Fibroblast activation protein (FAP) promotes liver fibrosis in mice

Lay AJ1, Xiang MSW1, Liu Y1, Wetzel S1, Lv Y1, Hamsom EJ1, Zhang HE1, Chowdhury S1, McCaughan GW1,2 and Gorrell MD1,2,3

  1. Centenary Institute, NSW.
  2. A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, NSW.
  3. University of Sydney, Faculty of Medicine and Health, NSW.

Chronic liver diseases resulting in cirrhosis are characterised by progressive inflammation and fibrosis, with continual extracellular matrix (ECM) remodelling resulting in scar tissue formation and eventual loss of function. However, the exact mechanisms underlying these changes are not well understood. Fibroblast activation protein (FAP) is an extracellular serine protease within the dipeptidyl peptidase IV (DPP4) family. FAP expression is known to regulate multiple processes including cell proliferation, adhesion and migration, which may impact upon ECM remodelling. Intrahepatic FAP expression has previously been shown to correlate positively with liver fibrosis severity in humans, implicating it in chronic liver disease. In our present study, we aimed to investigate the role of FAP during liver fibrosis and the underlying mechanisms. Using our unique FAPgki (gene knock-in) mouse model, we show that after 16 weeks of thioacetamide-induced fibrosis, mice deficient in FAP enzyme activity (FAPgki) developed significantly less liver fibrosis compared to WT littermate controls, as measured by digital image analysis of Sirius Red stained sections. This difference in fibrosis was accompanied by a significant decrease in intrahepatic leukocyte clusters. Furthermore, we showed that FAP modulated the abundance of proteins involved in ECM remodelling, including collagen, ECM-1 and fibronectin. Our data suggests that FAP promotes liver fibrosis, possibly though modulating ECM, and may be an important therapeutic target for the treatment of chronic liver disease.