Circulating FGF21 proteolytic processing mediated by fibroblast activation protein
Open accessAbstract
Fibroblast growth factor 21 (FGF21), a hormone implicated in the regulation of glucose homoeostasis, insulin sensitivity, lipid metabolism and body weight, is considered to be a promising therapeutic target for the treatment of metabolic disorders. Despite observations that FGF21 is rapidly proteolysed in circulation rending it potentially inactive, little is known regarding mechanisms by which FGF21 protein levels are regulated. We systematically investigated human FGF21 protein processing using mass spectrometry. In agreement with previous reports, circulating human FGF21 was found to be cleaved primarily after three proline residues at positions 2, 4 and 171. The extent of FGF21 processing was quantified in a small cohort of healthy human volunteers. Relative abundance of FGF21 proteins cleaved after Pro-2, Pro-4 and Pro-171 ranged from 16 to 30%, 10 to 25% and 10 to 34%, respectively. Dipeptidyl peptidase IV (DPP-IV) was found to be the primary protease responsible for N-terminal cleavages after residues Pro-2 and Pro-4. Importantly, fibroblast activation protein (FAP) was implicated as the protease responsible for C-terminal cleavage after Pro-171, rendering the protein inactive. The requirement of FAP for FGF21 proteolysis at the C-terminus was independently demonstrated by in vitro digestion, immunodepletion of FAP in human plasma, administration of an FAP-specific inhibitor and by human FGF21 protein processing patterns in FAP knockout mouse plasma. The discovery that FAP is responsible for FGF21 inactivation extends the FGF21 signalling pathway and may enable novel approaches to augment FGF21 actions for therapeutic applications.
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Human but not mouse FGF21 is cleaved and processed by FAP.
“Notably, human but not mouse FGF21 is cleaved and processed by FAP, because mouse FGF21 possesses a single–amino acid difference in the stringent FAP-recognition motif42,43.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [43]
FGF21 is cleaved by FAP and DPP-IV; cleavage at residue 171 inactivates FGF21 because the last ten residues are critical for KLB interaction.
“FGF21 is also subject to proteolytic cleavage by the serine proteases fibroblast activation protein (FAP) and dipeptidyl peptidase IV (DPP-IV)42,43.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [43]
Circulating human FGF21 is composed of 181 amino acids and is proteolytically cleaved, and inactivated, between Pro-171 and Ser-172 by the endopeptidase fibroblast activation protein (FAP).
“Circulating human FGF21 is composed of 181 amino acids and is proteolytically cleaved, and inactivated, between Pro-171 and Ser-172 by the endopeptidase fibroblast activation protein (FAP) (29, 150).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [150]
Mouse FGF21 is neither cleaved nor inactivated by FAP because mouse FGF21 has a glutamate residue at the corresponding glycine residue at position 170, which disrupts the stringent glycine-proline sequence required for FAP-mediated cleavage.
“Interestingly, mouse FGF21 is neither cleaved nor inactivated by FAP because mouse FGF21 has a glutamate residue at the corresponding glycine residue at position 170, which disrupts the stringent glycine–proline sequence required for FAP-mediated cleavage (29, 150).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [150]
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- Authors
- Zhen, E. Y., Jin, Z., Ackermann, B. L., Thomas, M. K., & Gutierrez, J. A.
- Affiliations
- Tailored Therapeutics, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, U.S.A.
- Eli Lilly (United States) (US)
- ORCID
- Thomas, Melissa K.
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2016-02-24
- Volume
- 473
- Issue
- 5
- Pages
- 605-614
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC4764976
- OpenAlex
- W2292257555
- Cited by
- 123
- References
- 54
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 11 · 2023: 16 · 2022: 9 · 2021: 17 · 2020: 16 · 2019: 7 · 2018: 15 · 2017: 12 · 2016: 7
- FWCI
- 4.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Biochemical Journal (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- University of Pennsylvania
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Oncology › Peptidase Inhibition and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Keywords
- FGF21, fibroblast activation protein, proteolytic processing, proteolytic cleavage, dipeptidyl peptidase IV, FAP inhibitors, metabolic disorders, glucose homeostasis, insulin sensitivity, lipid metabolism
- MeSH terms
- Animals, Fibroblasts, Humans, Insulin Resistance, Protein Processing, Post-Translational, Lipid Metabolism, Proteolysis
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