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Loss of hepatocyte identity following aberrant YAP activation: A key mechanism in alcoholic hepatitis
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BACKGROUND & AIMS: Alcoholic hepatitis (AH) is a life-threatening disease with limited therapeutic options, as the molecular mechanisms leading to death are not well understood. This study evaluates the Hippo/Yes-associated protein (YAP) pathway which has been shown to play a role in liver regeneration. METHOD: The Hippo/YAP pathway was dissected in explants of patients transplanted for AH or alcohol-related cirrhosis and in control livers, using RNA-seq, real-time PCR, western blot, immunohistochemistry and transcriptome analysis after laser microdissection. We transfected primary human hepatocytes with constitutively active YAP (YAPS127A) and treated HepaRG cells and primary hepatocytes isolated from AH livers with a YAP inhibitor. We also used mouse models of ethanol exposure (Lieber de Carli) and liver regeneration (carbon tetrachloride) after hepatocyte transduction of YAPS127A. RESULTS: In AH samples, RNA-seq analysis and immunohistochemistry of total liver and microdissected hepatocytes revealed marked downregulation of the Hippo pathway, demonstrated by lower levels of active MST1 kinase and abnormal activation of YAP in hepatocytes. Overactivation of YAP in hepatocytes in vitro and in vivo led to biliary differentiation and loss of key biological functions such as regeneration capacity. Conversely, a YAP inhibitor restored the mature hepatocyte phenotype in abnormal hepatocytes taken from patients with AH. In ethanol-fed mice, YAP activation using YAPS127A resulted in a loss of hepatocyte differentiation. Hepatocyte proliferation was hampered by YAPS127A after carbon tetrachloride intoxication. CONCLUSION: Aberrant activation of YAP plays an important role in hepatocyte transdifferentiation in AH, through a loss of hepatocyte identity and impaired regeneration. Thus, targeting YAP is a promising strategy for the treatment of patients with AH. LAY SUMMARY: Alcoholic hepatitis is characterized by inflammation and a life-threatening alteration of liver regeneration, although the mechanisms behind this have not been identified. Herein, we show that liver samples from patients with alcoholic hepatitis are characterized by profound deregulation of the Hippo/YAP pathway with uncontrolled activation of YAP in hepatocytes. We used human cell and mouse models to show that inhibition of YAP reverts this hepatocyte defect and could be a novel therapeutic strategy for alcoholic hepatitis.
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Hep-IDCONNECT transcription factors showed reduced expression levels in microdissected hepatocytes from alcohol-related human liver cirrhosis.
“Similar observations were made using transcriptomic data obtained from microdissected hepatocytes from alcohol‐related human liver cirrhosis (Bou Saleh et al, 2021; Fig 2E).”
From An extended transcription factor regulatory network controls hepatocyte identity (2023) · cites this paper as Bou Saleh et al, 2021
The Results section on microdissected tissue (Fig. 3A–D; page unavailable) reports transcriptomic changes in cirrhotic hepatocytes compared with controls, so the cited dataset is relevant. It identifies a significant loss of hepatic-identity gene expression in alcoholic hepatitis, but does not establish reduced expression of Hep-IDCONNECT transcription factors specifically in hepatocytes from alcohol-related cirrhosis. (LLM, conf=0.82)
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References 35 · Cited by 83
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Metadata
- Authors
- Bou Saleh, M., Louvet, A., Ntandja-Wandji, L. C., Boleslawski, E., Gnemmi, V., Lassailly, G., Truant, S., Maggiotto, F., Ningarhari, M., Artru, F., Anglo, E., Sancho-Bru, P., Corlu, A., Argemi, J., Dubois-Chevalier, J., Dharancy, S., Eeckhoute, J., Bataller, R., Mathurin, P., & Dubuquoy, L.
- Affiliations
- Inserm (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- UPMC Health System (US)
- Corresponding author
- Mathurin, Philippe
- Dubuquoy, Laurent
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2021-10
- Volume
- 75
- Issue
- 4
- Pages
- 912-923
- ISSN
- 0168-8278 (ISSN-L)
- PMC
- PMC11868489
- OpenAlex
- W3168356415
- Cited by
- 83
- References
- 35
- Citations by year
- 2026: 6 · 2025: 23 · 2024: 20 · 2023: 12 · 2022: 19 · 2021: 3
- FWCI
- 7.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Hepatology (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, other-oa)
- LillOA (Université de Lille (University Of Lille)) (submittedVersion, other-oa)
- LillOA (Université de Lille (University Of Lille)) (submittedVersion)
- Funders
- NIAAA (1U01AA021908)
- European Commission (1U01AA021908, PI17/00673, FIS PI20/00765)
- FRM (DEQ20150331724)
- FEDER
- AFEF
- INSERM
- National Institutes of Health
- European Regional Development Fund
- Agence Nationale de la Recherche (ANR-10-LABX-0046)
- Hauts-de-France Region
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Keywords
- alcoholic hepatitis, YAP, Hippo signaling pathway, hepatocyte transdifferentiation, biliary differentiation, liver regeneration, MST1, YAP inhibitor, hepatocyte proliferation, ethanol-induced liver injury, carbon tetrachloride, liver transplantation
- MeSH terms
- YAP-Signaling Proteins, Animals, Disease Models, Animal, Female, France, Hepatitis, Alcoholic, Hepatocytes, Mice
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