The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver
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The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver. / Patel, Kashyap; Foretz, Marc; Marion, Allison; Campbell, David G.; Gourlay, Robert; Boudaba, Nadia; Tournier, Emilie; Titchenell, Paul; Peggie, Mark; Deak, Maria; Wan, Min; Kaestner, Klaus H.; Göransson, Olga; Viollet, Benoit; Gray, Nathanael S.; Birnbaum, Morris J.; Sutherland, Calum; Sakamoto, Kei.
In: Nature Communications, Vol. 5, 4535, 04.08.2014.Research output: Contribution to journal › Journal article › Research › peer-review
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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.
UR - http://www.scopus.com/inward/record.url?scp=84905457029&partnerID=8YFLogxK
U2 - 10.1038/ncomms5535
DO - 10.1038/ncomms5535
M3 - Journal article
C2 - 25088745
AN - SCOPUS:84905457029
VL - 5
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 4535
ER -
ID: 239213063