title: Statin-activated nuclear receptor PXR promotes SGK2 dephosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis.
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.
authors.affiliation: Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Saki
authors.initials: S
authors.lastname: Gotoh
authors.affiliation: Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Negishi
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects* / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D000071636:Protein Phosphatase 2C; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011987:Receptors, Steroid / Q000819:agonists*; D014158:Transcription, Genetic; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017874:Immediate-Early Proteins; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D010749:Phosphoprotein Phosphatases; D000077297:Pregnane X Receptor; D000071636:Protein Phosphatase 2C; D017346:Protein Serine-Threonine Kinases; D011987:Receptors, Steroid; D000099184:Serum-Glucocorticoid Regulated Kinases; C000607456:PPM1A protein, human; C000607457:PPM1B protein, human; C000607460:PPM1G protein, human