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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.

2017-02-15 | PXD005659 | Pride

FGF19 as a Surgical Factor Contributing to the Metabolic Effects of Gastric Bypass Surgery

Project description:Gastric bypass surgery has proven to be the most effective treatment in controlling hyperglycemia in severely obese patients with diabetes. Here we show that FGF19, a gut hormone, is rapidly induced by bypass surgery in rodents and humans. Administration of FGF19 achieves remission of diabetes through mechanisms beyond weight loss in animal models of diabetes, supporting a role of FGF19 as part of hormonal changes that influence metabolism following surgery. Through an unbiased phenotypic screen in diabetic mice, we identified selective, safe and effective FGF19 analogues. Unexpectedly, FGF19 analogue failed to correct hyperglycemia in patients with type 2 diabetes. In contrast, administration of FGF19 analogue resulted in rapid, robust and sustained improvement in liver fat content and histology in patients with non-alcoholic steatohepatitis, faithfully replicating effect of the surgery. Thus, our work identifies a strategy of replacing gastric bypass surgery by equally effective, but less invasive, treatment for non-alcoholic steatohepatitis. We used microarrays to detail the global programme of gene expression affected by gastric bypass surgery in rats.

2021-09-25 | GSE120530 | GEO

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

Project description:Background: Fibroblast growth factor-19 (FGF19) is an intestinal hormone that mediates postprandial metabolic responses in the liver. The unusual orphan nuclear receptor, Small Heterodimer Partner (SHP), acts as a co-repressor for many transcriptional factors and has been implicated in diverse biological pathways including FGF19-mediated repression of bile acid synthesis. To explore global functions of SHP in mediating FGF19 action, we identify genome-wide SHP binding sites in hepatic chromatin in mice treated with vehicle or FGF19 by ChIP-seq analysis. Results: The overall pattern of SHP binding sites between these two groups is similar, but SHP binding is enhanced at the sites by addition of FGF19. SHP binding is detected preferentially in promoter regions that are enriched in motifs for unexpected non-nuclear receptors. We observe global co-localization of SHP sites with published sites for SREBP-2, a master transcriptional activator of cholesterol biosynthesis. FGF19 increases functional interaction between endogenous SHP and SREBP-2 and inhibits SREBP-2 target genes, and these effects were blunted in SHP-knockout mice. Furthermore, FGF19-induced phosphorylation of SHP at Thr-55 is shown to be important for its functional interaction with SREBP-2 and reduction of liver/serum cholesterol levels. Conclusion: This study reveals SHP as a global transcriptional partner of SREBP-2 in regulation of sterol biosynthetic gene networks and provides a potential mechanism for cholesterol-lowering action of FGF19. Genome-wide SHP binding profiles in hepatic chromatin in mice under treatment of FGF19 or vehicle were generated using high throughput sequencing followed by chromatin immunoprecipitation.

2015-11-12 | E-GEOD-74913 | biostudies-arrayexpress

Effect of FGF15 or FGF19 on mouse liver

Project description:Mouse FGF15 and human FGF19 are orthologous proteins that regulate bile acid metabolism. However, other hepatic functions of FGF15/19 are not well characterized. We used microarrays to analyze global hepatic gene expression in mice administered FGF15 or FGF19. Total liver RNA was isolated from wild-type mice administered vehicle, purified FGF15 or recombinant FGF19 for 6 hr via a jugular vein injection as described (Inagaki et al., 2005). Mice did not have access to food throughout the 6 hr treatment, and livers were harvested and immediately frozen in liquid nitrogen. Microarray analyses were performed using the Mouse Genome 430A 2.0 array.

2011-06-07 | E-GEOD-29426 | biostudies-arrayexpress

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

2015-11-12 | GSE74913 | GEO

RNA-seq of human primary hepatocytes treated with FGF19 and CDCA

Project description:Primary human hepatocytes were treated with recombinant FGF19 (n=3), CDCA (n=3), endogenously produced FGF19 (n=3), or vehicle controls (n=3+3). Total RNA was harvested and sequenced with a strand-specific paired end RNA-seq protocol.

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

Engineered FGF19 promotes HDL biogenesis and transhepatic cholesterol efflux to prevent atherosclerosis

Project description:Cholesterol is an essential cell membrane component and precursor in metabolic pathways. Control of cholesterol levels is essential to human health. The endocrine hormone FGF19 potently inhibits CYP7A1, which controls a key step in cholesterol catabolism. However, the molecular mechanisms that integrate FGF19 with other cholesterol metabolic pathways are incompletely understood. Here we show that FGF19 and analogue promote HDL biogenesis and cholesterol efflux from the liver by selectively modulating liver X receptor signaling without inducing hepatic steatosis. We further identify ATP-binding cassette transporter A1 and FGFR4 as mediators of this effect. In dyslipidemic Apoe-/- mice fed a Western diet, treatment with FGF19 analogue dramatically reduced atherosclerotic lesion area in aortas. In healthy human volunteers, FGF19 analogue caused a placebo-adjusted increase in HDL cholesterol levels of 26% in seven days. These findings outline a regulatory role for FGF19 in cholesterol metabolism and advance our understanding of the mechanisms that coordinate sterol homeostasis. We used microarrays to detail the global programme of gene expression affected by FGF19 treatment in mice.

2019-01-25 | GSE117855 | GEO

Effect of FGF15 or FGF19 on mouse liver

Project description:Mouse FGF15 and human FGF19 are orthologous proteins that regulate bile acid metabolism. However, other hepatic functions of FGF15/19 are not well characterized.

2011-06-07 | GSE29426 | GEO

FGF19 induces the inflammatory phenotype of LX-2 cells

Project description:Liver metastasis is the main cause of death for human colorectal cancer (CRC), thus effective biomarkers and therapeutic target of colorectal cancer liver metastasis (CRLM) are urgently needed. Here, we report that FGF19 mediated the polarization of hepatic stellate cells to inflammatory CAFs by activating the autocrine effect of IL-1α via JAK2-STAT3 pathway. FGF19-induced iCAFs produced complement C5a and IL-1β to enhance neutrophil extracellular traps (NETs) formation in liver metastases, which in turn accelerated the liver colonization of CRC cells.

2023-07-03 | GSE215882 | GEO

Effect of FGF19 and TNFalpha on human DU145 prostate cancer cells

Project description:DU145 prostate cancer cells were treated with 50 ng/ml FGF19 and 50 ug/ml heparin, or 10 ng/ml TNFalpha, or both drug treatment groups

2010-07-09 | E-GEOD-22807 | biostudies-arrayexpress

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