Dataset Information

Human FGF-21 Is a Substrate of Fibroblast Activation Protein.

ABSTRACT: FGF-21 is a key regulator of metabolism and potential drug candidate for the treatment of type II diabetes and other metabolic disorders. However, the half-life of active, circulating, human FGF-21 has recently been shown to be limited in mice and monkeys by a proteolytic cleavage between P171 and S172. Here, we show that fibroblast activation protein is the enzyme responsible for this proteolysis by demonstrating that purified FAP cleaves human FGF-21 at this site in vitro, and that an FAP-specific inhibitor, ARI-3099, blocks the activity in mouse, monkey and human plasma and prolongs the half-life of circulating human FGF-21 in mice. Mouse FGF-21, however, lacks the FAP cleavage site and is not cleaved by FAP. These findings indicate FAP may function in the regulation of metabolism and that FAP inhibitors may prove useful in the treatment of diabetes and metabolic disorders in humans, but pre-clinical proof of concept studies in rodents will be problematic.

SUBMITTER: Coppage AL

PROVIDER: S-EPMC4786124 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Human FGF-21 Is a Substrate of Fibroblast Activation Protein.

Coppage Andrew L AL Heard Kathryn R KR DiMare Matthew T MT Liu Yuxin Y Wu Wengen W Lai Jack H JH Bachovchin William W WW

PloS one 20160310 3

FGF-21 is a key regulator of metabolism and potential drug candidate for the treatment of type II diabetes and other metabolic disorders. However, the half-life of active, circulating, human FGF-21 has recently been shown to be limited in mice and monkeys by a proteolytic cleavage between P171 and S172. Here, we show that fibroblast activation protein is the enzyme responsible for this proteolysis by demonstrating that purified FAP cleaves human FGF-21 at this site in vitro, and that an FAP-spec ...[more]

PMID: 26962859

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Project description:BackgroundHuman fibroblast growth factor 21 (FGF-21) is an endocrine liver hormone that stimulates adipocyte glucose uptake independently of insulin, suppresses hepatic glucose production and is involved in the regulation of body fat. Peritoneal dialysis (PD) patients suffer potential interference with FGF-21 status with as yet unknown repercussions.ObjectivesThe aim of this study was to define the natural history of FGF-21 in PD patients, to analyze its relationship with glucose homeostasis parameters and to study the influence of residual renal function and peritoneal functional parameters on FGF-21 levels and their variation over time.MethodsWe studied 48 patients with uremia undergoing PD. Plasma samples were routinely obtained from each patient at baseline and at 1, 2 and 3 years after starting PD therapy.ResultsPlasma FGF-21 levels substantially increased over the first year and were maintained at high levels during the remainder of the study period (253 pg/ml (59; 685) at baseline; 582 pg/ml (60.5-949) at first year and 647 pg/ml (120.5-1116.6) at third year) (p<0.01). We found a positive correlation between time on dialysis and FGF-21 levels (p<0.001), and also, those patients with residual renal function (RRF) had significantly lower levels of FGF-21 than those without RRF (? -0.484, p<0.05). Lastly, there was also a significant association between FGF-21 levels and peritoneal protein losses (PPL), independent of the time on dialysis (? 0.410, p<0.05).ConclusionOur study shows that FGF-21 plasma levels in incident PD patients significantly increase during the first 3 years. This increment is dependent on or is associated with RRF and PPL (higher levels in patients with lower RRF and higher PPL). FGF-21 might be an important endocrine agent in PD patients and could act as hormonal signaling to maintain glucose homeostasis and prevent potential insulin resistance. These preliminary results suggest that FGF-21 might play a protective role as against the development of insulin resistance over time in patients undergoing a continuous glucose load.

Project description:Fibrosis is associated with aging and many cardiac pathologies. It is characterized both by myofibroblast differentiation and by excessive accumulation of extracellular matrix proteins. Fibrosis-related tissue remodeling results in significant changes in tissue structure and function, including passive mechanical properties. This research area has gained significant momentum with the recent development of new tools and approaches to better characterize and understand the ability of cells to sense and respond to their biophysical environment. We use a novel hydrogel, termed CyPhyGel, to provide an advanced in vitro model of remodeling-related changes in tissue stiffness. Based on light-controlled dimerization of a Cyanobacterial Phytochrome, it enables contactless and reversible tuning of hydrogel mechanical properties with high spatial and temporal resolution. Human primary atrial fibroblasts were cultured on CyPhyGels. After 4 days of culturing on stiff (~4.6 kPa) or soft (~2.7 kPa) CyPhyGels, we analyzed fibroblast cell area and stiffness. Cells grown on the softer substrate were smaller and softer, compared to cells grown on the stiffer substrate. This difference was absent when both soft and stiff growth substrates were combined in a single CyPhyGel, with the resulting cell areas being similar to those on homogeneously stiff gels and cell stiffnesses being similar to those on homogeneously soft substrates. Using CyPhyGels to mimic tissue stiffness heterogeneities in vitro, our results confirm the ability of cardiac fibroblasts to adapt to their mechanical environment, and suggest the presence of a paracrine mechanism that tunes fibroblast structural and functional properties associated with mechanically induced phenotype conversion toward myofibroblasts. In the context of regionally increased tissue stiffness, such as upon scarring or in diffuse fibrosis, such a mechanism could help to prevent abrupt changes in cell properties at the border zone between normal and diseased tissue. The light-tunable mechanical properties of CyPhyGels and their suitability for studying human primary cardiac cells make them an attractive model system for cardiac mechanobiology research. Further investigations will explore the interactions between biophysical and soluble factors in the response of cardiac fibroblasts to spatially and temporally heterogeneous mechanical cues.

Dataset Information

Human FGF-21 Is a Substrate of Fibroblast Activation Protein.

Publications

Human FGF-21 Is a Substrate of Fibroblast Activation Protein.

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