Loss of hepatocyte identity following ...
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Autre communication scientifique (congrès sans actes - poster - séminaire...)
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Title :
Loss of hepatocyte identity following aberrant YAP activation: a key mechanism in alcoholic hepatitis
Author(s) :
Bou Saleh, Mohamed [Auteur]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Louvet, Alexandre [Auteur]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Ntandja-Wandji, Line Carolle [Auteur]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Boleslawski, Emmanuel [Auteur]
Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 [ONCO-THAI]
Gnemmi, Viviane [Auteur]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Lassailly, Guillaume [Auteur]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Truant, Stéphanie [Auteur]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Maggiotto, François [Auteur]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Ningarhari, Massih [Auteur]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Artru, Florent [Auteur]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Anglo, Emilie [Auteur]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Sancho-Bru, Pau [Auteur]
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Corlu, Anne [Auteur]
Nutrition, Métabolismes et Cancer [NuMeCan]
Argemi, Josepmaria [Auteur]
University of Pittsburgh [PITT]
Dubois-Chevalier, Julie [Auteur]
Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD]
Dharancy, Sébastien [Auteur]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Eeckhoute, Jérôme [Auteur]
Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD]
Bataller, Ramon [Auteur]
University of Pittsburgh [PITT]
Mathurin, Philippe [Auteur correspondant]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Dubuquoy, Laurent [Auteur correspondant]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Louvet, Alexandre [Auteur]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Ntandja-Wandji, Line Carolle [Auteur]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Boleslawski, Emmanuel [Auteur]
Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 [ONCO-THAI]
Gnemmi, Viviane [Auteur]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Lassailly, Guillaume [Auteur]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Truant, Stéphanie [Auteur]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Maggiotto, François [Auteur]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Ningarhari, Massih [Auteur]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Artru, Florent [Auteur]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Anglo, Emilie [Auteur]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Sancho-Bru, Pau [Auteur]
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Corlu, Anne [Auteur]
Nutrition, Métabolismes et Cancer [NuMeCan]
Argemi, Josepmaria [Auteur]
University of Pittsburgh [PITT]
Dubois-Chevalier, Julie [Auteur]
Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD]
Dharancy, Sébastien [Auteur]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Eeckhoute, Jérôme [Auteur]
Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD]
Bataller, Ramon [Auteur]
University of Pittsburgh [PITT]
Mathurin, Philippe [Auteur correspondant]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Dubuquoy, Laurent [Auteur correspondant]
Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)]
Publisher :
Elsevier
Publication date :
2021-06-12
English keyword(s) :
Alcoholic hepatitis
Hepatocyte
Hippo/YAP
Regeneration
Transdifferentiation
Hepatocyte
Hippo/YAP
Regeneration
Transdifferentiation
HAL domain(s) :
Sciences cognitives
English abstract : [en]
Background & AimsAlcoholic 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 ...
Show more >Background & AimsAlcoholic 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.MethodThe 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.ResultsIn 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.ConclusionAberrant 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 summaryAlcoholic 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.Show less >
Show more >Background & AimsAlcoholic 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.MethodThe 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.ResultsIn 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.ConclusionAberrant 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 summaryAlcoholic 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.Show less >
Language :
Anglais
Peer reviewed article :
Oui
Audience :
Internationale
Popular science :
Non
Source :
Submission date :
2021-07-08T02:31:04Z
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