| dc.creator |
Patel, K |
|
| dc.creator |
Foretz, M |
|
| dc.creator |
Marion, A |
|
| dc.creator |
Campbell, DG |
|
| dc.creator |
Gourlay, R |
|
| dc.creator |
Boudaba, N |
|
| dc.creator |
Tournier, E |
|
| dc.creator |
Titchenell, P |
|
| dc.creator |
Peggie, M |
|
| dc.creator |
Deak, M |
|
| dc.creator |
Wan, M |
|
| dc.creator |
Kaestner, KH |
|
| dc.creator |
Göransson, O |
|
| dc.creator |
Viollet, B |
|
| dc.creator |
Gray, NS |
|
| dc.creator |
Birnbaum, MJ |
|
| dc.creator |
Sutherland, C |
|
| dc.creator |
Sakamoto, K |
|
| dc.date |
2017-11-08T14:43:26Z |
|
| dc.date |
2014-08-04 |
|
| dc.date |
2017-11-08T14:43:26Z |
|
| dc.identifier |
Vol. 5, article 4535 |
|
| dc.identifier |
10.1038/ncomms5535 |
|
| dc.identifier |
http://hdl.handle.net/10871/30210 |
|
| dc.identifier |
Nature Communications |
|
| dc.description |
This is the final version of the article. Available from Springer Nature via the DOI in this record. |
|
| dc.description |
LKB1 is a master kinase that regulates metabolism and growth through adenosine monophosphate-activated protein kinase (AMPK) and 12 other closely related kinases. Liver-specific ablation of LKB1 causes increased glucose production in hepatocytes in vitro and hyperglycaemia in fasting mice in vivo. Here we report that the salt-inducible kinases (SIK1, 2 and 3), members of the AMPK-related kinase family, play a key role as gluconeogenic suppressors downstream of LKB1 in the liver. The selective SIK inhibitor HG-9-91-01 promotes dephosphorylation of transcriptional co-activators CRTC2/3 resulting in enhanced gluconeogenic gene expression and glucose production in hepatocytes, an effect that is abolished when an HG-9-91-01-insensitive mutant SIK is introduced or LKB1 is ablated. Although SIK2 was proposed as a key regulator of insulin-mediated suppression of gluconeogenesis, we provide genetic evidence that liver-specific ablation of SIK2 alone has no effect on gluconeogenesis and insulin does not modulate SIK2 phosphorylation or activity. Collectively, we demonstrate that the LKB1-SIK pathway functions as a key gluconeogenic gatekeeper in the liver. |
|
| dc.description |
This work was supported
by the British MRC, the Re´gion Ile-de-France (CORDDIM), Socie´te´ Francophone du
Diabe´te (SFD) and the pharmaceutical companies supporting the Division of Signal
Transduction Therapy Unit (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline,
Merck KgaA, Janssen Pharmaceutica and Pfizer). K.P. is supported by the Wellcome Trust PhD Programme for Clinicians (093991/Z/10/Z) and A.M. is a recipient of a
post-doctoral fellowship from the Re´gion Ile-de-France (CORDDIM). This work is
supported by the NIH Grant RO1DK56886 to M.J.B. |
|
| dc.language |
en |
|
| dc.publisher |
Springer Nature |
|
| dc.relation |
The mass spectrometry data has been deposited to the ProteomeXchange
Consortium40 via the PRIDE partner repository under the accession code
PXD001032. |
|
| dc.relation |
https://www.ncbi.nlm.nih.gov/pubmed/25088745 |
|
| dc.rights |
Open access. This work is licensed under a Creative Commons Attribution 4.0
International License. The images or other third party material in this
article are included in the article’s Creative Commons license, unless indicated otherwise
in the credit line; if the material is not included under the Creative Commons license,
users will need to obtain permission from the license holder to reproduce the material.
To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
|
| dc.subject |
Animals |
|
| dc.subject |
Fasting |
|
| dc.subject |
Gene Expression Regulation |
|
| dc.subject |
Glucagon |
|
| dc.subject |
Gluconeogenesis |
|
| dc.subject |
Glucose |
|
| dc.subject |
Hepatocytes |
|
| dc.subject |
Hyperglycemia |
|
| dc.subject |
Insulin |
|
| dc.subject |
Liver |
|
| dc.subject |
Male |
|
| dc.subject |
Mice |
|
| dc.subject |
Mice, Knockout |
|
| dc.subject |
Phenylurea Compounds |
|
| dc.subject |
Phosphorylation |
|
| dc.subject |
Protein Kinase Inhibitors |
|
| dc.subject |
Protein-Serine-Threonine Kinases |
|
| dc.subject |
Pyrimidines |
|
| dc.subject |
Signal Transduction |
|
| dc.subject |
Transcription Factors |
|
| dc.title |
The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver |
|
| dc.type |
Article |
|