Control of hepatic gluconeogenesis by Argonaute2.
Control of hepatic gluconeogenesis by Argonaute2.
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Argonaute2 对肝糖异生的控制
DOI：
10.1016/j.molmet.2018.10.003
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发表时间：
2018-12
影响因子：
8.1
通讯作者：
Poy MN
中科院分区：
文献类型：
--
作者：
Yan X;Wang Z;Bishop CA;Weitkunat K;Feng X;Tarbier M;Luo J;Friedländer MR;Burkhardt R;Klaus S;Willnow TE;Poy MN
肝脏通过增加空腹期间的葡萄糖输出在调节能量稳态中发挥核心作用。Argonaute 2（Ago 2）是介导microRNA通路的关键RNA结合蛋白，最近的研究表明其在适应代谢需求变化的机制中发挥作用。在这里，我们试图表征Ago 2在肝脏中维持全身葡萄糖稳态的功能作用。我们首先分析了Ago 2在小鼠原代肝细胞培养物中的表达，在调节细胞外葡萄糖浓度和存在葡萄糖激酶活性的激活剂或抑制剂的情况下。然后，我们表征了肝脏中Ago 2的条件性功能丧失小鼠模型的全身能量代谢的改变。在这里，我们表明，Ago 2在肝脏中的表达是直接相关的细胞外葡萄糖浓度和调节葡萄糖激酶活性是足以影响肝脏Ago 2水平。肝脏中Ago 2的条件性缺失除了减少肝脏葡萄糖产生之外还导致空腹葡萄糖水平降低。此外，Ago 2的缺失通过解除miR-148 a（肝脏中丰富的microRNA）对其靶向的抑制而促进AMP活化蛋白激酶α1（AMPKα1）的肝脏表达。从高血糖、肥胖和胰岛素抵抗的Lepob/ob小鼠中删除Ago 2降低了随机和空腹血糖水平和体重，并改善了胰岛素敏感性。这些数据说明了Ago 2在肝脏对禁食的适应性反应中的核心作用。Ago 2介导miR-148 a对AMPKα1的抑制，从而确定非编码RNA与肝细胞中关键应激调节因子之间的调控联系。肝Ago 2水平与细胞外葡萄糖浓度的变化相关。肝脏中Ago 2的条件性缺失降低了空腹血糖水平。Ago 2的缺失通过解除miR-148 a对AMPKα 1靶向的抑制而促进AMPKα1的表达。从Lepob/ob小鼠中删除Ago 2改善了胰岛素敏感性和胰岛素敏感性。
The liver performs a central role in regulating energy homeostasis by increasing glucose output during fasting. Recent studies on Argonaute2 (Ago2), a key RNA-binding protein mediating the microRNA pathway, have illustrated its role in adaptive mechanisms according to changes in metabolic demand. Here we sought to characterize the functional role of Ago2 in the liver in the maintenance of systemic glucose homeostasis. We first analyzed Ago2 expression in mouse primary hepatocyte cultures after modulating extracellular glucose concentrations and in the presence of activators or inhibitors of glucokinase activity. We then characterized a conditional loss-of-function mouse model of Ago2 in liver for alterations in systemic energy metabolism. Here we show that Ago2 expression in liver is directly correlated to extracellular glucose concentrations and that modulating glucokinase activity is adequate to affect hepatic Ago2 levels. Conditional deletion of Ago2 in liver resulted in decreased fasting glucose levels in addition to reducing hepatic glucose production. Moreover, loss of Ago2 promoted hepatic expression of AMP-activated protein kinase α1 (AMPKα1) by de-repressing its targeting by miR-148a, an abundant microRNA in the liver. Deletion of Ago2 from hyperglycemic, obese, and insulin-resistant Lepob/ob mice reduced both random and fasted blood glucose levels and body weight and improved insulin sensitivity. These data illustrate a central role for Ago2 in the adaptive response of the liver to fasting. Ago2 mediates the suppression of AMPKα1 by miR-148a, thereby identifying a regulatory link between non-coding RNAs and a key stress regulator in the hepatocyte. Hepatic Ago2 levels correlate with changes in extracellular glucose concentrations. Conditional deletion of Ago2 in liver decreased fasting glucose levels. Loss of Ago2 promoted AMPKα1 by de-repressing its targeting by miR-148a. Deletion of Ago2 from Lepob/ob mice improved glycemia and insulin sensitivity.
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影响因子：
29
作者：
Lin HV;Accili D
通讯作者：
Accili D
调节健康和疾病中肝葡萄糖代谢。
DOI：
10.1038/nrendo.2017.80
发表时间：
2017-10
期刊：
Nature reviews. Endocrinology
影响因子：
--
作者：
Petersen MC;Vatner DF;Shulman GI
通讯作者：
Shulman GI
DOI：
10.1007/978-1-59745-019-5_13
发表时间：
2010-01-01
期刊：
MOUSE CELL CULTURE: METHODS AND PROTOCOLS
影响因子：
--
作者：
Li, Wan-Chun;Ralphs, Kate L.;Tosh, David
通讯作者：
Tosh, David
影响因子：
7.7
作者：
Foretz, M;Ancellin, N;Viollet, B
通讯作者：
Viollet, B
影响因子：
13.5
作者：
Hand, Nicholas J.;Master, Zankhana R.;Le Lay, John;Friedman, Joshua R.
通讯作者：
Friedman, Joshua R.