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Lkb1 suppresses amino acid-driven gluconeogenesis in the liver

Author

Listed:
  • Pierre-Alexandre Just

    (Université de Paris, Institut Cochin, INSERM, CNRS
    APHP, Centre–Université de Paris)

  • Sara Charawi

    (Université de Paris, Institut Cochin, INSERM, CNRS)

  • Raphaël G. P. Denis

    (Université Paris Diderot, Sorbonne Paris Cité)

  • Mathilde Savall

    (Université de Paris, Institut Cochin, INSERM, CNRS)

  • Massiré Traore

    (Université de Paris, Institut Cochin, INSERM, CNRS)

  • Marc Foretz

    (Université de Paris, Institut Cochin, INSERM, CNRS)

  • Sultan Bastu

    (Université de Paris, Institut Cochin, INSERM, CNRS)

  • Salimata Magassa

    (EA4466, PRETRAM, Université Paris Descartes)

  • Nadia Senni

    (Université de Paris, Institut Cochin, INSERM, CNRS)

  • Pierre Sohier

    (Université de Paris, Institut Cochin, INSERM, CNRS)

  • Maud Wursmer

    (Université de Paris, Institut Cochin, INSERM, CNRS)

  • Mireille Vasseur-Cognet

    (Sorbonne Universités Paris and Institut d’Ecologie et des Sciences de l’Environnement de Paris)

  • Alain Schmitt

    (Université de Paris, Institut Cochin, INSERM, CNRS
    Institut Cochin)

  • Morgane Gall

    (Université de Paris, Institut Cochin, INSERM, CNRS
    Université de Paris, Institut Cochin, INSERM, CNRS)

  • Marjorie Leduc

    (Université de Paris, Institut Cochin, INSERM, CNRS
    Université de Paris, Institut Cochin, INSERM, CNRS)

  • François Guillonneau

    (Université de Paris, Institut Cochin, INSERM, CNRS
    Université de Paris, Institut Cochin, INSERM, CNRS)

  • Jean-Pascal Bandt

    (EA4466, PRETRAM, Université Paris Descartes)

  • Patrick Mayeux

    (Université de Paris, Institut Cochin, INSERM, CNRS
    Université de Paris, Institut Cochin, INSERM, CNRS)

  • Béatrice Romagnolo

    (Université de Paris, Institut Cochin, INSERM, CNRS)

  • Serge Luquet

    (Université Paris Diderot, Sorbonne Paris Cité)

  • Pascale Bossard

    (Université de Paris, Institut Cochin, INSERM, CNRS)

  • Christine Perret

    (Université de Paris, Institut Cochin, INSERM, CNRS)

Abstract

Excessive glucose production by the liver is a key factor in the hyperglycemia observed in type 2 diabetes mellitus (T2DM). Here, we highlight a novel role of liver kinase B1 (Lkb1) in this regulation. We show that mice with a hepatocyte-specific deletion of Lkb1 have higher levels of hepatic amino acid catabolism, driving gluconeogenesis. This effect is observed during both fasting and the postprandial period, identifying Lkb1 as a critical suppressor of postprandial hepatic gluconeogenesis. Hepatic Lkb1 deletion is associated with major changes in whole-body metabolism, leading to a lower lean body mass and, in the longer term, sarcopenia and cachexia, as a consequence of the diversion of amino acids to liver metabolism at the expense of muscle. Using genetic, proteomic and pharmacological approaches, we identify the aminotransferases and specifically Agxt as effectors of the suppressor function of Lkb1 in amino acid-driven gluconeogenesis.

Suggested Citation

  • Pierre-Alexandre Just & Sara Charawi & Raphaël G. P. Denis & Mathilde Savall & Massiré Traore & Marc Foretz & Sultan Bastu & Salimata Magassa & Nadia Senni & Pierre Sohier & Maud Wursmer & Mireille Va, 2020. "Lkb1 suppresses amino acid-driven gluconeogenesis in the liver," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19490-6
    DOI: 10.1038/s41467-020-19490-6
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