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Cited by 471Wnt/β-catenin signaling in development and cancerLiver physiology and pathologyLiver Disease Diagnosis and Treatment

Wnt/β-Catenin Signaling in Liver Development, Homeostasis, and Pathobiology

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Russell, Jacquelyn O., Monga, Satdarshan P.·2018·Annual Review of Pathology: Mechanisms of Disease
DOI 10.1146/annurev-pathol-020117-044010PMC PMC5927358
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Abstract

The liver is an organ that performs a multitude of functions, and its health is pertinent and indispensable to survival. Thus, the cellular and molecular machinery driving hepatic functions is of utmost relevance. The Wnt signaling pathway is one such signaling cascade that enables hepatic homeostasis and contributes to unique hepatic attributes such as metabolic zonation and regeneration. The Wnt/β-catenin pathway plays a role in almost every facet of liver biology. Furthermore, its aberrant activation is also a hallmark of various hepatic pathologies. In addition to its signaling function, β-catenin also plays a role at adherens junctions. Wnt/β-catenin signaling also influences the function of many different cell types. Due to this myriad of functions, Wnt/β-catenin signaling is complex, context-dependent, and highly regulated. In this review, we discuss the Wnt/β-catenin signaling pathway, its role in cell-cell adhesion and liver function, and the cell type–specific roles of Wnt/β-catenin signaling as it relates to liver physiology and pathobiology.

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Crossref · 10.1146/annurev-pathol-020117-044010

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  • RSPO injections reversibly increased liver size by inducing hepatocyte proliferation, whereas WNT/β-catenin signalling blockade resulted in smaller livers.

    “RSPO injections reversibly increased liver size by inducing hepatocyte proliferation, whereas WNT/β-catenin signalling blockade resulted in smaller livers.44,90,91”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [91]

    The 'Wnt/β-Catenin Signaling in Hepatocytes' section (page unavailable) reports significantly reduced liver weight in mice lacking hepatocyte LGR4/LGR5 or Wnt coreceptors, supporting the smaller-liver part. Our copy does not report that RSPO injections reversibly increased liver size through hepatocyte proliferation; its reported proliferation-related increase followed liver-specific β-catenin overexpression instead. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Activating mutations in the WNT/β-catenin pathway are frequently found in liver tumours, and hepatocytes with high WNT/β-catenin activity are highly susceptible to malignant transformation in experimental tumour models.

    “Activating mutations in the WNT/β-catenin pathway are frequently found in liver tumours and hepatocytes with high WNT/β-catenin activity are highly susceptible to malignant transformation in experimental tumour models.50,90,91,85”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [91]

    The “Wnt/β-catenin signaling in liver tumors” discussion reports β-catenin activation in 20–35% of hepatocellular carcinomas and says mice with activated signaling are more susceptible to DEN-induced liver cancer. It does not establish that high-activity hepatocytes are generally *highly* susceptible to malignant transformation: β-catenin activation alone did not produce spontaneous liver cancer in the mouse models described. No page number is supplied in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Frequent mutations in HCC in downstream pathway nodes, such as AXIN1-inactivating or β-catenin-stabilising mutations, highlight the risk associated with uncontrolled WNT/β-catenin signalling in hepatocytes.

    “Frequent mutations in HCC in downstream pathway nodes, such as AXIN1-inactivating or β-catenin-stabilising mutations, highlight the risk associated with uncontrolled WNT/β-catenin signalling in hepatocytes91”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [91]

    The “Wnt/β-Catenin Signaling in Hepatocytes” section (page unavailable) reports β-catenin activation in 20–35% of HCC cases and describes CTNNB1 mutations that stabilize the protein. It also mentions AXIN1 mutations in HCC, but does not establish that they are frequently inactivating. The section links pathway activation to cancer risk while noting that β-catenin activation alone did not cause spontaneous HCC in the mouse models discussed. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • 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 [91]

    In “Wnt/β-Catenin Signaling in Hepatocytes” (page not provided), the review reports that altering β-catenin activity can shift hepatocytes between periportal and pericentral phenotypes. That supports the WNT/β-catenin part of the claim, but our copy does not establish that changes in an oxygen gradient affect hepatocyte identity. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Termination of liver regeneration occurs via redundant and overlapping pathways-including TGF-β, Hippo-YAP, and Wnt/β-catenin, GPC3 activation-each contributing to halting hepatocyte proliferation and suppressing further liver regrowth.

    “Rather than a single “off switch”, termination of liver regeneration occurs via redundant and overlapping pathways—including TGF-β, Hippo-YAP, and Wnt/β-catenin, GPC3 activation - each contributing to halting hepatocyte proliferation and suppressing further liver regrowth[96,100].”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [100]

    In “Wnt/β-Catenin Signaling in Hepatocytes” (page not provided), the review describes inhibitory Wnt5a as a possible mechanism for terminating hepatocyte proliferation after partial hepatectomy. It does not support the broader attribution that TGF-β, Hippo-YAP, and GPC3 activation are overlapping termination pathways that each halt proliferation. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Russell, J. O., & Monga, S. P.
Affiliations
University of Pittsburgh (US)
Corresponding author
Monga, Satdarshan P.
ORCID
Venue
Annual Review of Pathology: Mechanisms of Disease
Publisher
Annual Reviews
Published
2018-01-24
Volume
13
Issue
1
Pages
351-378
ISSN
  • 1553-4006 (ISSN-L)
  • 1553-4014
DOI
10.1146/annurev-pathol-020117-044010
PMC
PMC5927358
OpenAlex
W2767823610
Cited by
471
References
17
Citations by year
2026: 30 · 2025: 82 · 2024: 64 · 2023: 69 · 2022: 68 · 2021: 68 · 2020: 44 · 2019: 36 · 2018: 7 · 2014: 1
FWCI
2.22
Type
journal article
Language
en
Open access
Locations
  • Annual Review of Pathology Mechanisms of Disease (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (R01CA204586)
  • National Institute of Diabetes and Digestive and Kidney Diseases (F31DK115017, R01DK095498, R01DK100287, R01DK062277)
  • National Institute of Biomedical Imaging and Bioengineering (T32EB001026)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Keywords
Wnt/β-catenin signaling, liver development, hepatic homeostasis, liver regeneration, metabolic zonation, cell-cell adhesion, adherens junctions, cell type-specific signaling
MeSH terms
Animals, Humans, Liver, Wnt Signaling Pathway

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