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J Biol Chem. 2016 Mar 11;291(11):5986-96. doi: 10.1074/jbc.M115.710582. Epub 2016 Jan 21.

Fibroblast Activation Protein Cleaves and Inactivates Fibroblast Growth Factor 21.

Author information

1
From Molecular Biology.
2
Protein Chemistry.
3
Molecular Oncology.
4
Translational Oncology.
5
Drug Metabolism and Pharmacokinetics, and.
6
Discovery Chemistry, Genentech, Inc., South San Francisco, California 94080.
7
From Molecular Biology, junichis@gene.com.

Abstract

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.

KEYWORDS:

FGF; FGF21; dipeptidyl peptidase IV (DPPIV); fibroblast activation protein (FAP); metabolic disease; protease inhibitor; proteolytic enzyme; serine protease

PMID:
26797127
PMCID:
PMC4786731
DOI:
10.1074/jbc.M115.710582
[Indexed for MEDLINE]
Free PMC Article

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