Statin-activated nuclear receptor PXR promotes SGK2 dephosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis.
Statin-activated nuclear receptor PXR promotes SGK2 dephosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis.
复制标题
DOI：
10.1038/srep14076
复制
发表时间：
2015-09-22
影响因子：
4.6
通讯作者：
Negishi M
中科院分区：
文献类型：
--
作者：
Gotoh S;Negishi M
已知他汀类药物治疗会增加人体的血糖水平。他汀类药物利用胆甾烷X受体（PXR）和血清/糖皮质激素调节激酶2（SGK 2）激活磷酸烯醇丙酮酸羧激酶1（PEPCK 1）和葡萄糖-6-磷酸酶（G6 β）基因，从而增加人肝细胞中的葡萄糖产生。在这里，新的他汀类药物/PXR/SGK 2介导的信号通路现在已被表征为肝细胞增生。他汀激活的PXR支架蛋白磷酸酶2C（PP 2C）和SGK 2刺激PP 2C去磷酸化SGK 2在苏氨酸193。非磷酸化的SGK 2共激活PXR介导的人肝细胞中促凋亡基因启动子的反式激活，从而增强促凋亡。这种致肝硬化的他汀类药物-PXR-SGK 2信号在小鼠中不存在，其中他汀类药物治疗抑制肝硬化发生。这些发现为他汀类药物相关的副作用提供了依据，例如增加2型糖尿病的风险。
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.