他汀激活的核受体PXR通过搭建PP2C支架促进SGK2去磷酸化，从而诱导肝糖异生。
Statin-activated nuclear receptor PXR promotes SGK2 dephosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis.
作者信息
Gotoh Saki, Negishi Masahiko
机构信息
Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
出版信息
Sci Rep. 2015 Sep 22;5:14076. doi: 10.1038/srep14076.
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.
已知他汀类药物疗法会提高人体血糖水平。他汀类药物利用孕烷X受体（PXR）和血清/糖皮质激素调节激酶2（SGK2）来激活磷酸烯醇丙酮酸羧激酶1（PEPCK1）和葡萄糖-6-磷酸酶（G6Pase）基因，从而增加人肝细胞中的葡萄糖生成。在此，一种新型的他汀类药物/PXR/SGK2介导的信号通路现已被确定为肝脏糖异生的特征。他汀激活的PXR将蛋白磷酸酶2C（PP2C）和SGK2结合在一起，刺激PP2C使SGK2的苏氨酸193去磷酸化。非磷酸化的SGK2共同激活人肝细胞中PXR介导的糖异生基因启动子的反式激活，从而增强糖异生。这种糖异生的他汀-PXR-SGK2信号在小鼠中不存在，在小鼠中他汀治疗会抑制肝脏糖异生。这些发现为他汀类药物相关的副作用（如2型糖尿病风险增加）提供了依据。
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