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

Kashyap Patel, Marc Foretz (), Allison Marion, David G. Campbell, Robert Gourlay, Nadia Boudaba, Emilie Tournier, Paul Titchenell, Mark Peggie, Maria Deak, Min Wan, Klaus H. Kaestner, Olga Göransson, Benoit Viollet, Nathanael S. Gray, Morris J. Birnbaum, Calum Sutherland and Kei Sakamoto ()
Additional contact information
Kashyap Patel: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
Marc Foretz: INSERM, U1016, Institut Cochin
Allison Marion: INSERM, U1016, Institut Cochin
David G. Campbell: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
Robert Gourlay: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
Nadia Boudaba: INSERM, U1016, Institut Cochin
Emilie Tournier: INSERM, U1016, Institut Cochin
Paul Titchenell: The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania
Mark Peggie: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
Maria Deak: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
Min Wan: The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania
Klaus H. Kaestner: The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania
Olga Göransson: Lund University, BMC C11
Benoit Viollet: INSERM, U1016, Institut Cochin
Nathanael S. Gray: Harvard Medical School, Dana–Farber Cancer Institute
Morris J. Birnbaum: The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania
Calum Sutherland: Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee
Kei Sakamoto: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK

Nature Communications, 2014, vol. 5, issue 1, 1-16

Abstract: 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.

Date: 2014
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/ncomms5535 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5535

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms5535

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().