Human FGF-21 Is a Substrate of Fibroblast Activation Protein

Area of Science:

• Biochemistry
• Metabolic Regulation
• Enzymology

Background:

• Fibroblast activation protein (FAP) is implicated in various physiological and pathological processes.
• Fibroblast activation protein (FAP) cleaves human Fibroblast Growth Factor 21 (FGF-21), a key metabolic regulator.
• The limited half-life of human FGF-21 in circulation is a significant barrier to its therapeutic application for metabolic disorders like type II diabetes.

Purpose of the Study:

• To identify the enzyme responsible for the proteolytic cleavage of human FGF-21.
• To investigate the role of fibroblast activation protein (FAP) in FGF-21 metabolism.
• To evaluate the therapeutic potential of FAP inhibitors for metabolic diseases.

Main Methods:

• In vitro enzymatic assays using purified FAP and human FGF-21.
• Inhibition studies using a specific FAP inhibitor (ARI-3099) in plasma from various species.
• Pharmacokinetic analysis of human FGF-21 half-life in mice treated with FAP inhibitor.

Main Results:

• Purified fibroblast activation protein (FAP) was confirmed to cleave human FGF-21 at the P171-S172 site.
• The FAP-specific inhibitor ARI-3099 effectively blocked FAP activity in mouse, monkey, and human plasma.
• Administration of ARI-3099 significantly prolonged the half-life of circulating human FGF-21 in mice.
• Mouse FGF-21 lacks the FAP cleavage site and is resistant to FAP-mediated proteolysis.

Conclusions:

• Fibroblast activation protein (FAP) is the primary enzyme responsible for the degradation of human FGF-21.
• FAP plays a role in regulating metabolism, and its inhibition may offer a novel therapeutic strategy for type II diabetes and other metabolic disorders.
• Pre-clinical efficacy studies of FAP inhibitors in rodents may be complicated due to species-specific differences in FGF-21 processing.