title: Human FGF-21 Is a Substrate of Fibroblast Activation Protein.
abstract: 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.
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Tufts University Sackler School of Graduate Biomedical Sciences, Boston, Massachusetts, United States of America.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Coppage
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Tufts University Sackler School of Graduate Biomedical Sciences, Boston, Massachusetts, United States of America.|Arisaph Pharmaceuticals Inc., Boston, Massachusetts, United States of America.
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Heard
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Tufts University Sackler School of Graduate Biomedical Sciences, Boston, Massachusetts, United States of America.|Arisaph Pharmaceuticals Inc., Boston, Massachusetts, United States of America.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: DiMare
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Tufts University Sackler School of Graduate Biomedical Sciences, Boston, Massachusetts, United States of America.|Arisaph Pharmaceuticals Inc., Boston, Massachusetts, United States of America.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Tufts University Sackler School of Graduate Biomedical Sciences, Boston, Massachusetts, United States of America.|Arisaph Pharmaceuticals Inc., Boston, Massachusetts, United States of America.
authors.forename: Wengen
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Tufts University Sackler School of Graduate Biomedical Sciences, Boston, Massachusetts, United States of America.|Arisaph Pharmaceuticals Inc., Boston, Massachusetts, United States of America.
authors.forename: Jack H
authors.initials: JH
authors.lastname: Lai
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Tufts University Sackler School of Graduate Biomedical Sciences, Boston, Massachusetts, United States of America.|Arisaph Pharmaceuticals Inc., Boston, Massachusetts, United States of America.
authors.forename: William W
authors.initials: WW
authors.lastname: Bachovchin
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D010450:Endopeptidases; D005346:Fibroblast Growth Factors / Q000493:pharmacokinetics / Q000494:pharmacology; D018093:Gelatinases / Q000378:metabolism*; D006801:Humans; D008252:Macaca fascicularis; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D059748:Proteolysis; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism*; D013045:Species Specificity; 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