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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases
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Animals
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Fasting
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Gene Expression Regulation
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Glucagon / pharmacology
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Gluconeogenesis / drug effects
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Gluconeogenesis / genetics*
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Glucose / metabolism
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Hepatocytes / pathology
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Hyperglycemia / genetics*
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Hyperglycemia / metabolism
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Hyperglycemia / pathology
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Insulin / metabolism
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Liver / drug effects
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Liver / metabolism
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Liver / pathology
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Male
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Mice
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Mice, Knockout
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Phenylurea Compounds / pharmacology
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / pharmacology
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / metabolism
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Pyrimidines / pharmacology
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Signal Transduction
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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CRTC3 protein, mouse
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Crtc2 protein, mouse
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HG-9-91-01
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Insulin
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Phenylurea Compounds
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Protein Kinase Inhibitors
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Pyrimidines
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Transcription Factors
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Glucagon
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salt-inducible kinase-2, mouse
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Protein Serine-Threonine Kinases
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SIK3 protein, mouse
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Sik1 protein, mouse
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Stk11 protein, mouse
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AMP-Activated Protein Kinases
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Glucose