The Hippo pathway effector YAP controls mouse hepatic stellate cell activation
Abstract
Background & aims Hepatic stellate cell activation is a wound-healing response to liver injury. However, continued activation of stellate cells during chronic liver damage causes excessive matrix deposition and the formation of pathological scar tissue leading to fibrosis and ultimately cirrhosis. The importance of sustained stellate cell activation for this pathological process is well recognized, and several signalling pathways that can promote stellate cell activation have been identified, such as the TGFβ-, PDGF-, and LPS-dependent pathways. However, the mechanisms that trigger and drive the early steps in activation are not well understood. Methods and results We identified the Hippo pathway and its effector YAP as a key pathway that controls stellate cell activation. YAP is a transcriptional co-activator and we found that it drives the earliest changes in gene expression during stellate cell activation. Activation of stellate cells in vivo by CCl4 administration to mice or activation in vitro caused rapid activation of YAP as revealed by its nuclear translocation and by the induction of YAP target genes. YAP was also activated in stellate cells of human fibrotic livers as evidenced by its nuclear localization. Importantly, knockdown of YAP expression or pharmacological inhibition of YAP prevented hepatic stellate cell activation in vitro and pharmacological inhibition of YAP impeded fibrogenesis in mice. Conclusions YAP activation is a critical driver of hepatic stellat…
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In the liver, hepatic stellate cells regulate fibrosis through activation of MRTFA and YAP cofactors, controlling expression of several profibrotic proteins.
“In the liver, HSCs regulate fibrosis through the activation of MRTFA and YAP cofactors, controlling the expression of several profibrotic proteins [17, 18].”
From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [18]
Pharmaceutical inhibition of MRTFA and YAP cofactors significantly attenuates extracellular matrix deposition and expression of profibrotic regulators.
“Pharmaceutical inhibition of these cofactors significantly attenuates ECM deposition and the expression of profibrotic regulators [18, 19].”
From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [18]
It has been demonstrated that stiffness regulates activation of MRTcoF in liver fibrosis.
“It has been demonstrated that stiffness regulates the activation of MRTcoF in liver fibrosis; however, their simultaneous regulation has not been characterised entirely [17, 18].”
From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [18]
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- Authors
- Mannaerts, I., Leite, S. B., Verhulst, S., Claerhout, S., Eysackers, N., Thoen, L. F. R., Hoorens, A., Reynaert, H., Halder, G., & van Grunsven, L. A.
- Affiliations
- Vrije Universiteit Brussel (BE)
- KU Leuven (BE)
- Universitair Ziekenhuis Brussel (BE)
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 63
- Issue
- 3
- Pages
- 679-688
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W2154530183
- Cited by
- 410
- References
- 46
- Citations by year
- 2026: 37 · 2025: 44 · 2024: 43 · 2023: 29 · 2022: 60 · 2021: 49 · 2020: 35 · 2019: 38 · 2018: 29 · 2017: 23 · 2016: 19 · 2015: 4
- FWCI
- 14.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- YAP, Hippo signaling pathway, hepatic stellate cell activation, liver fibrosis, YAP inhibition, carbon tetrachloride-induced liver injury, nuclear translocation, transcriptional coactivator, liver cirrhosis, fibrogenesis
- MeSH terms
- Hippo Signaling Pathway, YAP-Signaling Proteins, Animals, Humans, Liver Cirrhosis, Mice, Inbred BALB C, Phosphoproteins, Transcription Factors, Signal Transduction, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Adaptor Proteins, Signal Transducing, Mice, Hepatic Stellate Cells
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