Carnosic acid stimulates glucose uptake in skeletal muscle cells via a PME-1/PP2A/PKB signalling axis
Carnosic acid stimulates glucose uptake in skeletal muscle cells via a PME-1/PP2A/PKB signalling axis
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DOI：
10.1016/j.cellsig.2014.07.022
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发表时间：
2014-11-01
影响因子：
4.8
通讯作者：
Hundal, Harinder S.
中科院分区：
文献类型：
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作者：
Lipina, Christopher;Hundal, Harinder S.
鼠尾草酸 (CA) 是唇形草本植物迷迭香 (Rosmarinus officinalis) 的主要成分，已被证明具有许多有益的健康特性。特别是，最近人们对 CA 的抗肥胖作用越来越感兴趣，包括其对抗肥胖相关高血糖和胰岛素抵抗的能力。然而，其抗糖尿病反应的机制尚不完全清楚。在这项研究中，我们假设 CA 可能通过增强外周葡萄糖清除率来改善血糖状态。在此，我们证明CA通过直接刺激大鼠骨骼L6肌管中的葡萄糖摄取来模拟胰岛素的代谢作用，同时增加GLUT4葡萄糖转运蛋白向质膜的易位。从机制上讲，CA 诱导的葡萄糖转运依赖于蛋白激酶 B (PKB/Akt)，而不是 AMPK，尽管这两种激酶均被 CA 激活。至关重要的是，根据其激活 PKB 和刺激葡萄糖摄取的能力，我们表明 CA 通过涉及 PME-1（蛋白磷酸酶甲酯酶-1）的途径传递这些作用，PME-1 是丝氨酸/苏氨酸磷酸酶 PP2A（蛋白磷酸酶 2A）的关键负调节因子。在此，我们证明 CA 促进 PME-1 介导的 PP2A 催化亚基去甲基化，导致其活性受到抑制，从而减轻 PP2A 对 PKB 的抑制作用。总的来说，我们的研究结果为 CA 如何通过 PME-1/PP2A/PKB 信号轴增强骨骼肌等组织中的外周葡萄糖清除率来改善葡萄糖稳态提供了新的见解，从而减轻与高血糖状态相关的病理效应。 (C) 2014 Elsevier Inc. 保留所有权利。
Carnosic acid (CA) is a major constituent of the labiate herbal plant Rosemary (Rosmarinus officinalis), which has been shown to exhibit a number of beneficial health properties. In particular, recently there has been growing interest into the anti-obesity effects conveyed by CA, including its ability to counteract obesity-associated hyperglycaemia and insulin resistance. However, the mechanisms underlying its anti-diabetic responses are not fully understood. In this study, we hypothesized that CA may act to improve glycaemic status through enhancing peripheral glucose clearance. Herein, we demonstrate that CA acts to mimic the metabolic actions of insulin by directly stimulating glucose uptake in rat skeletal L6 myotubes, concomitant with increased translocation of the GLUT4 glucose transporter to the plasma membrane. Mechanistically, CA-induced glucose transport was found to be dependent on protein kinase B (PKB/Akt) but not AMPK, despite both kinases being activated by CA. Crucially, in accordance with its ability to activate PKB and stimulate glucose uptake, we show that CA conveys these effects through a pathway involving PME-1 (protein phosphatase methylesterase-1), a key negative regulator of the serine/threonine phosphatase PP2A (protein phosphatase 2A). Herein, we demonstrate that CA promotes PME-1 mediated demethylation of the PP2A catalytic subunit leading to its suppressed activity, and in doing so, alleviates the repressive action of PP2A towards PKB. Collectively, our findings provide new insight into how CA may improve glucose homeostasis through enhancing peripheral glucose clearance in tissues such as skeletal muscle through a PME-1/PP2A/PKB signalling axis, thereby mitigating pathological effects associated with the hyperglycaemic state. (C) 2014 Elsevier Inc. All rights reserved.