Details

Autor(en) / Beteiligte

• Shaw, Reuben J
• Lamia, Katja A
• Vasquez, Debbie
• Koo, Seung-Hoi
• Bardeesy, Nabeel
• DePinho, Ronald A
• Montminy, Marc
• Cantley, Lewis C

Titel

Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin

Ist Teil von

• Science (American Association for the Advancement of Science), 2005-12, Vol.310 (5754), p.1642-1646

Ort / Verlag

Washington, DC: American Association for the Advancement of Science

Erscheinungsjahr

2005

Link zum Volltext

Quelle

American Association for the Advancement of Science

Beschreibungen/Notizen

• 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 1[alpha] (PGC-1[alpha]), which in turn drives gluconeogenesis. Adenoviral small hairpin RNA (shRNA) for TORC2 reduced PGC-1[alpha] 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.