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      Quantitative liver proteomics identifies FGF19 targets that couple metabolism and proliferation

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          Abstract

          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 13C 6-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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          Most cited references 55

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          Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins.

           Shona Kerr,  I Kerr,  G Stark (1994)
          Through the study of transcriptional activation in response to interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma), a previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that then phosphorylate substrate proteins called STATs (signal transducers and activators of transcription). The phosphorylated STAT proteins move to the nucleus, bind specific DNA elements, and direct transcription. Recognition of the molecules involved in the IFN-alpha and IFN-gamma pathway has led to discoveries that a number of STAT family members exist and that other polypeptide ligands also use the Jak-STAT molecules in signal transduction.
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            Combination of FASP and StageTip-based fractionation allows in-depth analysis of the hippocampal membrane proteome.

            Membrane proteomics is challenging because the desirable strong detergents are incompatible with downstream analysis. Recently, we demonstrated efficient removal of SDS by the filter aided sample preparation method (FASP). Here we combine FASP with our previously described small-scale membrane enrichment protocol. Analysis of a single mouse hippocampus enables identification of more than 1000 membrane proteins in a single LC-MS/MS run without protein or peptide prefractionation. To extend proteome coverage, we developed a simple anion exchange fractionation method in a StageTip format. When separating peptides into six fractions, a duplicate analysis resulted in identification of 4206 proteins of which 64% were membrane proteins. This data set covers 83% of glutamate and GABA receptor subunits identified in hippocampus in the Allen Brain Atlas and adds further isoforms. The combined method provides a streamlined protocol for rapid and sensitive membrane proteome mapping. We also provide a generic protocol for combining FASP with StageTip-based ion exchange fractionation, which is generally applicable to proteome analysis.
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              Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes.

              Hormonal control of metabolic rate can be important in regulating the imbalance between energy intake and expenditure that underlies the development of obesity. In mice fed a high-fat diet, human fibroblast growth factor 19 (FGF19) increased metabolic rate [1.53 +/- 0.06 liters O(2)/h.kg(0.75) (vehicle) vs. 1.93 +/- 0.05 liters O(2)/h.kg(0.75) (FGF19); P < 0.001] and decreased respiratory quotient [0.82 +/- 0.01 (vehicle) vs. 0.80 +/- 0.01 (FGF19); P < 0.05]. In contrast to the vehicle-treated mice that gained weight (0.14 +/- 0.05 g/mouse.d), FGF19-treated mice lost weight (-0.13 +/- 0.03 g/mouse.d; P < 0.001) without a significant change in food intake. Furthermore, in addition to a reduction in weight gain, treatment with FGF19 prevented or reversed the diabetes that develops in mice made obese by genetic ablation of brown adipose tissue or genetic absence of leptin. To explore the mechanisms underlying the FGF19-mediated increase in metabolic rate, we profiled the FGF19-induced gene expression changes in the liver and brown fat. In brown adipose tissue, chronic exposure to FGF19 led to a gene expression profile that is consistent with activation of this tissue. We also found that FGF19 acutely increased liver expression of the leptin receptor (1.8-fold; P < 0.05) and decreased the expression of acetyl coenzyme A carboxylase 2 (0.6-fold; P < 0.05). The gene expression changes were consistent with the experimentally determined increase in fat oxidation and decrease in liver triglycerides. Thus, FGF19 is able to increase metabolic rate concurrently with an increase in fatty acid oxidation.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                8 February 2017
                2017
                : 12
                : 2
                Affiliations
                Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands
                University of Navarra School of Medicine and Center for Applied Medical Research (CIMA), SPAIN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: AM VM SWCvM.

                • Formal analysis: VM.

                • Funding acquisition: SWCvM HRV.

                • Investigation: VM AM HRV.

                • Methodology: VM HRV AM.

                • Project administration: SWCvM.

                • Resources: HRV AM.

                • Supervision: BMTB.

                • Validation: VM.

                • Visualization: VM.

                • Writing – original draft: VM SWCvM.

                • Writing – review & editing: AM BMTB.

                Article
                PONE-D-16-47589
                10.1371/journal.pone.0171185
                5298232
                28178326
                © 2017 Massafra et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 5, Tables: 1, Pages: 18
                Product
                Funding
                Funded by: NWO Project VIDI
                Award ID: 917.11.365
                Award Recipient :
                Funded by: FP7 Marie Curie Actions IAPP
                Award ID: 611979
                Award Recipient :
                Funded by: Utrecht University Support Grant
                Award Recipient :
                Funded by: Wilhelmina Children’s Hospital Research Fund
                Award Recipient :
                Funded by: Proteins At Work (NWO)
                Award Recipient :
                S.W.C.v.M. is supported by the Netherlands Organization for Scientific Research (NWO) Project VIDI (917.11.365), FP7 Marie Curie Actions IAPP (FXR-IBD, 611979), the Utrecht University Support Grant, Wilhelmina Children’s Hospital Research Fund. H.R.V. is supported by Proteins At Work (NWO).
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Metabolism
                Protein Metabolism
                Medicine and Health Sciences
                Endocrinology
                Endocrine Physiology
                Growth Factors
                Fibroblast Growth Factor
                Biology and Life Sciences
                Physiology
                Endocrine Physiology
                Growth Factors
                Fibroblast Growth Factor
                Medicine and Health Sciences
                Physiology
                Endocrine Physiology
                Growth Factors
                Fibroblast Growth Factor
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Gene Expression and Vector Techniques
                Protein Expression
                Research and Analysis Methods
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Gene Expression and Vector Techniques
                Protein Expression
                Biology and Life Sciences
                Genetics
                Gene Expression
                Biology and Life Sciences
                Biochemistry
                Metabolism
                Carbohydrate Metabolism
                Glucose Metabolism
                Biology and Life Sciences
                Genetics
                Gene Types
                Regulator Genes
                Biology and Life Sciences
                Cell Biology
                Cell Physiology
                Cell Metabolism
                Biology and Life Sciences
                Genetics
                Gene Expression
                Gene Regulation
                Custom metadata
                All proteomics/mass-spectrometry files are available from the ProteomeXchange Consortium via the PRIDE partner repository (accession number PXD005659).

                Uncategorized

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