The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin

Science. 2005 Dec 9;310(5754):1642-6. doi: 10.1126/science.1120781. Epub 2005 Nov 24.

Abstract

The Peutz-Jegher syndrome tumor-suppressor gene encodes a protein-threonine kinase, LKB1, which phosphorylates and activates AMPK [adenosine monophosphate (AMP)-activated protein kinase]. The deletion of LKB1 in the liver of adult mice resulted in a nearly complete loss of AMPK activity. Loss of LKB1 function resulted in hyperglycemia with increased gluconeogenic and lipogenic gene expression. In LKB1-deficient livers, TORC2, a transcriptional coactivator of CREB (cAMP response element-binding protein), was dephosphorylated and entered the nucleus, driving the expression of peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), which in turn drives gluconeogenesis. Adenoviral small hairpin RNA (shRNA) for TORC2 reduced PGC-1alpha expression and normalized blood glucose levels in mice with deleted liver LKB1, indicating that TORC2 is a critical target of LKB1/AMPK signals in the regulation of gluconeogenesis. Finally, we show that metformin, one of the most widely prescribed type 2 diabetes therapeutics, requires LKB1 in the liver to lower blood glucose levels.

Publication types

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

MeSH terms

  • AMP-Activated Protein Kinases
  • Animals
  • Blood Glucose / analysis
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism
  • Enzyme Activation
  • Female
  • Gene Expression Regulation
  • Gluconeogenesis / genetics
  • Glucose / metabolism*
  • HeLa Cells
  • Homeostasis
  • Humans
  • Hyperglycemia / drug therapy
  • Hyperglycemia / metabolism
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Lipogenesis / genetics
  • Liver / enzymology
  • Liver / metabolism*
  • Male
  • Metformin / pharmacology*
  • Metformin / therapeutic use
  • Mice
  • Mice, Obese
  • Multienzyme Complexes / metabolism*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors

Substances

  • Blood Glucose
  • Crtc2 protein, mouse
  • Hypoglycemic Agents
  • Multienzyme Complexes
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Trans-Activators
  • Transcription Factors
  • Metformin
  • Stk11 protein, mouse
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Glucose