The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver

Kashyap Patel; Marc Foretz; Allison Marion; David G. Campbell; Robert Gourlay; Nadia Boudaba; Emilie Tournier; Paul Titchenell; Mark Peggie; Maria Deak; Min Wan; Klaus H. Kaestner; Olga Göransson; Benoit Viollet; Nathanael S. Gray; Morris J. Birnbaum; Calum Sutherland; Kei Sakamoto

doi:10.1038/ncomms5535

The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver

Kashyap Patel
, Marc Foretz (Lead / Corresponding author)
, Allison Marion
, David G. Campbell
, Robert Gourlay
, Nadia Boudaba
, Emilie Tournier
, Paul Titchenell
, Mark Peggie
, Maria Deak
, Min Wan
, Klaus H. Kaestner
, Olga Göransson
, Benoit Viollet
, Nathanael S. Gray
, Morris J. Birnbaum
, Calum Sutherland
, Kei Sakamoto (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

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Abstract

LKB1 is a master kinase that regulates metabolism and growth through adenosine monophosphate-activated protein kinase (AMPK) and 12 other closely related kinases. Liver-specific ablation of LKB1 causes increased glucose production in hepatocytes in vitro and hyperglycaemia in fasting mice in vivo. Here we report that the salt-inducible kinases (SIK1, 2 and 3), members of the AMPK-related kinase family, play a key role as gluconeogenic suppressors downstream of LKB1 in the liver. The selective SIK inhibitor HG-9-91-01 promotes dephosphorylation of transcriptional co-activators CRTC2/3 resulting in enhanced gluconeogenic gene expression and glucose production in hepatocytes, an effect that is abolished when an HG-9-91-01-insensitive mutant SIK is introduced or LKB1 is ablated. Although SIK2 was proposed as a key regulator of insulin-mediated suppression of gluconeogenesis, we provide genetic evidence that liver-specific ablation of SIK2 alone has no effect on gluconeogenesis and insulin does not modulate SIK2 phosphorylation or activity. Collectively, we demonstrate that the LKB1-SIK pathway functions as a key gluconeogenic gatekeeper in the liver.

Original language	English
Article number	4535
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5535
Publication status	Published - 4 Aug 2014

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http://www.nature.com/ncomms/2014/140804/ncomms5535/full/ncomms5535.html#affil-auth

Sutherland, Calum
- Diabetes Endocrinology and Reproductive Biology - Professor (Teaching and Research) of Molecular and Cellular Diabetes
Person: Academic

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Patel, K., Foretz, M., Marion, A., Campbell, D. G., Gourlay, R., Boudaba, N., Tournier, E., Titchenell, P., Peggie, M., Deak, M., Wan, M., Kaestner, K. H., Göransson, O., Viollet, B., Gray, N. S., Birnbaum, M. J., Sutherland, C., & Sakamoto, K. (2014). The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver. Nature Communications, 5, Article 4535. https://doi.org/10.1038/ncomms5535

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title = "The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver",

abstract = "LKB1 is a master kinase that regulates metabolism and growth through adenosine monophosphate-activated protein kinase (AMPK) and 12 other closely related kinases. Liver-specific ablation of LKB1 causes increased glucose production in hepatocytes in vitro and hyperglycaemia in fasting mice in vivo. Here we report that the salt-inducible kinases (SIK1, 2 and 3), members of the AMPK-related kinase family, play a key role as gluconeogenic suppressors downstream of LKB1 in the liver. The selective SIK inhibitor HG-9-91-01 promotes dephosphorylation of transcriptional co-activators CRTC2/3 resulting in enhanced gluconeogenic gene expression and glucose production in hepatocytes, an effect that is abolished when an HG-9-91-01-insensitive mutant SIK is introduced or LKB1 is ablated. Although SIK2 was proposed as a key regulator of insulin-mediated suppression of gluconeogenesis, we provide genetic evidence that liver-specific ablation of SIK2 alone has no effect on gluconeogenesis and insulin does not modulate SIK2 phosphorylation or activity. Collectively, we demonstrate that the LKB1-SIK pathway functions as a key gluconeogenic gatekeeper in the liver.",

author = "Kashyap Patel and Marc Foretz and Allison Marion and Campbell, \{David G.\} and Robert Gourlay and Nadia Boudaba and Emilie Tournier and Paul Titchenell and Mark Peggie and Maria Deak and Min Wan and Kaestner, \{Klaus H.\} and Olga G{\"o}ransson and Benoit Viollet and Gray, \{Nathanael S.\} and Birnbaum, \{Morris J.\} and Calum Sutherland and Kei Sakamoto",

