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The LKB1-salt-induc...
The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver.
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Patel, Kashyap (author)
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Foretz, Marc (author)
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Marion, Allison (author)
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Campbell, David G (author)
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Gourlay, Robert (author)
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Boudaba, Nadia (author)
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Tournier, Emilie (author)
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Titchenell, Paul (author)
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Peggie, Mark (author)
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Deak, Maria (author)
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Wan, Min (author)
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Kaestner, Klaus H (author)
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- Göransson, Olga (author)
- Lund University,Lunds universitet,Proteinfosforylering,Forskargrupper vid Lunds universitet,Protein Phosphorylation,Lund University Research Groups
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Viollet, Benoit (author)
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Gray, Nathanael S (author)
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Birnbaum, Morris J (author)
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Sutherland, Calum (author)
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Sakamoto, Kei (author)
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(creator_code:org_t)
- 2014-08-04
- 2014
- English.
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5:Aug 4
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
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- art (subject category)
- ref (subject category)
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- By the author/editor
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Patel, Kashyap
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Foretz, Marc
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Marion, Allison
-
Campbell, David ...
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Gourlay, Robert
-
Boudaba, Nadia
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show more...
-
Tournier, Emilie
-
Titchenell, Paul
-
Peggie, Mark
-
Deak, Maria
-
Wan, Min
-
Kaestner, Klaus ...
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Göransson, Olga
-
Viollet, Benoit
-
Gray, Nathanael ...
-
Birnbaum, Morris ...
-
Sutherland, Calu ...
-
Sakamoto, Kei
-
show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Endocrinology an ...
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Nature Communica ...
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Lund University