Glucose sensing O-GlcNAcylation pathway regulates the nuclear bile acid receptor farnesoid X receptor (FXR)

Authors

  • Wahiba Berrabah,

    1. European Genomic Institute for Diabetes (EGID), Lille, France
    2. INSERM UMR1011, Lille, France
    3. Univ Lille 2, Lille, France
    4. Institut Pasteur de Lille, Lille, France
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  • Pierrette Aumercier,

    1. European Genomic Institute for Diabetes (EGID), Lille, France
    2. INSERM UMR1011, Lille, France
    3. Univ Lille 2, Lille, France
    4. Institut Pasteur de Lille, Lille, France
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  • Céline Gheeraert,

    1. European Genomic Institute for Diabetes (EGID), Lille, France
    2. INSERM UMR1011, Lille, France
    3. Univ Lille 2, Lille, France
    4. Institut Pasteur de Lille, Lille, France
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  • Hélène Dehondt,

    1. European Genomic Institute for Diabetes (EGID), Lille, France
    2. INSERM UMR1011, Lille, France
    3. Univ Lille 2, Lille, France
    4. Institut Pasteur de Lille, Lille, France
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  • Emmanuel Bouchaert,

    1. European Genomic Institute for Diabetes (EGID), Lille, France
    2. INSERM UMR1011, Lille, France
    3. Univ Lille 2, Lille, France
    4. Institut Pasteur de Lille, Lille, France
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  • Jérémy Alexandre,

    1. European Genomic Institute for Diabetes (EGID), Lille, France
    2. INSERM UMR1011, Lille, France
    3. Univ Lille 2, Lille, France
    4. Institut Pasteur de Lille, Lille, France
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  • Maheul Ploton,

    1. European Genomic Institute for Diabetes (EGID), Lille, France
    2. INSERM UMR1011, Lille, France
    3. Univ Lille 2, Lille, France
    4. Institut Pasteur de Lille, Lille, France
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  • Claire Mazuy,

    1. European Genomic Institute for Diabetes (EGID), Lille, France
    2. INSERM UMR1011, Lille, France
    3. Univ Lille 2, Lille, France
    4. Institut Pasteur de Lille, Lille, France
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  • Sandrine Caron,

    1. European Genomic Institute for Diabetes (EGID), Lille, France
    2. INSERM UMR1011, Lille, France
    3. Univ Lille 2, Lille, France
    4. Institut Pasteur de Lille, Lille, France
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  • Anne Tailleux,

    1. European Genomic Institute for Diabetes (EGID), Lille, France
    2. INSERM UMR1011, Lille, France
    3. Univ Lille 2, Lille, France
    4. Institut Pasteur de Lille, Lille, France
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  • Jérôme Eeckhoute,

    1. European Genomic Institute for Diabetes (EGID), Lille, France
    2. INSERM UMR1011, Lille, France
    3. Univ Lille 2, Lille, France
    4. Institut Pasteur de Lille, Lille, France
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  • Tony Lefebvre,

    1. UMR 8576, CNRS, Laboratoire de Chimie Biologique, Villeneuve d Ascq, France
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  • Bart Staels,

    Corresponding author
    1. European Genomic Institute for Diabetes (EGID), Lille, France
    2. INSERM UMR1011, Lille, France
    3. Univ Lille 2, Lille, France
    4. Institut Pasteur de Lille, Lille, France
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  • Philippe Lefebvre

    Corresponding author
    1. European Genomic Institute for Diabetes (EGID), Lille, France
    2. INSERM UMR1011, Lille, France
    3. Univ Lille 2, Lille, France
    4. Institut Pasteur de Lille, Lille, France
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  • See Editorial on Page 1665

    Potential conflict of interest: Nothing to report.

  • W.B. was supported by a fellowship from the French Ministry for Education and Research. This work was supported by grants from Institut National de la Santé et de la Recherche Médicale, EU grants Hepadip (#018734), A.N.R. (FXRen), European Genomic Institute for Diabetes (E.G.I.D., ANR-10-LABX-46), Région Nord-Pas de Calais, FEDER and Cost Action BM0602.

Abstract

Bile acid metabolism is intimately linked to the control of energy homeostasis and glucose and lipid metabolism. The nuclear receptor farnesoid X receptor (FXR) plays a major role in the enterohepatic cycling of bile acids, but the impact of nutrients on bile acid homeostasis is poorly characterized. Metabolically active hepatocytes cope with increases in intracellular glucose concentrations by directing glucose into storage (glycogen) or oxidation (glycolysis) pathways, as well as to the pentose phosphate shunt and the hexosamine biosynthetic pathway. Here we studied whether the glucose nonoxidative hexosamine biosynthetic pathway modulates FXR activity. Our results show that FXR interacts with and is O-GlcNAcylated by O-GlcNAc transferase in its N-terminal AF1 domain. Increased FXR O-GlcNAcylation enhances FXR gene expression and protein stability in a cell type-specific manner. High glucose concentrations increased FXR O-GlcNAcylation, hence its protein stability and transcriptional activity by inactivating corepressor complexes, which associate in a ligand-dependent manner with FXR, and increased FXR binding to chromatin. Finally, in vivo fasting-refeeding experiments show that FXR undergoes O-GlcNAcylation in fed conditions associated with increased direct FXR target gene expression and decreased liver bile acid content. Conclusion: FXR activity is regulated by glucose fluxes in hepatocytes through a direct posttranslational modification catalyzed by the glucose-sensing hexosamine biosynthetic pathway. (Hepatology 2014;59:2022–2033)

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