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.
Highlights
In attempt to provide the basis of drug-induced gluconeogenesis, here we have determined the molecular mechanism by which PXR utilizes SGK2 to activate gluconeogenic genes following simvastatin treatment
SGK2 was involved in simvastatin-induced activation of the PEPCK1 gene but not CYP3A4 gene
Treatment with PXR siRNA confirmed that the simvastatin-induced activation of the PEPCK1 gene required both PXR and SGK2 (Fig. 1c)
Summary
Treatment with PXR siRNA confirmed that the simvastatin-induced activation of the PEPCK1 gene required both PXR and SGK2 (Fig. 1c). In addition to PEPCK1, simvastatin induction of G6Pase mRNA was regulated by both PXR and SGK2 in human primary hepatocytes as well as ShP51 cells (Supplementary Fig. 1a,b). Simvastatin and not pravastatin (non-PXR activator17,18) that stimulated the dephosphorylation of Thr[193] in ShP51 cells (Fig. 2b).
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