Statin-activated nuclear receptor PXR promotes SGK2 dephosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis

Sci Rep. 2015 Sep 22:5:14076. doi: 10.1038/srep14076.

Abstract

Statin therapy is known to increase blood glucose levels in humans. Statins utilize pregnane X receptor (PXR) and serum/glucocorticoid regulated kinase 2 (SGK2) to activate phosphoenolpyruvate carboxykinase 1 (PEPCK1) and glucose-6-phosphatase (G6Pase) genes, thereby increasing glucose production in human liver cells. Here, the novel statin/PXR/SGK2-mediated signaling pathway has now been characterized for hepatic gluconeogenesis. Statin-activated PXR scaffolds the protein phosphatase 2C (PP2C) and SGK2 to stimulate PP2C to dephosphorylate SGK2 at threonine 193. Non-phosphorylated SGK2 co-activates PXR-mediated trans-activation of promoters of gluconeogenic genes in human liver cells, thereby enhancing gluconeogenesis. This gluconeogenic statin-PXR-SGK2 signal is not present in mice, in which statin treatment suppresses hepatic gluconeogenesis. These findings provide the basis for statin-associated side effects such as an increased risk for Type 2 diabetes.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Gene Expression Regulation / drug effects
  • Gluconeogenesis / drug effects*
  • Gluconeogenesis / genetics
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • Liver / drug effects*
  • Liver / metabolism*
  • Mice
  • Models, Biological
  • Phosphoenolpyruvate Carboxykinase (ATP) / genetics
  • Phosphoenolpyruvate Carboxykinase (ATP) / metabolism
  • Phosphoprotein Phosphatases / metabolism*
  • Pregnane X Receptor
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Phosphatase 2C
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • Receptors, Steroid / agonists*
  • Transcription, Genetic

Substances

  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Immediate-Early Proteins
  • Pregnane X Receptor
  • Receptors, Steroid
  • Protein Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase
  • PPM1A protein, human
  • PPM1B protein, human
  • PPM1G protein, human
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2C
  • Phosphoenolpyruvate Carboxykinase (ATP)