title: Fibroblast Activation Protein Cleaves and Inactivates Fibroblast Growth Factor 21.
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.
authors.affiliation: From Molecular Biology.
authors.forename: Diana Ronai
authors.initials: DR
authors.lastname: Dunshee
authors.affiliation: Protein Chemistry.
authors.forename: Travis W
authors.initials: TW
authors.lastname: Bainbridge
authors.affiliation: Molecular Oncology.
authors.forename: Noelyn M
authors.initials: NM
authors.lastname: Kljavin
authors.affiliation: From Molecular Biology.
authors.forename: Jose
authors.initials: J
authors.lastname: Zavala-Solorio
authors.affiliation: From Molecular Biology.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Schroeder
authors.affiliation: Protein Chemistry.
authors.forename: Ruby
authors.initials: R
authors.lastname: Chan
authors.affiliation: Protein Chemistry.
authors.forename: Racquel
authors.initials: R
authors.lastname: Corpuz
authors.affiliation: Protein Chemistry.
authors.forename: Manda
authors.initials: M
authors.lastname: Wong
authors.affiliation: Translational Oncology.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Drug Metabolism and Pharmacokinetics, and.
authors.forename: Gauri
authors.initials: G
authors.lastname: Deshmukh
authors.affiliation: Drug Metabolism and Pharmacokinetics, and.
authors.forename: Justin
authors.initials: J
authors.lastname: Ly
authors.affiliation: Discovery Chemistry, Genentech, Inc., South San Francisco, California 94080.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Sutherlin
authors.affiliation: Protein Chemistry.
authors.forename: James A
authors.initials: JA
authors.lastname: Ernst
authors.affiliation: From Molecular Biology,. Electronic address: junichis@gene.com.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Sonoda
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D010450:Endopeptidases; D005346:Fibroblast Growth Factors / Q000737:chemistry / Q000378:metabolism*; D018093:Gelatinases / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D059748:Proteolysis; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D010450:Endopeptidases; D005346:Fibroblast Growth Factors; D018093:Gelatinases; D008565:Membrane Proteins; D011994:Recombinant Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha; C414620:fibroblast growth factor 21
keywords: FGF; FGF21; dipeptidyl peptidase IV (DPPIV); fibroblast activation protein (FAP); metabolic disease; protease inhibitor; proteolytic enzyme; serine protease