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

  • Nat Commun. 2014 Aug 4;5:4535. doi: 10.1038/ncomms5535.
Kashyap Patel  1 ,  Marc Foretz  2 ,  Allison Marion  3 ,  David G Campbell  4 ,  Robert Gourlay  4 ,  Nadia Boudaba  3 ,  Emilie Tournier  3 ,  Paul Titchenell  5 ,  Mark Peggie  4 ,  Maria Deak  4 ,  Min Wan  5 ,  Klaus H Kaestner  5 ,  Olga Göransson  6 ,  Benoit Viollet  3 ,  Nathanael S Gray  7 ,  Morris J Birnbaum  5 ,  Calum Sutherland  8 ,  Kei Sakamoto  1
Affiliations
  • 1. 1] MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK [2].
  • 2. 1] INSERM, U1016, Institut Cochin, 75014 Paris, France [2] CNRS, UMR8104, 75014 Paris, France [3] Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France [4].
  • 3. 1] INSERM, U1016, Institut Cochin, 75014 Paris, France [2] CNRS, UMR8104, 75014 Paris, France [3] Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
  • 4. MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
  • 5. The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
  • 6. The Department of Experimental Medical Science, Lund University, BMC C11, 221 84 Lund, Sweden.
  • 7. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
  • 8. Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.
PMID: 25088745 DOI: 10.1038/ncomms5535
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.

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