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Lkb1 suppresses amino acid-driven gluconeogenesis in the liver

Pierre-Alexandre Just 1 Sara Charawi 1 Raphaël Denis 2 Mathilde Savall 1 Massiré Traore 1 Marc Foretz 1 Sultan Bastu 1 Salimata Magassa 3 Nadia Senni 1 Pierre Sohier 1 Maud Wursmer 1 Mireille Vasseur-Cognet 4 Alain Schmitt 1 Morgane Le Gall 1 Marjorie Leduc 1 François Guillonneau 1 Jean-Pascal de Bandt 3 Patrick Mayeux 1 Béatrice Romagnolo 1 Serge Luquet 2 Pascale Bossard 1 Christine Perret 1
1 IC UM3 (UMR 8104 / U1016) - Institut Cochin
2 BFA (UMR_8251 / U1133) - Unité de Biologie Fonctionnelle et Adaptative
3 PRETRRAM - EA 4466 - Prévention et traitement de la perte protéique musculaire en situation de résistance à l'anabolisme
4 IEES (UMR_7618 / UMR_D_242 / UMR_A_1392 / UM_113) - Institut d'écologie et des sciences de l'environnement de Paris
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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https://hal.archives-ouvertes.fr/hal-03097133
Contributor : Pascale Bossard <>
Submitted on : Tuesday, January 5, 2021 - 11:53:21 AM
Last modification on : Monday, January 11, 2021 - 11:54:19 AM

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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, Nature Publishing Group, 2020, 11, pp.6127. ⟨10.1038/s41467-020-19490-6⟩. ⟨hal-03097133⟩

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