Quantitative liver proteomics identifies FGF19 targets that couple metabolism and proliferation.
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 the...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0171185&type=printable |
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| author | Vittoria Massafra Alexandra Milona Harmjan R Vos Boudewijn M T Burgering Saskia W C van Mil |
| author_facet | Vittoria Massafra Alexandra Milona Harmjan R Vos Boudewijn M T Burgering Saskia W C van Mil |
| author_sort | Vittoria Massafra |
| collection | DOAJ |
| 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 for the 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 fully uncouple metabolic benefit from mitogenic potential. |
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| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2025-03-14T14:17:26Z |
| publishDate | 2017-01-01 |
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| spelling | doaj.art-9eca865fe0ec407388563b1cf17b01b72025-02-27T05:33:14ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01122e017118510.1371/journal.pone.0171185Quantitative liver proteomics identifies FGF19 targets that couple metabolism and proliferation.Vittoria MassafraAlexandra MilonaHarmjan R VosBoudewijn M T BurgeringSaskia W C van MilFibroblast 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 for the 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 fully uncouple metabolic benefit from mitogenic potential.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0171185&type=printable |
| spellingShingle | Vittoria Massafra Alexandra Milona Harmjan R Vos Boudewijn M T Burgering Saskia W C van Mil Quantitative liver proteomics identifies FGF19 targets that couple metabolism and proliferation. PLoS ONE |
| title | Quantitative liver proteomics identifies FGF19 targets that couple metabolism and proliferation. |
| title_full | Quantitative liver proteomics identifies FGF19 targets that couple metabolism and proliferation. |
| title_fullStr | Quantitative liver proteomics identifies FGF19 targets that couple metabolism and proliferation. |
| title_full_unstemmed | Quantitative liver proteomics identifies FGF19 targets that couple metabolism and proliferation. |
| title_short | Quantitative liver proteomics identifies FGF19 targets that couple metabolism and proliferation. |
| title_sort | quantitative liver proteomics identifies fgf19 targets that couple metabolism and proliferation |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0171185&type=printable |
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