Human FGF-21 Is a Substrate of Fibroblast Activation Protein

• Published in: PloS one 2016-03, Vol.11 (3), p.e0151269
• Main Authors: Coppage, Andrew L, Heard, Kathryn R, DiMare, Matthew T, Liu, Yuxin, Wu, Wengen, Lai, Jack H, Bachovchin, William W
• Format: Article
• Language: English
• Subjects: Adipocytes; Animals; Biology; Biology and Life Sciences; Blood plasma; Cell metabolism; Cleavage; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Disorders; Drug metabolism; Enzymes; Fibroblast activation protein; Fibroblast growth factors; Fibroblast Growth Factors - pharmacokinetics; Fibroblast Growth Factors - pharmacology; Fibroblasts; Gelatinases - metabolism; Genetic aspects; Growth factors; Half-life; Health aspects; Homeostasis; Humans; Lipids; Macaca fascicularis; Medicine and Health Sciences; Membrane Proteins - metabolism; Metabolic disorders; Metabolism; Mice; Monkeys; Pharmaceuticals; Physical Sciences; Properties; Proteins; Proteolysis; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - pharmacology; Regulation; Research and Analysis Methods; Rodents; Serine Endopeptidases - metabolism; Solvents; Species Specificity; Sterols; Substrates
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0151269

FGF-21 is a key regulator of metabolism and potential drug candidate for the treatment of type II diabetes and other metabolic disorders. However, the half-life of active, circulating, human FGF-21 has recently been shown to be limited in mice and monkeys by a proteolytic cleavage between P171 and S172. Here, we show that fibroblast activation protein is the enzyme responsible for this proteolysis by demonstrating that purified FAP cleaves human FGF-21 at this site in vitro, and that an FAP-specific inhibitor, ARI-3099, blocks the activity in mouse, monkey and human plasma and prolongs the half-life of circulating human FGF-21 in mice. Mouse FGF-21, however, lacks the FAP cleavage site and is not cleaved by FAP. These findings indicate FAP may function in the regulation of metabolism and that FAP inhibitors may prove useful in the treatment of diabetes and metabolic disorders in humans, but pre-clinical proof of concept studies in rodents will be problematic.