Reuben J. Shaw1,2,3,4,5, Katja Lamia1,2,3,4,5, Debbie S. Vasquez1,2,3,4,5, Seung‐Hoi Koo1,2,3,4,5, Nabeel Bardeesy1,2,3,4,5, Ronald A. DePinho1,2,3,4,5, Marc Montminy1,2,3,4,5, Lewis C. Cantley1,2,3,4,5
1Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea
2Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
3Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
4Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
5Peptide Biology Laboratories, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Tóm tắt
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.
