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

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Author

  • 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
  • Kei Sakamoto
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Summary, in English

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.

Publishing year

2014

Language

English

Publication/Series

Nature Communications

Volume

5

Issue

Aug 4

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Protein Phosphorylation

ISBN/ISSN/Other

  • ISSN: 2041-1723