Expression and function of the atypical cadherin Fat1 in liver fibrosis

The activation of hepatic stellate cells (HSC) is a key event of hepatic fibrosis, and previous studies found that cadherin expression is altered in activated hepatic stellate cells. Fat1 is an atypical cadherin of more than 500kDa and is characterized by large extracellular domains.

The aim of this study was to assess the expression and function of Fat1 in liver fibrosis.

Method and Results: Hepatic Fat1 expression was assessed in two different murine models of chronic liver injury: (i) the bile duct ligation model (BDL) and (ii) a dietary model of non-alcoholic steatohepatitis (NASH). In both models we observed a time dependent increase of FAT1 expression that paralleled fibrosis progression in these models. The activation of hepatic stellate cells (HSC) is the key event of hepatic fibrosis, and interestingly, we observed quantitative PCR and Western blotting revealed increased Fat1 expression in HSC during in vitro activation. Of note, immunofluorescence analysis and Western blotting of cell fractions revealed Fat1 localization in the cytoplasm in addition to the membrane, and the half life of Fat1 protein in activated HSC was determined to be more than 7 days. By siRNA we achieved an almost complete suppression of Fat1 in activated HSC after 14 days, and functional analysis revealed a significant alteration of the profibrogenic phenotype of these cells.

Conclusion: These findings suggest that Fat1 plays a role in activation of hepatic stellate cells and we propose this atypical cadherin has pathophysiological relevance in the progression of chronic liver disease.