title: Histone deacetylase 4 promotes cholestatic liver injury in the absence of prohibitin-1.
abstract: Prohibitin-1 (PHB1) is an evolutionarily conserved pleiotropic protein that participates in diverse processes depending on its subcellular localization and interactome. Recent data have indicated a diverse role for PHB1 in the pathogenesis of obesity, cancer, and inflammatory bowel disease, among others. Data presented here suggest that PHB1 is also linked to cholestatic liver disease. Expression of PHB1 is markedly reduced in patients with primary biliary cirrhosis and biliary atresia or with Alagille syndrome, two major pediatric cholestatic conditions. In the experimental model of bile duct ligation, silencing of PHB1 induced liver fibrosis, reduced animal survival, and induced bile duct proliferation. Importantly, the modulatory effect of PHB1 is not dependent on its known mitochondrial function. Also, PHB1 interacts with histone deacetylase 4 (HDAC4) in the presence of bile acids. Hence, PHB1 depletion leads to increased nuclear HDAC4 content and its associated epigenetic changes. Remarkably, HDAC4 silencing and the administration of the HDAC inhibitor parthenolide during obstructive cholestasis in vivo promote genomic reprogramming, leading to regression of the fibrotic phenotype in liver-specific Phb1 knockout mice.
  
  
  CONCLUSIONS
  PHB1 is an important mediator of cholestatic liver injury that regulates the activity of HDAC4, which controls specific epigenetic markers; these results identify potential novel strategies to treat liver injury and fibrosis, particularly as a consequence of chronic cholestasis.
authors.affiliation: CIC bioGUNE, Metabolomics Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Barbier-Torres
authors.affiliation: CIC bioGUNE, Metabolomics Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia, Spain.
authors.forename: Naiara
authors.initials: N
authors.lastname: Beraza
authors.affiliation: CIC bioGUNE, Metabolomics Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Fernández-Tussy
authors.affiliation: CIC bioGUNE, Metabolomics Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Lopitz-Otsoa
authors.affiliation: CIC bioGUNE, Metabolomics Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Fernández-Ramos
authors.affiliation: CIC bioGUNE, Metabolomics Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia, Spain.
authors.forename: Imanol
authors.initials: I
authors.lastname: Zubiete-Franco
authors.affiliation: CIC bioGUNE, Metabolomics Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Varela-Rey
authors.affiliation: CIC bioGUNE, Metabolomics Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia, Spain.
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Delgado
authors.affiliation: CIC bioGUNE, Metabolomics Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Gutiérrez
authors.affiliation: CIC bioGUNE, Proteomics Unit, Bizkaia, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Anguita
authors.affiliation: Liver Unit, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), IDIBAPS, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Pares
authors.affiliation: Biodonostia Research Health Institute, Donostia University Hospital (HUD), University of the Basque Country (UPV/EHU), Ikerbasque, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), San Sebastian, Spain.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Banales
authors.affiliation: Department of Gastroenterology, Azienda Ospedaliero-Universitaria and University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Villa
authors.affiliation: Liver Unit, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), IDIBAPS, Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Caballería
authors.affiliation: La Paz University Hospital Health Research Institute-IdiPAZ, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Alvarez
authors.affiliation: Division of Gastroenterology, Cedars-Sinai Medical Center, and USC Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA.
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
authors.affiliation: CIC bioGUNE, Metabolomics Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Mato
authors.affiliation: CIC bioGUNE, Metabolomics Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia, Spain.
authors.forename: María Luz
authors.initials: ML
authors.lastname: Martínez-Chantar
mesh_terms: D000818:Animals; D002780:Cholestasis, Intrahepatic / Q000150:complications / Q000201:enzymology*; D006655:Histone Deacetylases / Q000502:physiology*; D006801:Humans; D008107:Liver Diseases / Q000201:enzymology* / Q000209:etiology; D008297:Male; D051379:Mice; D000091402:Prohibitins; D012097:Repressor Proteins / Q000502:physiology*
chemical_list: C000717328:PHB protein, human; D000091402:Prohibitins; D012097:Repressor Proteins; C400300:HDAC4 protein, human; D006655:Histone Deacetylases