The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver.
Författare
Summary, in English
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.
Publiceringsår
2014
Språk
Engelska
Publikation/Tidskrift/Serie
Nature Communications
Volym
5
Issue
Aug 4
Fulltext
Länkar
Dokumenttyp
Artikel i tidskrift
Förlag
Nature Publishing Group
Ämne
- Endocrinology and Diabetes
Status
Published
Forskningsgrupp
- Protein Phosphorylation
ISBN/ISSN/Övrigt
- ISSN: 2041-1723