Nature communications, 2014-08, Vol.5 (1), p.4535, Article 4535
2014
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- Autor(en) / Beteiligte
- Titel
- The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver
- Ist Teil von
- Nature communications, 2014-08, Vol.5 (1), p.4535, Article 4535
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2014
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/ncomms5535Titel-ID: cdi_swepub_primary_oai_lup_lub_lu_se_1e0aab87_e13a_47c4_b51b_13a4009f4a5f
- Format
- –
- Schlagworte
- AMP-Activated Protein Kinases, Animals, Clinical Medicine, Endocrinology and Diabetes, Endokrinologi och diabetes, Fasting, Gene Expression Regulation, Glucagon - pharmacology, Gluconeogenesis - drug effects, Gluconeogenesis - genetics, Glucose - metabolism, Hepatocytes - drug effects, Hepatocytes - metabolism, Hepatocytes - pathology, Hyperglycemia - genetics, Hyperglycemia - metabolism, Hyperglycemia - pathology, Insulin - metabolism, Klinisk medicin, Liver - drug effects, Liver - metabolism, Liver - pathology, Male, Medical and Health Sciences, Medicin och hälsovetenskap, Mice, Mice, Knockout, Phenylurea Compounds - pharmacology, Phosphorylation - drug effects, Protein Kinase Inhibitors - pharmacology, Protein Serine-Threonine Kinases - deficiency, Protein Serine-Threonine Kinases - genetics, Protein Serine-Threonine Kinases - metabolism, Pyrimidines - pharmacology, Signal Transduction, Transcription Factors - genetics, Transcription Factors - metabolism