Lkb1 suppresses amino acid-driven gluconeogenesis in the liver

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 Vasseur-Cognet, Alain Schmitt, Morgane Gall, Marjorie Leduc, François Guillonneau, Jean-Pascal Bandt, Patrick Mayeux, Béatrice Romagnolo, Serge Luquet, Pascale Bossard and Christine Perret ()
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Pierre-Alexandre Just: Université de Paris, Institut Cochin, INSERM, CNRS
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
Morgane Gall: Université de Paris, Institut Cochin, INSERM, CNRS
Marjorie Leduc: Université de Paris, Institut Cochin, INSERM, CNRS
François Guillonneau: Université de Paris, Institut Cochin, INSERM, CNRS
Jean-Pascal Bandt: EA4466, PRETRAM, Université Paris Descartes
Patrick Mayeux: 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

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19490-6

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