title: Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease.
abstract: OBJECTIVE
  Mechanisms that regulate regeneration of injured livers are complex. YAP, a stem cell associated factor, controls liver growth in healthy adult mice. Increasing nuclear localization of YAP triggers accumulation of reactive-appearing ductular cells (YAP+RDC) with liver progenitor capabilities. The significance of YAP activation, and mechanisms involved, are unknown in diseased livers. We evaluated the hypothesis that YAP is more activated in injured livers that are scarring than in those that are regenerating effectively.
  
  
  METHODS
  Immunohistochemistry and qRT-PCR analysis were used to localize and quantify changes in YAP and RDC in 52 patients with non-alcoholic fatty liver disease (NAFLD) and two mouse models of diet-induced non-alcoholic steatohepatitis (NASH). Results were correlated with liver disease severity, metabolic risk factors, and factors proven to control NAFLD progression.
  
  
  RESULTS
  YAP increased in NAFLD where it mainly localized in nuclei of RDC that expressed progenitor markers. Accumulation of YAP+RDC paralleled the severity of hepatocyte injury and accumulation of Sonic hedgehog, but not steatosis or metabolic risk factors. YAP+RDC expressed osteopontin, a Shh-regulated fibrogenic factor. Myofibroblast accumulation, fibrosis, and numbers of YAP+RDC strongly correlated. In murine NASH models, atrophic fibrotic livers contained significantly more YAP+RDC than livers with less severe NASH.
  
  
  CONCLUSIONS
  YAP+RDC promote scarring, rather than effective regeneration, during NASH.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA; Gastroenterology Department, Hospital de Santa Maria, CHLN, Lisbon, Portugal.
authors.forename: Mariana Verdelho
authors.initials: MV
authors.lastname: Machado
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Gregory Alexander
authors.initials: GA
authors.lastname: Michelotti
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Thiago Almeida
authors.initials: TA
authors.lastname: Pereira
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Guanhua
authors.initials: G
authors.lastname: Xie
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Premont
authors.affiliation: Gastroenterology Department, Hospital de Santa Maria, CHLN, Lisbon, Portugal.
authors.forename: Helena
authors.initials: H
authors.lastname: Cortez-Pinto
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: diehl004@mc.duke.edu.
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics*; D000328:Adult; D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism* / Q000473:pathology; D001706:Biopsy; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism / Q000473:pathology*; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse
keywords: Ductular reaction; Fibrosis; Non-alcoholic steatohepatitis; Regeneration; YAP