Fibroblast Activation Protein Cleaves and Inactivates Fibroblast Growth Factor 21

• Published in: The Journal of biological chemistry Vol. 291; no. 11; pp. 5986 - 5996
• Main Authors: Dunshee, Diana Ronai, Bainbridge, Travis W., Kljavin, Noelyn M., Zavala-Solorio, Jose, Schroeder, Amy C., Chan, Ruby, Corpuz, Racquel, Wong, Manda, Zhou, Wei, Deshmukh, Gauri, Ly, Justin, Sutherlin, Daniel P., Ernst, James A., Sonoda, Junichiro
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.03.2016; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Sequence; Animals; dipeptidyl peptidase IV (DPPIV); FGF; FGF21; fibroblast activation protein (FAP); Fibroblast Growth Factors - chemistry; Fibroblast Growth Factors - metabolism; Gelatinases - genetics; Gelatinases - metabolism; Gene Deletion; HEK293 Cells; Humans; Macaca fascicularis; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; metabolic disease; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; protease inhibitor; Proteolysis; proteolytic enzyme; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; serine protease; protease inhibitor; proteolytic enzyme; FGF; dipeptidyl peptidase IV (DPPIV); metabolic disease; serine protease; fibroblast activation protein (FAP); FGF21
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.710582

FGF21 is a stress-induced hormone with potent anti-obesity, insulin-sensitizing, and hepatoprotective properties. Although proteolytic cleavage of recombinant human FGF21 in preclinical species has been observed previously, the regulation of endogenously produced FGF21 is not well understood. Here we identify fibroblast activation protein (FAP) as the enzyme that cleaves and inactivates human FGF21. A selective chemical inhibitor, immunodepletion, or genetic deletion of Fap stabilized recombinant human FGF21 in serum. In addition, administration of a selective FAP inhibitor acutely increased circulating intact FGF21 levels in cynomolgus monkeys. On the basis of our findings, we propose selective FAP inhibition as a potential therapeutic approach to increase endogenous FGF21 activity for the treatment of obesity, type 2 diabetes, non-alcoholic steatohepatitis, and related metabolic disorders.