PPP1R3C mediates metformin-inhibited hepatic gluconeogenesis
PPP1R3C mediates metformin-inhibited hepatic gluconeogenesis
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PPP1R3C 介导二甲双胍抑制的肝脏糖异生
DOI：
10.1016/j.metabol.2019.06.002
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发表时间：
2019-09-01
影响因子：
9.8
通讯作者：
Zhou, Libin
中科院分区：
文献类型：
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作者：
Ji, Xueying;Wang, Shushu;Zhou, Libin
背景：二甲双胍已被广泛用于减轻2型糖尿病患者的高血糖症，主要是通过抑制肝糖异生。但是，基本机制仍然尚不完全清楚。在这里，我们旨在探讨PPP1R3C在二甲双胍介导的肝糖异生抑制中的作用。方法：通过微阵列分析了与8-BR-兼营和二甲双胍孵育的原代小鼠肝细胞中差异表达的基因。腺病毒介导的过表达或体外PPP1R3C沉默后，检测到肝葡萄糖的产生和糖原基因表达。通过蛋白质印迹和免疫荧光确定了调节CREB活性2（TORC2）的透明度水平和位置。回归：二甲双胍和腺病毒介导的AMPK激活AMPK抑制了8- BR-CAMP刺激的PPP1R3C MRNA在初级小鼠Hepatocytes中的PPP1R3C mRNA表达。 PPP1R3C在原代小鼠肝细胞或野生型小鼠的肝脏中的过表达促进了肝葡萄糖的产生和糖生成基因表达。相反，腺病毒介导的原代小鼠肝细胞中PPP1R3C的敲低降低了肝糖异生，并抑制了CAMP刺激的糖生成基因表达和Torc2 dephosphoration。值得注意的是，DB/DB小鼠的肝脏中PPP1R3C的表达增加。在野生型和DB/DB小鼠的肝脏中PPP1R3C沉默后，血糖水平和肝葡萄糖产生显着降低，显着降低了葡萄糖生成酶和转录因子和转录因子的表达降低，以及肝脏糖原含量。通过阻断cAMP刺激的torc2去磷酸化，糖异生。 PPP1R3C的肝比沉默为2型糖尿病提供了有希望的治疗策略。 （c）2019 Elsevier Inc.保留所有权利。
Background: Metformin has been widely used to alleviate hyperglycemia in patients with type 2 diabetes mainly via suppressing hepatic gluconeogenesis. However, the underlying mechanism remains incompletely clear. Here, we aimed to explore the role of PPP1R3C in metformin-mediated inhibition of hepatic gluconeogenesis.Methods: The differentially expressed genes in primary mouse hepatocytes incubated with 8-Br-cAMP and metformin were analyzed by microarrays. Hepatic glucose production and gluconeogenic gene expressions were detected after adenovirus-mediated overexpression or silence of PPP1R3C in vitro and in vivo. The phosphorylation level and location of transducer of regulated CREB activity 2 (TORC2) were determined by Western blot and immunofluorescence.Results: Metformin and adenovirus-mediated activation of AMPK suppressed 8-Br-cAMP-stimulated Ppp1r3c mRNA expression in primary mouse hepatocytes. Overexpression of PPP1R3C in primary mouse hepatocytes or the livers of wild-type mice promoted hepatic glucose production and gluconeogenic gene expressions. On the contrary, adenovirus-mediated knockdown of PPP1R3C in primary mouse hepatocytes decreased hepatic gluconeogenesis, with the suppression of cAMP-stimulated gluconeogenic gene expressions and TORC2 dephosphorylation. Notably, Ppp1r3c expression was increased in the liver of db/db mice. After PPP1R3C silence in the livers of wild-type and db/db mice, blood glucose levels and hepatic glucose production were markedly lowered, with decreased expressions of key gluconeogenic enzymes and transcript factors as well as liver glycogen content.Conclusion: Metformin-activated AMPK decreases hepatic PPP1R3C expression, leading to the suppression of hepatic gluconeogenesis through blocking cAMP-stimulated TORC2 dephosphorylation. Hepatic specific silence of PPP1R3C provides a promising therapeutic strategy for type 2 diabetes. (C) 2019 Elsevier Inc. All rights reserved.