Fibroblast Activation Protein (FAP) is a post-proline dipeptidyl peptidase and prolyl endopeptidase that has cell surface and soluble forms. Perichondrial mesenchymal cells express FAP in the mouse embryo but, in non-diseased adult mice and humans, FAP is not readily detectable. No phenotypic defect has been associated with the absence of FAP in FAP-deficient humans or mice. FAP is strongly expressed by tumor stromal fibroblasts and by activated myofibroblasts in healing wounds and in chronic diseases. FAP-positive cells are seen in pulmonary fibrosis, osteoarthritis, rheumatoid arthritis and atherosclerotic plaques. FAP is a potential therapeutic target in these and other chronic diseases.

The FAP substrates collagen type I and α2-antiplasmin are consistent with roles in fibrinolysis and extracellular matrix remodeling.

We have shown that, in chronic human liver injury, FAP expression is proportional to fibrosis severity. Our FAP gene knockout [gko] mouse data shows roles for FAP in fibrosis, chronic obesity, fatty liver and diabetes. On a high fat diet, FAP gko mice had improved glucose tolerance and improved insulin sensitivity and were resistant to liver injury and fatty liver. Reduced fibrosis severity was associated with reduced intrahepatic B cell densities in FAP gko mice. The FAP gko mice in diet-induced obesity model had less intrahepatic mRNA expression of glucokinase, a key lipogenic gene, and of CD36, which drives hepatic triglyceride and fatty acid uptake.

In vitro, we found that FAP overexpression by stellate cells increases cell apoptosis, migration and adhesion on collagen and fibronectin. In addition, we found that several small bioactive peptides including B-type natriuretic peptide and neuropeptide Y are FAP substrates.

 The substrate data suggest several mechanisms by which FAP may progress chronic disease. The preclinical data suggest that FAP has pro-fibrotic and pro-inflammatory roles in experimental chronic liver injury and that FAP inhibition may be protective in several conditions.