Co-expression of the homologous proteases fibroblast activation protein and dipeptidyl peptidase-IV in the adult human Langerhans islets

Abstract

Fibroblast activation protein (FAP, seprase, EC 3.4.21.B28) and dipeptidyl peptidase-IV (DPP-IV, CD26, EC 3.4.14.5) are homologous serine proteases implicated in the modulation of the bioavailability and thus the function of a number of biologically active peptides. In spite of their generally nonoverlapping expression patterns, DPP-IV and FAP are co-expressed and probably co-regulated in certain cell types suggesting that for some biological processes their functional synergy is essential. By an in situ enzymatic activity assay, we show an abundant DPP-IV-like enzymatic activity sensitive to a highly specific DPP-IV inhibitor sitagliptin and corresponding DPP-IV immunoreactivity in the adult human islets of Langerhans. Moreover, the homologous protease FAP was present in the human endocrine pancreas and was co-expressed with DPP-IV. DPP-IV and FAP were found in the pancreatic alpha cells as determined by the co-localization with glucagon immunoreactivity. In summary, we show abundant enzymatic activity of the canonical DPP-IV (CD26) in Langerhans islets in the natural tissue context and demonstrate for the first time the co-expression of FAP and DPP-IV in pancreatic alpha cells in adult humans. Given their ability to proteolytically modify several biologically active peptides, both proteases have the potential to modulate the paracrine signaling in the human Langerhans islets.

Single-cell transcriptomics of human islet ontogeny defines the molecular basis of β-cell dedifferentiation in T2D

“…FAP plays an important role in modulating both the tumour microenvironment [ 55 ] as well as normal tissue biology during developmental and wound-healing processes through its gelatinase activity, which degrades extracellular matrix (for review see [ 56 ]). FAP belongs to the prolyl-oligopeptidase family, which includes dipeptidyl peptidase 4 (DPP4), also present on α- but not β-cells in humans [ 57 , 58 ], which is the enzyme that cleaves and inactivates the incretin, glucagon-like peptide 1 (GLP1). In contrast, FAP was shown to cleave and inactivate human FGF21, a liver-secreted hormone that reduces hepatic glucose output and stimulates glucose uptake [ 58 ].…”

“…FAP belongs to the prolyl-oligopeptidase family, which includes dipeptidyl peptidase 4 (DPP4), also present on α- but not β-cells in humans [ 57 , 58 ], which is the enzyme that cleaves and inactivates the incretin, glucagon-like peptide 1 (GLP1). In contrast, FAP was shown to cleave and inactivate human FGF21, a liver-secreted hormone that reduces hepatic glucose output and stimulates glucose uptake [ 58 ]. Therefore, FAP in α-cells may be involved in a novel metabolic role yet to be determined.…”

Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics

“…Mature adipocytes undergo rapid de-differentiation when cultured in vitro , and this process was associated with induction of FAP expression( 26 ). In human pancreas, FAP was expressed in glucagon + alpha cells, often co-localizing with DPPIV expression( 27 ). In glioma, using double immunofluorescence (IF) FAP was seen on mesenchymal stromal cells, but also on astrocytes, neural stem cells, and scattered CD45 + cells( 22 ).…”

Evidence for the existence and potential roles of intra-islet glucagon-like peptide-1

“…Consequently, DPP4 expression in human islets has been used as a surface marker to sort for enriched alpha cell populations by FACS, while DPP4 gene expression has been considered a signature gene to identify alpha cells in transcriptomic studies. 70 Indeed, DPP4 is found in human alpha cell multivesicular bodies, 46,55,[71][72][73] and these compartments are distinct from glucagoncontaining secretory granules. 20 DPP4 is also derived from endothelial cells, therefore, a local source of soluble DPP4 produced in the islet vasculature.…”