Postprandial FGF19 signaling-induced phosphorylation of FXR by Src modulates its activity in bile acid homeostasis
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ABSTRACT:
PROVIDER: PRJNA453740 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7068280.fastq.gz | Fastqsanger.gz | |||
| SRR7068281.fastq.gz | Fastqsanger.gz | |||
| SRR7068282.fastq.gz | Fastqsanger.gz | |||
| SRR7068283.fastq.gz | Fastqsanger.gz | |||
| SRR7068278.fastq.gz | Fastqsanger.gz |
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Project description:Farnesoid-X-Receptor (FXR) plays a central role in maintaining bile acid (BA) homeostasis by transcriptional control of numerous enterohepatic genes, including intestinal FGF19, a hormone that strongly represses hepatic BA synthesis. How activation of the FGF19 receptor at the membrane is transmitted to the nucleus for transcriptional regulation of BA levels and whether FGF19 signaling posttranslationally modulates function of FXR remain largely unknown. Here we show that FXR is phosphorylated at Y67 by non-receptor tyrosine kinase, Src, in response to postprandial FGF19, which is critical for its nuclear localization and transcriptional regulation of BA levels. Liver-specific expression of phospho-defective Y67F-FXR or Src-downregulation in mice result in impaired homeostatic responses to acute BA feeding, and exacerbate cholestatic pathologies upon drug-induced hepatobiliary insults. Also, the hepatic FGF19-Src-FXR pathway is defective in primary biliary cirrhosis patients. This study identifies Src-mediated FXR phosphorylation as a potential therapeutic target and biomarker for BA-related enterohepatic diseases.
2018-04-27 | GSE113707 | GEO
Project description:We studied the effect of bile acid CDCA, FXR agonsit GW4064 and FGF19 on the expression levels of microRNA in cultured human primary hepatocytes
2010-04-20 | E-TABM-691 | biostudies-arrayexpress
Project description:Farnesoid-X-Receptor (FXR) plays a central role in maintaining bile acid (BA) homeostasis by transcriptional control of numerous enterohepatic genes, including intestinal FGF19, a hormone that strongly represses hepatic BA synthesis. How activation of the FGF19 receptor at the membrane is transmitted to the nucleus for transcriptional regulation of BA levels and whether FGF19 signaling posttranslationally modulates FXR function remain largely unknown. Here we show that FXR is phosphorylated at Y67 by non-receptor tyrosine kinase, Src, in response to postprandial FGF19, which is critical for its nuclear localization and transcriptional regulation of BA levels. Liver-specific expression of phospho-defective Y67F-FXR or Src downregulation in mice results in impaired homeostatic responses to acute BA feeding, and exacerbates cholestatic pathologies upon drug-induced hepatobiliary insults. Also, the hepatic FGF19-Src-FXR pathway is defective in primary biliary cirrhosis (PBC) patients. This study identifies Src-mediated FXR phosphorylation as a potential therapeutic target and biomarker for BA-related enterohepatic diseases.
| S-EPMC6030054 | biostudies-literature
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
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
Project description:ABSTRACT Background & aims: The role of the intestine in the maintenance of cholesterol homeostasis is increasingly recognized. Fecal excretion of cholesterol is the last step in the atheroprotective reverse cholesterol transport (RCT) pathway, to which both biliary and transintestinal cholesterol excretion (TICE) contribute. The mechanisms controlling the flux of cholesterol through the TICE pathway are,however, poorly understood. In the current study we aimed to identify treatment modalities that stimulate TICE and to uncover underlying driving mechanisms. Methods: TICE was assessed in a panel of knock-out and transgenic mice as well as in mice treated with the FXR agonist PX20606 either or not combined with the cholesterol absorption inhibitor ezetimibe. Results: We show that TICE is regulated by intestinal farnesoid X receptor (FXR) via its target fibroblast growth factor 15/19 (FGF15/19) and that the pathway can be stimulated to such an extent that mice excrete ~60% of their total cholesterol content each day. Both PX20606 and FGF19 increased the muricholate/cholate ratio in bile, inducing a more hydrophilic bile salt pool. The altered bile salt pool robustly stimulated secretion of cholesterol into the intestinal lumen via the sterol exporting heterodimer ATP binding cassette subfamily G member 5/8 (ABCG5/G8). Of note, we demonstrate that the increase in TICE induced by PX20206 is independent of changes in cholesterol absorption. Conclusions: Hydrophilicity of the bile salt pool, controlled by FXR and FGF15/19, is an important determinant of cholesterol removal via TICE. Translation of these results to humans may offer new treatment modalities for prevention of cardiovascular disease.
2017-01-10 | GSE74101 | GEO
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.
2015-11-12 | GSE74913 | GEO
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
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
Project description:Breast cancer (BC) is the most common malignancy and the leading cause of cancer mortality in women. It is possible that signals arising from the gut microbiome are protective in BC. We used common drugs designed to turn on pathways to mimic one major signal coming from gut microbes, namely bile acids. Taking advantage of a drug called Ocaliva, which is commercially available for another disease, we repurposed this drug to test its anti-cancer potential. Ocaliva worked on a specific protein target called FXR to reduce tumor growth and kill cancer cells. In contrast, a similar drug that targets a different protein called TGR5 was not effective in killing cancer cells. Taken together, these findings suggest that using Ocaliva or other bile acid signals derived from the gut microbiome to target the protein FXR could be an important new therapeutic strategy for individuals with aggressive BC.
2024-04-04 | GSE263255 | GEO