Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease

J Hepatol. 2015 Oct;63(4):962-70. doi: 10.1016/j.jhep.2015.05.031. Epub 2015 Jun 10.

Abstract

Background & aims: 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.

Conclusion: YAP+RDC promote scarring, rather than effective regeneration, during NASH.

Keywords: Ductular reaction; Fibrosis; Non-alcoholic steatohepatitis; Regeneration; YAP.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / biosynthesis
  • Adaptor Proteins, Signal Transducing / genetics*
  • Adult
  • Animals
  • Bile Ducts, Intrahepatic / metabolism*
  • Bile Ducts, Intrahepatic / pathology
  • Biopsy
  • Blotting, Western
  • Cell Cycle Proteins
  • Disease Progression
  • Female
  • Gene Expression Regulation*
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Immunohistochemistry
  • Liver Cirrhosis, Experimental / metabolism
  • Liver Cirrhosis, Experimental / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology*
  • Phosphoproteins / biosynthesis
  • Phosphoproteins / genetics*
  • RNA, Messenger / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Phosphoproteins
  • RNA, Messenger
  • Yap1 protein, mouse