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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Fasting
  • Gene Expression Regulation
  • Glucagon / pharmacology
  • Gluconeogenesis / drug effects
  • Gluconeogenesis / genetics*
  • Glucose / metabolism
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Hyperglycemia / genetics*
  • Hyperglycemia / metabolism
  • Hyperglycemia / pathology
  • Insulin / metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Phenylurea Compounds / pharmacology
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyrimidines / pharmacology
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • CRTC3 protein, mouse
  • Crtc2 protein, mouse
  • HG-9-91-01
  • Insulin
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Transcription Factors
  • Glucagon
  • Stk11 protein, mouse
  • salt-inducible kinase-2, mouse
  • Protein-Serine-Threonine Kinases
  • SIK3 protein, mouse
  • Sik1 protein, mouse
  • Glucose