Abstract
Understanding the molecular mechanisms of liver regeneration is essential to improve the survival rate of patients after surgical resection of large amounts of liver tissue. Focal adhesion kinase (FAK) regulates different cellular functions, including cell survival, proliferation and cell migration. The role of FAK in liver regeneration remains unknown. In this study, we found that Fak is activated and induced during liver regeneration after two-thirds partial hepatectomy (PHx). We used mice with liver-specific deletion of Fak and investigated the role of Fak in liver regeneration in 2/3 PHx model (removal of 2/3 of the liver). We found that specific deletion of Fak accelerates liver regeneration. Fak deletion enhances hepatocyte proliferation prior to day 3 post-PHx but attenuates hepatocyte proliferation 3 days after PHx. Moreover, we demonstrated that the deletion of Fak in liver transiently increases EGFR activation by regulating the TNFα/HB-EGF axis during liver regeneration. Furthermore, we found more apoptosis in Fak-deficient mouse livers compared to WT mouse livers after PHx. Conclusion: Our data suggest that Fak is involved in the process of liver regeneration, and inhibition of FAK may be a promising strategy to accelerate liver regeneration in recipients after liver transplantation.
Highlights
Understanding the molecular mechanisms of liver regeneration is essential to improve the survival rate of patients after surgical resection of large amounts of liver tissue
These data suggest that Fak deletion might accelerate liver regeneration by enhancing epidermal growth factor receptor (EGFR)/STAT3 activation
Understanding the molecular mechanism underlying liver regeneration is important for improving the survival rate of patients after surgical resection or reducing the amount of liver tissue required for liver transplantation
Summary
Understanding the molecular mechanisms of liver regeneration is essential to improve the survival rate of patients after surgical resection of large amounts of liver tissue. We found that Fak is activated and induced during liver regeneration after two-thirds partial hepatectomy (PHx). Two-thirds partial hepatectomy (PHx) in rodents has become a useful paradigm for studying liver regeneration[2] With this model, molecular mechanisms of liver regeneration have been emerging. A number of kinases that are targets of HGF/c-MET and EGFR signaling, such as protein kinase B (PKB or AKT)[6], extracellular receptor kinase (ERK)[7] or signal transducer and activator of transcription 3 (Stat3)[8], play important roles in liver regeneration. Activation of FAK can target multiple downstream signaling pathways (e.g., AKT, ERK and Ras-related C3 botulinum toxin substrate (Rac)), thereby regulating different cellular functions, including cell survival, proliferation and migration[13]. Quantification of Western blotting by Image J software. (B) Liver weight/body weight ratio was analyzed in Alb-Cre (HepWT) and Alb-Cre; Fakflox/flox (Hep∆Fak) mice after PHx (5 mice per strain at each time point)
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