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

详细信息    查看全文

• 作者：Mariana Verdelho Machado¹ ; ² ; Gregory Alexander Michelotti¹ ; Thiago Almeida Pereira¹ ; Guanhua Xie¹ ; Richard Premont¹ ; Helena Cortez-Pinto² ; Anna Mae Diehl¹ ; ^{diehl004@mc.duke.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：YAP ; yes-associated protein ; RDC ; reactive-appearing ductular cells ; NAFLD ; non-alcoholic fatty liver disease ; NASH ; non-alcoholic steatohepatitis ; Shh ; sonic hedgehog ; WT ; wild-type ; MCD ; methionine choline deficient ; IHC ; immunohistochemistry ; TUNEL ; terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling ; MF ; myofibroblast ; K19 ; keratin 19 ; 伪-SMA ; 伪-smooth muscle actin ; OPN ; osteopontin ; TNF-伪 ; tumor necrosis factor 伪 ; TGF ; transforming growth factor ; CTGF ; connective tissue gro
• 刊名：Journal of Hepatology
• 出版年：2015
• 出版时间：October 2015
• 年：2015
• 卷：63
• 期：4
• 页码：962-970
• 全文大小：4048 K

文摘

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.