Expression of the atypical cadherin Fat1 in hepatic 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.

Methods and Results: Hepatic Fat1 expression was increased in different murine models of chronic liver injury (bile duct ligation, chronic CCl4 injury and two dietary models of non-alcoholic fatty liver disease(NAFLD)) and patients with liver cirrhosis of different origin and NAFLD of different degree. The increased FAT1 expression paralleled fibrosis progression, and quantitative PCR and Western blotting revealed increased Fat1 expression in HSC during in vitro activation. Hypoxia and formation of free oxygen radicals (ROS) further increased FAT1 expression, while ROS-scavengers inhibited both basal as well as hypoxia induced FAT1 expression in activated HSCs. The half life of Fat1 protein in activated HSCs was determined to be more than 7 days but by siRNA we achieved an almost complete suppression of Fat1 in activated HSC after 14 days, which significantly reduced resistance towards apoptosis as assessed by FACS and analysis of caspase–3 activity. Further, functional analysis revealed effects on attachment and proliferation.

Conclusion: These findings suggest that targeting Fat1 may be a promising target to inhibit fibrosis in chronic liver disease.