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [9]
Changes in porto-central WNT/β-catenin activity or oxygen gradient can significantly affect hepatocyte identity.
“As described in previous sections, changes, for example in porto-central WNT/β-catenin activity or oxygen gradient, can significantly affect hepatocyte identity.9,41,91”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [9]
The citation lists haven’t been fetched yet
References 170 · Cited by 113
- Authors
- Martini, T., Naef, F., & Tchorz, J. S.
- Affiliations
- Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland;
- Novartis (Switzerland) (CH)
- ORCID
- Tchorz, Jan S.
- Venue
- Annual Review of Pathology: Mechanisms of Disease
- Publisher
- Annual Reviews
- Published
- 2023-01-24
- Volume
- 18
- Issue
- 1
- Pages
- 439-466
- ISSN
- 1553-4006 (ISSN-L)
- 1553-4014
- OpenAlex
- W4317864609
- Cited by
- 113
- References
- 170
- Citations by year
- 2026: 40 · 2025: 38 · 2024: 24 · 2023: 11
- FWCI
- 4.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Annual Review of Pathology Mechanisms of Disease (publishedVersion, cc-by)
- PubMed (publishedVersion)
- The Novartis Repository (Novartis) (acceptedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- 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
- hepatocyte zonation, spatiotemporal gene expression, hepatic metabolism, glucose homeostasis, lipid homeostasis, xenobiotic metabolism, nonalcoholic steatohepatitis, diabetes mellitus
- MeSH terms
- Homeostasis, Humans, Liver, Hepatocytes, Non-alcoholic Fatty Liver Disease
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
