Human FGF-21 Is a Substrate of Fibroblast Activation Protein.
Human FGF-21 Is a Substrate of Fibroblast Activation Protein.
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DOI：
10.1371/journal.pone.0151269
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Bachovchin WW
中科院分区：
文献类型：
--
作者：
Coppage AL;Heard KR;DiMare MT;Liu Y;Wu W;Lai JH;Bachovchin WW
FGF-21是代谢的关键调节剂，并且是用于治疗II型糖尿病和其他代谢紊乱的潜在候选药物。然而，最近已显示活性循环人FGF-21的半衰期在小鼠和猴中受到P171和S172之间的蛋白水解裂解的限制。在这里，我们表明，成纤维细胞活化蛋白是负责这种蛋白水解的酶，通过证明纯化的FAP在体外切割人FGF-21，在这个网站上，和FAP特异性抑制剂，ARI-3099，阻断在小鼠，猴和人血浆中的活性，并延长小鼠中循环的人FGF-21的半衰期。然而，小鼠FGF-21缺乏FAP切割位点并且不被FAP切割。这些发现表明FAP可能在代谢调节中起作用，并且FAP抑制剂可能被证明在人类糖尿病和代谢紊乱的治疗中是有用的，但是在啮齿动物中的临床前概念验证研究将是有问题的。
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.