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Cited by 87Liver physiology and pathologyHippo pathway signaling and YAP/TAZDrug-Induced Hepatotoxicity and Protection

Regeneration Defects in Yap and Taz Mutant Mouse Livers Are Caused by Bile Duct Disruption and Cholestasis

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Verboven, Elisabeth, Moya, Iván M., Sansores-Garcia, Leticia, Xie, Jun, Hillen, Hanne, Kowalczyk, Weronika, Vella, Gerlanda, Verhulst, Stefaan +14 more·2021·Gastroenterology
DOI 10.1053/j.gastro.2020.10.035
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Abstract

BACKGROUND AND AIMS: The Hippo pathway and its downstream effectors YAP and TAZ (YAP/TAZ) are heralded as important regulators of organ growth and regeneration. However, different studies provided contradictory conclusions about their role during regeneration of different organs, ranging from promoting proliferation to inhibiting it. Here we resolve the function of YAP/TAZ during regeneration of the liver, where Hippo's role in growth control has been studied most intensely. METHODS: We evaluated liver regeneration after carbon tetrachloride toxic liver injury in mice with conditional deletion of Yap/Taz in hepatocytes and/or biliary epithelial cells, and measured the behavior of different cell types during regeneration by histology, RNA sequencing, and flow cytometry. RESULTS: We found that YAP/TAZ were activated in hepatocytes in response to carbon tetrachloride toxic injury. However, their targeted deletion in adult hepatocytes did not noticeably impair liver regeneration. In contrast, Yap/Taz deletion in adult bile ducts caused severe defects and delay in liver regeneration. Mechanistically, we showed that Yap/Taz mutant bile ducts degenerated, causing cholestasis, which stalled the recruitment of phagocytic macrophages and the removal of cellular corpses from injury sites. Elevated bile acids activated pregnane X receptor, which was sufficient to recapitulate the phenotype observed in mutant mice. CONCLUSIONS: Our data show that YAP/TAZ are practically dispensable in hepatocytes for liver development and regeneration. Rather, YAP/TAZ play an indirect role in liver regeneration by preserving bile duct integrity and securing immune cell recruitment and function.

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  • Activated YAP signalling reversibly increased liver size, but its deletion did not affect liver size during homeostasis.

    “While activated YAP signalling reversibly increased liver size,93 its deletion did not affect liver size during homeostasis.57,58,94”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [58]

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References 52 · Cited by 87

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Authors
Verboven, E., Moya, I. M., Sansores-Garcia, L., Xie, J., Hillen, H., Kowalczyk, W., Vella, G., Verhulst, S., Castaldo, S. A., Algueró-Nadal, A., Romanelli, L., Mercader-Celma, C., Souza, N. A., Soheily, S., Van Huffel, L., Van Brussel, T., Lambrechts, D., Roskams, T., Lemaigre, F. P., Bergers, G., van Grunsven, L. A., & Halder, G.
Affiliations
  • Vlaams Instituut voor Biotechnologie (BE)
  • Vrije Universiteit Brussel (BE)
  • KU Leuven (BE)
  • de Duve Institute (BE)
Corresponding author
Halder, Georg
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2021-02
Volume
160
Issue
3
Pages
847-862
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2020.10.035
OpenAlex
W3096901923
Cited by
87
References
52
Citations by year
2026: 7 · 2025: 16 · 2024: 12 · 2023: 13 · 2022: 34 · 2021: 5
FWCI
7.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Gastroenterology (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Lirias (KU Leuven) (submittedVersion, other-oa)
  • DIAL (Catholic University of Leuven) (submittedVersion, other-oa)
  • VUBIR (Vrije Universiteit Brussel) (submittedVersion)
Funders
  • Fonds Wetenschappelijk Onderzoek
  • Stichting Tegen Kanker
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
YAP/TAZ, Hippo signaling pathway, liver regeneration, cholestasis, carbon tetrachloride-induced liver injury, conditional gene deletion, hepatocytes, cholangiocytes, bile acids, pregnane X receptor, macrophage recruitment, phagocytosis, liver development
MeSH terms
Hippo Signaling Pathway, YAP-Signaling Proteins, Animals, Bile Ducts, Carbon Tetrachloride, Cholestasis, Disease Models, Animal, Humans, Liver, Liver Regeneration, Signal Transduction, Protein Serine-Threonine Kinases, Mice, Knockout, Hepatocytes, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, Chemical and Drug Induced Liver Injury

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