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Science 310 (5754): 1642-1646

Copyright © 2005 by the American Association for the Advancement of Science

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

Reuben J. Shaw,1,2*{dagger} Katja A. Lamia,1,2 Debbie Vasquez,2 Seung-Hoi Koo,3,4 Nabeel Bardeesy,5 Ronald A. DePinho,6 Marc Montminy,3 Lewis C. Cantley1,2

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 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.

1 Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
2 Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
3 Peptide Biology Laboratories, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
4 Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea.
5 Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
6 Center for Applied Cancer Science and Department of Medical Oncology, Dana Farber Cancer Institute and Departments of Medicine and Genetics, Harvard Medical School, Boston, MA 02115, USA.

{dagger} Present address: Molecular and Cell Biology Laboratories, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037–1002, USA.

* To whom correspondence should be addressed. E-mail: shaw{at}salk.edu


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AMPK-dependent Repression of Hepatic Gluconeogenesis via Disruption of CREB{middle dot}CRTC2 Complex by Orphan Nuclear Receptor Small Heterodimer Partner.
J.-M. Lee, W.-Y. Seo, K.-H. Song, D. Chanda, Y. D. Kim, D.-K. Kim, M.-W. Lee, D. Ryu, Y.-H. Kim, J.-R. Noh, et al. (2010)
J. Biol. Chem. 285, 32182-32191
   Abstract »    Full Text »    PDF »
Regulation of bile canalicular network formation and maintenance by AMP-activated protein kinase and LKB1.
D. Fu, Y. Wakabayashi, Y. Ido, J. Lippincott-Schwartz, and I. M. Arias (2010)
J. Cell Sci. 123, 3294-3302
   Abstract »    Full Text »    PDF »
Signaling Kinase AMPK Activates Stress-Promoted Transcription via Histone H2B Phosphorylation.
D. Bungard, B. J. Fuerth, P.-Y. Zeng, B. Faubert, N. L. Maas, B. Viollet, D. Carling, C. B. Thompson, R. G. Jones, and S. L. Berger (2010)
Science 329, 1201-1205
   Abstract »    Full Text »    PDF »
Metformin Prevents Tobacco Carcinogen-Induced Lung Tumorigenesis.
R. M. Memmott, J. R. Mercado, C. R. Maier, S. Kawabata, S. D. Fox, and P. A. Dennis (2010)
Cancer Prevention Research 3, 1066-1076
   Abstract »    Full Text »    PDF »
Metformin and Other Biguanides in Oncology: Advancing the Research Agenda.
M. Pollak (2010)
Cancer Prevention Research 3, 1060-1065
   Abstract »    Full Text »    PDF »
Metformin Suppresses Colorectal Aberrant Crypt Foci in a Short-term Clinical Trial.
K. Hosono, H. Endo, H. Takahashi, M. Sugiyama, E. Sakai, T. Uchiyama, K. Suzuki, H. Iida, Y. Sakamoto, K. Yoneda, et al. (2010)
Cancer Prevention Research 3, 1077-1083
   Abstract »    Full Text »    PDF »
Sucrose nonfermenting AMPK-related kinase (SNARK) mediates contraction-stimulated glucose transport in mouse skeletal muscle.
H.-J. Koh, T. Toyoda, N. Fujii, M. M. Jung, A. Rathod, R. J.-W. Middelbeek, S. J. Lessard, J. T. Treebak, K. Tsuchihara, H. Esumi, et al. (2010)
PNAS 107, 15541-15546
   Abstract »    Full Text »    PDF »
LKB1 Deficiency in Tie2-Cre-expressing Cells Impairs Ischemia-induced Angiogenesis.
K. Ohashi, N. Ouchi, A. Higuchi, R. J. Shaw, and K. Walsh (2010)
J. Biol. Chem. 285, 22291-22298
   Abstract »    Full Text »    PDF »
Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1{alpha} pathway.
M. D. L. Chau, J. Gao, Q. Yang, Z. Wu, and J. Gromada (2010)
PNAS 107, 12553-12558
   Abstract »    Full Text »    PDF »
Diabetes and Cancer: A consensus report.
E. Giovannucci, D. M. Harlan, M. C. Archer, R. M. Bergenstal, S. M. Gapstur, L. A. Habel, M. Pollak, J. G. Regensteiner, and D. Yee (2010)
Diabetes Care 33, 1674-1685
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A Single Nucleotide Polymorphism in STK11 Influences Insulin Sensitivity and Metformin Efficacy in Hyperinsulinemic Girls With Androgen Excess.
A. Lopez-Bermejo, M. Diaz, E. Moran, F. de Zegher, and L. Ibanez (2010)
Diabetes Care 33, 1544-1548
   Abstract »    Full Text »    PDF »
Role of KLF15 in Regulation of Hepatic Gluconeogenesis and Metformin Action.
M. Takashima, W. Ogawa, K. Hayashi, H. Inoue, S. Kinoshita, Y. Okamoto, H. Sakaue, Y. Wataoka, A. Emi, Y. Senga, et al. (2010)
Diabetes 59, 1608-1615
   Abstract »    Full Text »    PDF »
Enhanced hepatitis C virus genome replication and lipid accumulation mediated by inhibition of AMP-activated protein kinase.
J. Mankouri, P. R. Tedbury, S. Gretton, M. E. Hughes, S. D. C. Griffin, M. L. Dallas, K. A. Green, D. G. Hardie, C. Peers, and M. Harris (2010)
PNAS 107, 11549-11554
   Abstract »    Full Text »    PDF »
Metformin in Cancer Therapy: A New Perspective for an Old Antidiabetic Drug?.
I. Ben Sahra, Y. Le Marchand-Brustel, J.-F. Tanti, and F. Bost (2010)
Mol. Cancer Ther. 9, 1092-1099
   Abstract »    Full Text »    PDF »
Crosstalk between Insulin/Insulin-like Growth Factor-1 Receptors and G Protein-Coupled Receptor Signaling Systems: A Novel Target for the Antidiabetic Drug Metformin in Pancreatic Cancer.
E. Rozengurt, J. Sinnett-Smith, and K. Kisfalvi (2010)
Clin. Cancer Res. 16, 2505-2511
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Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5.
P. W Caton, N. K Nayuni, J. Kieswich, N. Q Khan, M. M Yaqoob, and R. Corder (2010)
J. Endocrinol. 205, 97-106
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Potent and Specific Inhibition of mMate1-Mediated Efflux of Type I Organic Cations in the Liver and Kidney by Pyrimethamine.
S. Ito, H. Kusuhara, Y. Kuroiwa, C. Wu, Y. Moriyama, K. Inoue, T. Kondo, H. Yuasa, H. Nakayama, S. Horita, et al. (2010)
J. Pharmacol. Exp. Ther. 333, 341-350
   Abstract »    Full Text »    PDF »
AMPK and SIRT1: a long-standing partnership?.
N. B. Ruderman, X. Julia Xu, L. Nelson, J. M. Cacicedo, A. K. Saha, F. Lan, and Y. Ido (2010)
Am J Physiol Endocrinol Metab 298, E751-E760
   Abstract »    Full Text »    PDF »

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