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Alleviating FGF19’s tumorigenic risk by suppressing its FGF Receptor dimerization ability

ABSTRACT: Administration of FGF19 - a physiological regulator of bile acid homeostasis - to diabetic and diet-induced-obese mice can suppress plasma glucose concentration and improve insulin sensitivity. Repurposing FGF19 as a therapeutic agent for treating type 2 diabetes and cholestatic liver disease is therefore of significant interest. However, the tumorigenic risk associated with prolonged FGF19 administration is a major hurdle in realizing its full clinical potential. Here we show that non-mitogenic FGF19 variants that retain full beneficial glucose-lowering activity of wild-type FGF19 (FGF19WT) can be engineered by diminishing FGF19’s ability to induce dimerization of its cognate FGF receptors (FGFR). As proof-of-principle, we generated three such mutants, each with a partial defect in binding affinity to FGFR (FGF19ΔFGFR), and its co-receptors klotho (FGF19ΔKLB) or heparan sulfate (FGF19ΔHBS). Pharmacological assays in healthy and db/db mice confirmed that these variants incur a dramatic loss in mitogenic activity, yet are indistinguishable from FGF19WT in eliciting glycemic control. Our approach provides a simple framework for the development of safer and efficacious FGF19 analogs.

ORGANISM(S): Mus musculus

PROVIDER: GSE148997 | GEO | 2020/12/07

REPOSITORIES: GEO

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Quantitative liver proteomics identifies FGF19 targets that couple metabolism and proliferation

Project description:Fibroblast growth factor 19 (FGF19) is a gut-derived peptide hormone that is produced following activation of Farnesoid X Receptor (FXR). FGF19 is secreted and signals to the liver, where it contributes to the homeostasis of bile acid (BA), lipid and carbohydrate metabolism. FGF19 is a promising therapeutic target in metabolic syndrome and cholestatic diseases, but enthusiasm for its use has been tempered by FGF19-mediated induction of proliferation and hepatocellular carcinoma. To inform future rational design of FGF19-variants, we have conducted temporal quantitative proteomic and gene expression analyses to identify FGF19-targets related to metabolism and proliferation. Mice were fasted for 16 hours, and injected with human FGF19 (1 mg/kg body weight) or vehicle. Liver protein extracts (containing 'light' lysine) were mixed 1:1 with a spike-in protein extract from 13C6-lysine metabolically labelled mouse liver (containing 'heavy' lysine) and analysed by LC-MS/MS. Our analyses provide a resource of FGF19 target proteins in the liver. 189 proteins were upregulated (≥ 1.5 folds) and 73 proteins were downregulated (≤ -1.5 folds) by FGF19. FGF19 treatment decreased the expression of proteins involved in fatty acid (FA) synthesis, i.e. Fabp5, Scd1, and Acsl3 and increased the expression of Acox1, involved in FA oxidation. As expected, FGF19 increased the expression of proteins known to drive proliferation (i.e. Tgfbi, Vcam1, Anxa2 and Hdlbp). Importantly, many of the FGF19 targets (i.e. Pdk4, Apoa4, Fas and Stat3) have a dual function in both metabolism and cell proliferation. Therefore, our findings challenge the development of FGF19-variants that uncouple full metabolic benefit from mitogenic potential.

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Liver ChIP-seq analysis in FGF19-treated mice reveals SHP as a global transcriptional partner of SREBP-2

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2021-02-13 | E-MTAB-8627 | biostudies-arrayexpress

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