PMID- 33257663
OWN - NLM
STAT- MEDLINE
DCOM- 20201221
LR  - 20211204
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 11
IP  - 1
DP  - 2020 Nov 30
TI  - Lkb1 suppresses amino acid-driven gluconeogenesis in the liver.
PG  - 6127
LID - 10.1038/s41467-020-19490-6 [doi]
LID - 6127
AB  - 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.
FAU - Just, Pierre-Alexandre
AU  - Just PA
AD  - Universite de Paris, Institut Cochin, INSERM, CNRS, F75014, Paris, France.
AD  - APHP, Centre-Universite de Paris, Paris, France.
FAU - Charawi, Sara
AU  - Charawi S
AD  - Universite de Paris, Institut Cochin, INSERM, CNRS, F75014, Paris, France.
FAU - Denis, Raphael G P
AU  - Denis RGP
AUID- ORCID: 0000-0002-7677-7460
AD  - Unite de Biologie Fonctionnelle et Adaptative, Centre National la Recherche 
      Scientifique, Unite Mixte de Recherche 8251, Universite Paris Diderot, Sorbonne 
      Paris Cite, 75205, Paris, France.
FAU - Savall, Mathilde
AU  - Savall M
AD  - Universite de Paris, Institut Cochin, INSERM, CNRS, F75014, Paris, France.
FAU - Traore, Massire
AU  - Traore M
AD  - Universite de Paris, Institut Cochin, INSERM, CNRS, F75014, Paris, France.
FAU - Foretz, Marc
AU  - Foretz M
AUID- ORCID: 0000-0001-7017-9032
AD  - Universite de Paris, Institut Cochin, INSERM, CNRS, F75014, Paris, France.
FAU - Bastu, Sultan
AU  - Bastu S
AD  - Universite de Paris, Institut Cochin, INSERM, CNRS, F75014, Paris, France.
FAU - Magassa, Salimata
AU  - Magassa S
AD  - EA4466, PRETRAM, Universite Paris Descartes, Paris, France.
FAU - Senni, Nadia
AU  - Senni N
AD  - Universite de Paris, Institut Cochin, INSERM, CNRS, F75014, Paris, France.
FAU - Sohier, Pierre
AU  - Sohier P
AD  - Universite de Paris, Institut Cochin, INSERM, CNRS, F75014, Paris, France.
FAU - Wursmer, Maud
AU  - Wursmer M
AD  - Universite de Paris, Institut Cochin, INSERM, CNRS, F75014, Paris, France.
FAU - Vasseur-Cognet, Mireille
AU  - Vasseur-Cognet M
AD  - UMR IRD 242, UPEC, CNRS 7618, UPMC 113, INRA 1392, Sorbonne Universites Paris and 
      Institut d'Ecologie et des Sciences de l'Environnement de Paris, Bondy, France.
FAU - Schmitt, Alain
AU  - Schmitt A
AD  - Universite de Paris, Institut Cochin, INSERM, CNRS, F75014, Paris, France.
AD  - Electron Miscroscopy Facility, Institut Cochin, F75014, Paris, France.
FAU - Le Gall, Morgane
AU  - Le Gall M
AD  - Universite de Paris, Institut Cochin, INSERM, CNRS, F75014, Paris, France.
AD  - 3P5 proteom'IC Facility, Universite de Paris, Institut Cochin, INSERM, CNRS, 
      F-75014, Paris, France.
FAU - Leduc, Marjorie
AU  - Leduc M
AD  - Universite de Paris, Institut Cochin, INSERM, CNRS, F75014, Paris, France.
AD  - 3P5 proteom'IC Facility, Universite de Paris, Institut Cochin, INSERM, CNRS, 
      F-75014, Paris, France.
FAU - Guillonneau, Francois
AU  - Guillonneau F
AUID- ORCID: 0000-0003-1484-4696
AD  - Universite de Paris, Institut Cochin, INSERM, CNRS, F75014, Paris, France.
AD  - 3P5 proteom'IC Facility, Universite de Paris, Institut Cochin, INSERM, CNRS, 
      F-75014, Paris, France.
FAU - De Bandt, Jean-Pascal
AU  - De Bandt JP
AD  - EA4466, PRETRAM, Universite Paris Descartes, Paris, France.
FAU - Mayeux, Patrick
AU  - Mayeux P
AD  - Universite de Paris, Institut Cochin, INSERM, CNRS, F75014, Paris, France.
AD  - 3P5 proteom'IC Facility, Universite de Paris, Institut Cochin, INSERM, CNRS, 
      F-75014, Paris, France.
FAU - Romagnolo, Beatrice
AU  - Romagnolo B
AD  - Universite de Paris, Institut Cochin, INSERM, CNRS, F75014, Paris, France.
FAU - Luquet, Serge
AU  - Luquet S
AD  - Unite de Biologie Fonctionnelle et Adaptative, Centre National la Recherche 
      Scientifique, Unite Mixte de Recherche 8251, Universite Paris Diderot, Sorbonne 
      Paris Cite, 75205, Paris, France.
FAU - Bossard, Pascale
AU  - Bossard P
AD  - Universite de Paris, Institut Cochin, INSERM, CNRS, F75014, Paris, France.
FAU - Perret, Christine
AU  - Perret C
AUID- ORCID: 0000-0003-4710-7051
AD  - Universite de Paris, Institut Cochin, INSERM, CNRS, F75014, Paris, France. 
      christine.perret@inserm.fr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201130
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (Amino Acids)
RN  - EC 2.6.1.- (Transaminases)
RN  - EC 2.6.1.44 (Alanine-glyoxylate transaminase)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Stk11 protein, mouse)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
EIN - Nat Commun. 2021 Mar 17;12(1):1831. PMID: 33731695
MH  - AMP-Activated Protein Kinases
MH  - Amino Acids/*metabolism
MH  - Animals
MH  - Cachexia
MH  - Diabetes Mellitus, Type 2/metabolism
MH  - Fasting
MH  - Female
MH  - Gluconeogenesis/*physiology
MH  - Glucose/metabolism
MH  - Hepatocytes/metabolism
MH  - Hyperglycemia/metabolism
MH  - Liver/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Protein Serine-Threonine Kinases/genetics/*metabolism
MH  - Proteomics
MH  - Sarcopenia
MH  - Transaminases/metabolism
PMC - PMC7705018
COIS- The authors declare no competing interests.
EDAT- 2020/12/02 06:00
MHDA- 2020/12/22 06:00
PMCR- 2020/11/30
CRDT- 2020/12/01 05:56
PHST- 2019/05/22 00:00 [received]
PHST- 2020/10/12 00:00 [accepted]
PHST- 2020/12/01 05:56 [entrez]
PHST- 2020/12/02 06:00 [pubmed]
PHST- 2020/12/22 06:00 [medline]
PHST- 2020/11/30 00:00 [pmc-release]
AID - 10.1038/s41467-020-19490-6 [pii]
AID - 19490 [pii]
AID - 10.1038/s41467-020-19490-6 [doi]
PST - epublish
SO  - Nat Commun. 2020 Nov 30;11(1):6127. doi: 10.1038/s41467-020-19490-6.