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Patel, K, Foretz, M, Marion, A, Campbell, DG, Gourlay, R, Boudaba, N, Tournier, E, Titchenell, P, Peggie, M, Deak, M, Wan, M, Kaestner, KH, Göransson, O, Viollet, B, Gray, NS, Birnbaum, MJ, Sutherland, C & Sakamoto, K 2014, 'The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver', Nature Communications, vol. 5, 4535. https://doi.org/10.1038/ncomms5535

TY - JOUR

T1 - The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver

AU - Patel, Kashyap

AU - Foretz, Marc

AU - Marion, Allison

AU - Campbell, David G.

AU - Gourlay, Robert

AU - Boudaba, Nadia

AU - Tournier, Emilie

AU - Titchenell, Paul

AU - Peggie, Mark

AU - Deak, Maria

AU - Wan, Min

AU - Kaestner, Klaus H.

AU - Göransson, Olga

AU - Viollet, Benoit

AU - Gray, Nathanael S.

AU - Birnbaum, Morris J.

AU - Sutherland, Calum

AU - Sakamoto, Kei

PY - 2014/8/4

Y1 - 2014/8/4

N2 - LKB1 is a master kinase that regulates metabolism and growth through adenosine monophosphate-activated protein kinase (AMPK) and 12 other closely related kinases. Liver-specific ablation of LKB1 causes increased glucose production in hepatocytes in vitro and hyperglycaemia in fasting mice in vivo. Here we report that the salt-inducible kinases (SIK1, 2 and 3), members of the AMPK-related kinase family, play a key role as gluconeogenic suppressors downstream of LKB1 in the liver. The selective SIK inhibitor HG-9-91-01 promotes dephosphorylation of transcriptional co-activators CRTC2/3 resulting in enhanced gluconeogenic gene expression and glucose production in hepatocytes, an effect that is abolished when an HG-9-91-01-insensitive mutant SIK is introduced or LKB1 is ablated. Although SIK2 was proposed as a key regulator of insulin-mediated suppression of gluconeogenesis, we provide genetic evidence that liver-specific ablation of SIK2 alone has no effect on gluconeogenesis and insulin does not modulate SIK2 phosphorylation or activity. Collectively, we demonstrate that the LKB1-SIK pathway functions as a key gluconeogenic gatekeeper in the liver.

AB - LKB1 is a master kinase that regulates metabolism and growth through adenosine monophosphate-activated protein kinase (AMPK) and 12 other closely related kinases. Liver-specific ablation of LKB1 causes increased glucose production in hepatocytes in vitro and hyperglycaemia in fasting mice in vivo. Here we report that the salt-inducible kinases (SIK1, 2 and 3), members of the AMPK-related kinase family, play a key role as gluconeogenic suppressors downstream of LKB1 in the liver. The selective SIK inhibitor HG-9-91-01 promotes dephosphorylation of transcriptional co-activators CRTC2/3 resulting in enhanced gluconeogenic gene expression and glucose production in hepatocytes, an effect that is abolished when an HG-9-91-01-insensitive mutant SIK is introduced or LKB1 is ablated. Although SIK2 was proposed as a key regulator of insulin-mediated suppression of gluconeogenesis, we provide genetic evidence that liver-specific ablation of SIK2 alone has no effect on gluconeogenesis and insulin does not modulate SIK2 phosphorylation or activity. Collectively, we demonstrate that the LKB1-SIK pathway functions as a key gluconeogenic gatekeeper in the liver.

U2 - 10.1038/ncomms5535

DO - 10.1038/ncomms5535

M3 - Article

C2 - 25088745

SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

M1 - 4535

ER -

The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver

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