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

作者：Kashyap Patel, Marc Foretz, Allison Marion, David G. Campbell, Robert Gourlay, Nadia Boudaba, É. Tournier, Paul M. Titchenell, Mark Peggie, Mária Deák, Min Wan, Klaus H. Kaestner, Olga Göransson, Benoı̂t Viollet, Nathanael S. Gray, Morris J. Birnbaum, Calum Sutherland, Kei Sakamoto · 发表于：Nature Communications · 年份：2014 · DOI：10.1038/ncomms5535 · 被引用次数：165 · 研究领域：Metabolism, Diabetes, and Cancer、Pancreatic function and diabetes、Plant nutrient uptake and metabolism

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.