TY - JOUR
T1 - Medicine
T2 - The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin
AU - Shaw, Reuben J.
AU - Lamia, Katja A.
AU - Vasquez, Debbie
AU - Koo, Seung Hoi
AU - Bardeesy, Nabeel
AU - DePinho, Ronald A.
AU - Montminy, Marc
AU - Cantley, Lewis C.
PY - 2005/12/9
Y1 - 2005/12/9
N2 - 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-γ coactivator 1α (PGC-1α), which in turn drives gluconeogenesis. Adenoviral small hairpin RNA (shRNA) for TORC2 reduced PGC-1α 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.
AB - 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-γ coactivator 1α (PGC-1α), which in turn drives gluconeogenesis. Adenoviral small hairpin RNA (shRNA) for TORC2 reduced PGC-1α 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.
UR - http://www.scopus.com/inward/record.url?scp=28844433635&partnerID=8YFLogxK
U2 - 10.1126/science.1120781
DO - 10.1126/science.1120781
M3 - Article
C2 - 16308421
AN - SCOPUS:28844433635
SN - 0036-8075
VL - 310
SP - 1642
EP - 1646
JO - Science
JF - Science
IS - 5754
ER -
