The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver.
(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:
https://lup.lub.lu.se/record/4615622
- author
- Patel, Kashyap
; Foretz, Marc
; Marion, Allison
; Campbell, David G
; Gourlay, Robert
; Boudaba, Nadia
; Tournier, Emilie
; Titchenell, Paul
; Peggie, Mark
; Deak, Maria
; Wan, Min
; Kaestner, Klaus H
; Göransson, Olga
LU
; Viollet, Benoit
; Gray, Nathanael S
; Birnbaum, Morris J
; Sutherland, Calum
and Sakamoto, Kei
(Less) - organization
- publishing date
- 2014
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Nature Communications
- volume
- 5
- issue
- Aug 4
- article number
- 4535
- 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
- 2016-04-01 14:59:36
- date last changed
- 2024-03-28 00:15:54
@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.}},
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 = {{https://lup.lub.lu.se/search/files/4288635/7864277}},
doi = {{10.1038/ncomms5535}},
volume = {{5}},
year = {{2014}},
}