Background: Dipeptidyl-peptidase4 (DPP4) inhibitors are a successful class of anti-hyperglycemic agent. We investigated the role of DPP4 and its most closely related protease, Fibroblast Activation Protein (FAP), in energy metabolism, liver fibrosis and wound healing.
Methods: Mice were fed high-fat diet for 20 weeks (diet induced obesity (DIO) model), or administered CCl4 for 4 weeks (liver fibrosis model). DPP4 inhibitor treatment was daily per os. Primary mouse embryonic fibroblast (MEF) cell lines isolated from FAP gene knockout mice (KO) were engineered to express functional human FAP enzyme (FAPe+) versus inactive FAP (FAPe-).
Results: FAP-KO mice were protected from DIO-induced glucose intolerance (GTT AUC WT:1399±22; KO:1090±32 mmol.L-1.120min-1; p=0.01), impaired insulin sensitivity (ITT AUC WT:859±66; KO:729±28 mmol.L-1.120min-1; p=0.04), hyperinsulinaemia and insulin-resistance (HOMA-IR WT:2.4±0.3; KO:0.7±0.06; p=0.008). KO mice were also protected from DIO-induced fatty liver, as seen by less micro- and macro-vesicular inclusions in the liver, hepatocyte ballooning, liver lipid (WT:3.82±0.9; KO:2.18±0.63 mg/g; p=0.03), serum alanine-transaminase (WT:67.6±6.55; KO:49.5±6.18 U/L; p=0.05) and cholesterol (WT:3.60±0.3; KO:3.03±0.13mmol/L; p=0.03). DPP4-inhibitor treatment improved GTT in KO (AUC Vehicle:771.3±43.4; DP4-inhibitor:687.9±27.3 mmol.L-1.60min-1; p=0.07), suggesting potential synergy from targeting both enzymes. In in-vitro ‘wound-healing’ FAPe+MEF cells exhibited greater cell migration (1.83±0.22 units/pixel) than FAPe- (0.77±0.04 units/pixel; p=0.04). CCl4-induced liver fibrosis (%Sirius-red stain WT:3.0±0.18; KO:2.21±0.16; p=0.01) progression was less at 4 weeks in KO mice than in WT.
Conclusions: These data suggest that (1) FAP has important roles in glucose and lipid metabolism, (2) FAP has a potential role in wound-healing and (3) inhibiting both DPP4 and FAP enzymes may synergise in treating metabolic disorders and liver fibrosis.