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, Kei Sakamoto

Research output: Contribution to journalArticlepeer-review

94 Citations (SciVal)
249 Downloads (Pure)

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.
Original languageEnglish
Article number4535
JournalNature Communications
Volume5
Issue numberAug 4
DOIs
Publication statusPublished - 2014

Subject classification (UKÄ)

  • Endocrinology and Diabetes

Fingerprint

Dive into the research topics of 'The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver.'. Together they form a unique fingerprint.

Cite this