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

Adult Male 0303 health sciences Biopsy Blotting, Western Cell Cycle Proteins Liver Cirrhosis, Experimental Phosphoproteins Immunohistochemistry 3. Good health Mice, Inbred C57BL Mice 03 medical and health sciences Bile Ducts, Intrahepatic Gene Expression Regulation Non-alcoholic Fatty Liver Disease Disease Progression Hepatocytes Animals Humans Female RNA, Messenger Adaptor Proteins, Signal Transducing
DOI: 10.1016/j.jhep.2015.05.031 Publication Date: 2015-06-12T23:29:05Z
ABSTRACT
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.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.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.YAP+RDC promote scarring, rather than effective regeneration, during NASH.
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