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

2005; American Association for the Advancement of Science; Volume: 310; Issue: 5754 Linguagem: Inglês

10.1126/science.1120781

1095-9203

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

FOXO transcription factor regulation

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.