Fibroblast Activation Protein Cleaves and Inactivates Fibroblast Growth Factor 21

被引：120

作者：

Dunshee, Diana Ronai ^{[1
]}

Bainbridge, Travis W. ^{[2
]}

Kljavin, Noelyn M. ^{[3
]}

Zavala-Solorio, Jose ^{[1
]}

Schroeder, Amy C. ^{[1
]}

Chan, Ruby ^{[2
]}

Corpuz, Racquel ^{[2
]}

Wong, Manda ^{[2
]}

Zhou, Wei ^{[4
]}

Deshmukh, Gauri ^{[5
]}

Ly, Justin ^{[5
]}

Sutherlin, Daniel P. ^{[6
]}

Ernst, James A. ^{[2
]}

Sonoda, Junichiro ^{[1
]}

机构：

[1] Genentech Inc, Mol Biol, San Francisco, CA 94080 USA

[2] Genentech Inc, Prot Chem, San Francisco, CA 94080 USA

[3] Genentech Inc, Mol Oncol, San Francisco, CA 94080 USA

[4] Genentech Inc, Translat Oncol, San Francisco, CA 94080 USA

[5] Genentech Inc, Drug Metab & Pharmacokinet, San Francisco, CA 94080 USA

[6] Genentech Inc, Discovery Chem, San Francisco, CA 94080 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2016年 / 291卷 / 11期

关键词：

FGF; metabolic disease; protease inhibitor; proteolytic enzyme; serine protease; FGF21; dipeptidyl peptidase IV (DPPIV); fibroblast activation protein (FAP); DIPEPTIDYL PEPTIDASE-4 INHIBITORS; ENDOPLASMIC-RETICULUM STRESS; SERUM FGF21 LEVELS; INSULIN SENSITIVITY; ENERGY-EXPENDITURE; METABOLIC SYNDROME; HEPATIC STEATOSIS; MICE; OBESITY; EXPRESSION;

D O I：

10.1074/jbc.M115.710582

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：5986 / 5996

页数：11

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