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Fibroblast Activation Protein Cleaves and Inactivates Fibroblast Growth Factor 21

Diana Ronai Dunshee1, Travis W Bainbridge2, Noelyn M Kljavin3

  • 1From Molecular Biology.

The Journal of Biological Chemistry
|January 23, 2016
PubMed

Insights

Fibroblast activation protein (FAP) inactivates the hormone FGF21. Inhibiting FAP stabilizes FGF21, offering a potential therapy for metabolic disorders like obesity and type 2 diabetes.

Area of Science:

  • Endocrinology
  • Metabolic disease research
  • Enzymology

Background:

  • Fibroblast activation protein (FAP) is an enzyme implicated in various physiological and pathological processes.
  • Fibroblast Growth Factor 21 (FGF21) is a hormone known for its metabolic benefits, including anti-obesity and insulin-sensitizing effects.
  • The endogenous regulation and degradation pathways of FGF21 are not fully elucidated.

Purpose of the Study:

  • To identify the specific enzyme responsible for the proteolytic cleavage and inactivation of endogenously produced human FGF21.
  • To investigate the potential of targeting this enzyme for therapeutic intervention in metabolic diseases.

Main Methods:

  • Utilized biochemical assays to identify the protease cleaving human FGF21.
  • Employed a selective chemical inhibitor of FAP, FAP immunodepletion, and genetic deletion of Fap to assess its effect on FGF21 stability.
  • Administered a selective FAP inhibitor to cynomolgus monkeys to measure changes in circulating intact FGF21 levels.

Main Results:

  • Identified fibroblast activation protein (FAP) as the primary enzyme that cleaves and inactivates human FGF21.
  • Demonstrated that FAP inhibition (chemical, immunologic, or genetic) stabilizes recombinant human FGF21 in serum.
  • Showed that acute administration of a selective FAP inhibitor increases circulating intact FGF21 levels in non-human primates.

Conclusions:

  • Fibroblast activation protein (FAP) plays a key role in the degradation of FGF21.
  • Selective FAP inhibition represents a promising therapeutic strategy to enhance endogenous FGF21 activity.
  • This approach holds potential for treating metabolic disorders such as obesity, type 2 diabetes, and non-alcoholic steatohepatitis.
Keywords:
FGFFGF21dipeptidyl peptidase IV (DPPIV)fibroblast activation protein (FAP)metabolic diseaseprotease inhibitorproteolytic enzymeserine protease

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