Direct molecular and spectroscopic evidence for increased ammonia removal capacity of skeletal muscle in acute liver failure
Direct molecular and spectroscopic evidence for increased ammonia removal capacity of skeletal muscle in acute liver failure
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DOI：
10.1016/j.jhep.2005.11.048
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发表时间：
2006-06-01
影响因子：
25.7
通讯作者：
Butterworth, Roger F.
中科院分区：
文献类型：
--
作者：
Chatauret, Nicolas;Desjardins, Paul;Butterworth, Roger F.
背景/目的：有人提出，在急性肝衰竭时，骨骼肌通过增加谷氨酰胺合成来适应并成为负责清除血氨的主要器官，谷氨酰胺合成是由胞质中依赖ATP的谷氨酰胺合成酶催化的反应。为了研究这个问题，对肝血流阻断导致急性肝衰竭的大鼠骨骼肌中的谷氨酰胺合成酶表达及活性进行了检测。
方法：采用免疫印迹法和半定量逆转录聚合酶链反应分析来研究谷氨酰胺合成酶蛋白及基因表达。分别使用标准酶学测定法和[C - 13] - 核磁共振波谱法来测定谷氨酰胺合成酶活性和谷氨酰胺从头合成。
结果：在急性肝衰竭时，谷氨酰胺合成酶蛋白（而非基因）表达和酶活性显著上调，导致谷氨酰胺从头合成增加以及骨骼肌清除氨的能力增强。与骨骼肌相反，大脑中谷氨酰胺合成酶的表达和活性显著降低。
结论：这些发现表明，在急性肝衰竭时，骨骼肌通过谷氨酰胺合成酶的快速诱导来适应，从而增加其清除血氨的能力。维持肌肉量以及开发能够刺激肌肉谷氨酰胺合成酶的药物，可能为这种疾病提供有效的降氨策略。（c）2005年欧洲肝脏研究协会。由爱思唯尔出版社出版。保留所有权利。
Background/Aims: It has been proposed that, in acute liver failure, skeletal muscle adapts to become the principle organ responsible for removal of blood-borne ammonia by increasing glutamine synthesis, a reaction that is catalyzed by the cytosolic ATP-dependent enzyme glutamine synthetase. To address this issue, glutamine synthetase expression and activities were measured in skeletal muscle of rats with acute liver failure resulting from hepatic devascularization.Methods: Glutamine synthetase protein and gene expression were investigated using immunoblotting and semi-quantitative RT-PCR analysis. Glutamine synthetase activity and glutamine de novo synthesis were measured using, respectively, a standard enzymatic assay and [C-13]-nuclear magnetic resonance spectroscopy.Results: Glutamine synthetase protein (but not gene) expression and enzyme activities were significantly up-regulated leading to increased de novo synthesis of glutamine and increased skeletal muscle capacity for ammonia removal in acute liver failure. In contrast to skeletal muscle, expression and activities of glutamine synthetase in the brain were significantly decreased.Conclusions: These findings demonstrate that skeletal muscle adapts, through a rapid induction of glutamine synthetase, to increase its capacity for removal of blood-borne ammonia in acute liver failure. Maintenance of muscle mass together With the development of agents with the capacity to stimulate muscle glutamine synthetase could provide effective ammonia-lowering strategies in this disorder. (c) 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.