Investigation of salicylate hepatic responses in comparison with chemical analogues of the drug.
Investigation of salicylate hepatic responses in comparison with chemical analogues of the drug.
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DOI：
10.1016/j.bbadis.2016.04.015
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发表时间：
2016-08
期刊：
影响因子：
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通讯作者：
Rena G
中科院分区：
文献类型：
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作者：
Cameron AR;Logie L;Patel K;Bacon S;Forteath C;Harthill J;Roberts A;Sutherland C;Stewart D;Viollet B;Sakamoto K;McDougall G;Foretz M;Rena G
羟基苯甲酸水杨酸的抗高血压作用可能源于药物对线粒体解偶联、AMP活化蛋白激酶的激活和NF-κB信号传导的抑制。在这里，我们已经衡量了这些影响的贡献，以控制肝细胞葡萄糖的生产，比较水杨酸酯与无活性羟基苯甲酸类似物的药物。在大鼠H4 IIE肝癌细胞中，水杨酸盐是唯一一种激活AMPK的药物。水杨酸盐也降低mTOR信号传导，但在类似物中广泛观察到这种性质。在一个类似物小组中，水杨酸盐单独降低了小鼠原代肝细胞中关键的促凋亡酶葡萄糖6-磷酸酶的启动子活性，并抑制了基础葡萄糖的产生。水杨酸和2，6-二羟基苯甲酸均能抑制TNFα诱导的IκB降解，并且在基因敲除实验中，我们发现水杨酸对IκB降解的作用不依赖于AMPK。先前的数据也确定了AMPK对葡萄糖的非依赖性调节，但我们发现直接抑制NF-κB和mTOR信号都不能抑制葡萄糖的产生，这表明可能需要考虑除了这些细胞信号通路之外的其他因素来解释水杨酸的这种反应。我们发现，例如，H4 IIE细胞对适度剂量的水杨酸盐解偶联非常敏感，这与另一种抗高血压解偶联剂2，4-二硝基苯酚的时间过程相似，而两种不抗高血压的水杨酸盐类似物没有明显的效果。这一发现支持了更早的文献，表明水杨酸盐至少部分通过解偶联发挥抗高血压作用。药理学和基因敲除方法用于研究水杨酸在肝细胞中的作用。水杨酸盐抑制NF-κB信号传导不需要AMPK。抑制NF-κB和mTOR都不能抑制肝细胞葡萄糖的产生。水杨酸盐在生理学相关剂量下充当解偶联剂。解偶联性质可能有助于抗高血压药物作用。
Anti-hyperglycaemic effects of the hydroxybenzoic acid salicylate might stem from effects of the drug on mitochondrial uncoupling, activation of AMP-activated protein kinase, and inhibition of NF-κB signalling. Here, we have gauged the contribution of these effects to control of hepatocyte glucose production, comparing salicylate with inactive hydroxybenzoic acid analogues of the drug. In rat H4IIE hepatoma cells, salicylate was the only drug tested that activated AMPK. Salicylate also reduced mTOR signalling, but this property was observed widely among the analogues. In a sub-panel of analogues, salicylate alone reduced promoter activity of the key gluconeogenic enzyme glucose 6-phosphatase and suppressed basal glucose production in mouse primary hepatocytes. Both salicylate and 2,6 dihydroxybenzoic acid suppressed TNFα-induced IκB degradation, and in genetic knockout experiments, we found that the effect of salicylate on IκB degradation was AMPK-independent. Previous data also identified AMPK-independent regulation of glucose but we found that direct inhibition of neither NF-κB nor mTOR signalling suppressed glucose production, suggesting that other factors besides these cell signalling pathways may need to be considered to account for this response to salicylate. We found, for example, that H4IIE cells were exquisitely sensitive to uncoupling with modest doses of salicylate, which occurred on a similar time course to another anti-hyperglycaemic uncoupling agent 2,4-dinitrophenol, while there was no discernible effect at all of two salicylate analogues which are not anti-hyperglycaemic. This finding supports much earlier literature suggesting that salicylates exert anti-hyperglycaemic effects at least in part through uncoupling. Pharmacology and knockout approaches were used to study salicylate in hepatocytes. AMPK is not required for salicylate to inhibit NF-κB signalling. Inhibition of neither NF-κB nor mTOR can suppress hepatocyte glucose production. Salicylate acts as an uncoupler at a physiologically relevant dose. Uncoupling properties are likely to contribute to anti-hyperglycaemic drug action.