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

K Patel, M Foretz, A Marion, DG Campbell… - Nature …, 2014 - nature.com
K Patel, M Foretz, A Marion, DG Campbell, R Gourlay, N Boudaba, E Tournier, P Titchenell
Nature communications, 2014nature.com
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 …
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.
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