Advanced

The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver.

Patel, Kashyap; Foretz, Marc; Marion, Allison; Campbell, David G; Gourlay, Robert; Boudaba, Nadia; Tournier, Emilie; Titchenell, Paul; Peggie, Mark and Deak, Maria, et al. (2014) In Nature Communications 5(Aug 4).
Abstract
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
5
issue
Aug 4
publisher
Nature Publishing Group
external identifiers
  • pmid:25088745
  • wos:000341044300001
  • scopus:84905457029
ISSN
2041-1723
DOI
10.1038/ncomms5535
language
English
LU publication?
yes
id
1e0aab87-e13a-47c4-b51b-13a4009f4a5f (old id 4615622)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25088745?dopt=Abstract
date added to LUP
2014-09-03 21:39:36
date last changed
2017-10-01 04:31:18
@article{1e0aab87-e13a-47c4-b51b-13a4009f4a5f,
  abstract     = {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.},
  articleno    = {4535},
  author       = {Patel, Kashyap and Foretz, Marc and Marion, Allison and Campbell, David G and Gourlay, Robert and Boudaba, Nadia and Tournier, Emilie and Titchenell, Paul and Peggie, Mark and Deak, Maria and Wan, Min and Kaestner, Klaus H and Göransson, Olga and Viollet, Benoit and Gray, Nathanael S and Birnbaum, Morris J and Sutherland, Calum and Sakamoto, Kei},
  issn         = {2041-1723},
  language     = {eng},
  number       = {Aug 4},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver.},
  url          = {http://dx.doi.org/10.1038/ncomms5535},
  volume       = {5},
  year         = {2014},
}