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)

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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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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

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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.

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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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