Human FGF-21 Is a Substrate of Fibroblast Activation Protein

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.FGF-21（成纤维细胞生长因子21，fibroblast growth factor 21）是代谢的关键调控因子，亦是治疗II型糖尿病及其他代谢紊乱疾病的潜在药物候选物。然而，近期研究表明，循环状态下的活性人源FGF-21在小鼠与猴体内的半衰期，会因P171与S172位点间的蛋白水解切割而被缩短。本研究证实，成纤维细胞激活蛋白（fibroblast activation protein, FAP）正是介导该蛋白水解过程的酶：我们通过体外实验证明，纯化的FAP可在该位点切割人源FGF-21；同时，FAP特异性抑制剂ARI-3099可在小鼠、猴及人血浆中阻断该酶活性，并可延长小鼠体内循环人源FGF-21的半衰期。但小鼠FGF-21并不具备FAP的切割位点，因此无法被FAP切割。上述研究结果表明，FAP可能参与代谢调控，且FAP抑制剂或可用于人类糖尿病及代谢紊乱疾病的治疗；但在啮齿类动物中开展的临床前概念验证研究将面临挑战。