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Journal Articles Nature Communications Year : 2020

Lkb1 suppresses amino acid-driven gluconeogenesis in the liver

Sara Charawi
  • Function : relator_co_first_author
Mathilde Savall
  • Function : Author
Massiré Traore
Marc Foretz
Sultan Bastu
  • Function : Author
Nadia Senni
  • Function : Author
Pierre Sohier
Maud Wursmer
  • Function : Author
Alain Schmitt
  • Function : Author
Morgane Le Gall
  • Function : Author
Marjorie Leduc
François Guillonneau
Patrick Mayeux
  • Function : Author
Serge Luquet
Pascale Bossard
Christine Perret
  • Function : Correspondent author
  • PersonId : 974574

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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.
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Dates and versions

hal-03097133 , version 1 (05-01-2021)

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Pierre-Alexandre Just, Sara Charawi, Raphaël Denis, Mathilde Savall, Massiré Traore, et al.. Lkb1 suppresses amino acid-driven gluconeogenesis in the liver. Nature Communications, 2020, 11, pp.6127. ⟨10.1038/s41467-020-19490-6⟩. ⟨hal-03097133⟩
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