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
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Gene Expression Regulation / drug effects
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Gluconeogenesis / drug effects*
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Gluconeogenesis / genetics
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
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Immediate-Early Proteins / genetics
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Immediate-Early Proteins / metabolism*
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Liver / drug effects*
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Liver / metabolism*
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Mice
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Models, Biological
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Phosphoenolpyruvate Carboxykinase (ATP) / genetics
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Phosphoenolpyruvate Carboxykinase (ATP) / metabolism
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Phosphoprotein Phosphatases / metabolism*
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Pregnane X Receptor
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Promoter Regions, Genetic
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Protein Binding
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Protein Phosphatase 2C
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA Interference
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Receptors, Steroid / agonists*
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Transcription, Genetic
Substances
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Immediate-Early Proteins
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Pregnane X Receptor
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Receptors, Steroid
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Protein Serine-Threonine Kinases
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serum-glucocorticoid regulated kinase
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PPM1A protein, human
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PPM1B protein, human
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PPM1G protein, human
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Phosphoprotein Phosphatases
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Protein Phosphatase 2C
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Phosphoenolpyruvate Carboxykinase (ATP)