Involvement of pregnane X receptor in the suppression of carboxylesterases by metformin in vivo and in vitro, mediated by the activation of AMPK and JNK signaling pathway
Involvement of pregnane X receptor in the suppression of carboxylesterases by metformin in vivo and in vitro, mediated by the activation of AMPK and JNK signaling pathway
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通过激活 AMPK 和 JNK 信号通路介导孕烷 X 受体参与二甲双胍体内外对羧酸酯酶的抑制
DOI：
10.1016/j.ejps.2017.02.031
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发表时间：
2017-05-01
影响因子：
4.6
通讯作者：
Xiong, Jing
中科院分区：
文献类型：
--
作者：
Shan, Enfang;Zhu, Zhu;Xiong, Jing
2型糖尿病（T2D）是一种复杂的代谢性疾病，临床上需要多药治疗，其中二甲双胍是广泛使用的降血糖药物。然而，迄今为止，二甲双胍作为诱发潜在药物间相互作用和药物不良反应的肇事者的机制尚不清楚。羧酸酯酶 (CES) 是在肝脏中高表达的主要水解酶，包括小鼠羧酸酯酶 1d (Ces1d) 和 Ces1e。在本研究中，实验旨在研究二甲双胍在体内和体外对Ces1d和Ces1e的影响和机制。结果显示，二甲双胍以剂量和时间依赖性方式抑制 Ces1d 和 Ces1e 的表达和活性。核受体PXR及其靶基因P-gp表达的降低表明PXR参与了二甲双胍抑制羧酸酯酶表达的过程。此外，二甲双胍显着抑制AMPK和JNK的磷酸化，并且二甲双胍诱导的羧酸酯酶的抑制被AMPK抑制剂Compound C和JNK抑制剂SP600125反复消除。这意味着 AMPK 和 JNK 途径的激活介导了二甲双胍对羧酸酯酶的抑制。这些发现值得进一步阐明，包括临床试验，并有可能为 T2D 患者的合理用药做出贡献。 (C) 2017 Elsevier B.V. 保留所有权利。
Type 2 diabetes mellitus (T2D) is a complex metabolic disorder requiring polypharmacy treatment in clinic, with metformin being widely used antihyperglycemic drug. However, the mechanisms of metformin as a perpetrator inducing potential drug-drug interactions and adverse drug reactions are scarcely known to date. Carboxylesterases (CESs) are major hydrolytic enzymes highly expressed in the liver, including mouse carboxylesterase 1d (Ces1d) and Ces1e. In the present study, experiments are designed to investigate the effects and mechanisms of metformin on Ces1d and Ces1e in vivo and in vitro. In results, metformin suppresses the expression and activity of Ces1d and Ces1e in a dose- and time-dependent manner. The decreased expression of nuclear receptor PXR and its target gene P-gp indicates the involvements of PXR in the suppressed expression of carboxylesterases by metformin. Furthermore, metformin significantly suppresses the phosphorylation of AMPK and JNK, and the suppression of carboxylesterases induced by metformin is repeatedly abolished by AMPK inhibitor Compound C and JNK inhibitor SP600125. It implies that the activation of AMPK and JNK pathways mediates the suppression of carboxylesterases by metformin. The findings deserve further elucidation including clinical trials and have a potential to make contribution for the rational medication in the treatment of T2D patients. (C) 2017 Elsevier B.V. All rights reserved.