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Loss of hepatocyte identity following aberrant YAP activation: a key mechanism in alcoholic hepatitis

Abstract : Background & Aims Alcoholic hepatitis (AH) is a life-threatening disease with limited therapeutic options, because understanding of the molecular drivers 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 alcoholic cirrhosis and in control livers, using RNA-Seq, real-time PCR, Western blot, immunohistochemistry (IHC) 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 (CCl4) after hepatocyte transduction of YAPS127A. Results In AH samples RNA-Seq analysis and IHC of total liver and microdissected hepatocytes revealed marked down-regulation of Hippo shown by lower 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, treatment of abnormal hepatocytes from AH patients with a YAP inhibitor restored the mature hepatocyte phenotype. In ethanol-fed mice, YAP activation using YAPS127A resulted in a loss of hepatocyte differentiation. Hepatocyte proliferation was hampered using YAPS127A after CCl4 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 (AH) is characterized by inflammation and a life-threatening alteration of liver regeneration by mechanisms that have not been identified. We show that AH livers are characterized by profound deregulation of the Hippo/YAP pathway with uncontrolled activation of the transcription co-factor YAP in hepatocytes. YAP activation in hepatocytes leads to their transdifferentiation towards a biliary phenotype associated with inflammation as well as a regeneration defect. YAP inhibition reverts this hepatocyte defect and appears to be an original therapeutic strategy of regenerative treatment for AH.
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Contributeur : Lilloa Université de Lille <>
Soumis le : mardi 6 juillet 2021 - 16:30:36
Dernière modification le : vendredi 9 juillet 2021 - 03:46:47


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Mohamed Bou Saleh, Alexandre Louvet, Line Carolle Ntandja-Wandji, Emmanuel Boleslawski, Viviane Gnemmi, et al.. Loss of hepatocyte identity following aberrant YAP activation: a key mechanism in alcoholic hepatitis. Journal of Hepatology, Elsevier, 2021, ⟨10.1016/j.jhep.2021.05.041⟩. ⟨hal-03279721⟩



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