Metabolic adaptation of skeletal muscle to hyperammonemia drives the beneficial effects of l-leucine in cirrhosis.
Metabolic adaptation of skeletal muscle to hyperammonemia drives the beneficial effects of l-leucine in cirrhosis.
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DOI：
10.1016/j.jhep.2016.06.004
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发表时间：
2016-11
影响因子：
25.7
通讯作者：
Dasarathy S
中科院分区：
文献类型：
--
作者：
Davuluri G;Krokowski D;Guan BJ;Kumar A;Thapaliya S;Singh D;Hatzoglou M;Dasarathy S
骨骼肌氨摄取增加与肌肉质量损失对肝硬化的临床结果不利。高氨血症导致蛋白质合成减少和肌肉减少，但细胞对蛋白质平衡受损的反应和l -亮氨酸诱导的适应氨诱导应激的分子机制尚不清楚。定量分析肝硬化患者和门静脉吻合（PCA）大鼠骨骼肌对氨基酸缺乏传感器GCN2激活的反应。在高氨血症和补充l -亮氨酸的过程中，我们量化了蛋白质合成、eIF2α磷酸化、mTORC1信号传导、l -亮氨酸运输和对l -亮氨酸补充的反应。通过ATF4及其靶基因GADD34对细胞应激的适应也被确定。在肝硬化患者和PCA大鼠的骨骼肌中观察到eIF2α激酶GCN2的激活和mTORC1信号通路的受损。氨激活GCN2介导的eIF2α磷酸化（eIF2α - p），并破坏mTORC1信号，抑制肌管和mef中的蛋白质合成。对氨胁迫的适应不涉及通过激活转录因子4 （ATF4）依赖性诱导的eIF2α-P磷酸酶亚基GADD34的翻译重编程。相反，氨增加了亮氨酸/谷氨酰胺交换器SLC7A5的表达、l -亮氨酸摄取和细胞内l -亮氨酸水平，后者不足以挽救蛋白质合成的抑制，因为可能增强了l -亮氨酸的线粒体封存。补充l -亮氨酸可缓解高氨血症引起的蛋白质合成抑制。对高氨血症的反应让人想起细胞对氨基酸饥饿的反应，但缺乏适应性ATF4依赖的综合应激反应（ISR）。相反，高氨诱导的l -亮氨酸摄取是对gcn2介导的蛋白质合成减少的适应性反应。
Increased skeletal muscle ammonia uptake with loss of muscle mass adversely affects clinical outcomes in cirrhosis. Hyperammonemia causes reduced protein synthesis and sarcopenia but the cellular responses to impaired proteostasis and molecular mechanism of L-leucine induced adaptation to ammonia-induced stress were determined. Response to activation of amino acid deficiency sensor, GCN2, in the skeletal muscle from cirrhotic patients and the portacaval anastomosis (PCA) rat were quantified. During hyperammonemia and L-leucine supplementation, protein synthesis, phosphorylation of eIF2α, mTORC1 signaling, L-leucine transport and response to L-leucine supplementation were quantified. Adaptation to cellular stress via ATF4 and its target GADD34 were also determined. Activation of the eIF2α kinase GCN2 and impaired mTORC1 signaling were observed in skeletal muscle from cirrhotic patients and PCA rats. Ammonia activated GCN2 mediated eIF2α phosphorylation (eIF2α–P) and impaired mTORC1 signaling that inhibit protein synthesis in myotubes and MEFs. Adaptation to ammonia-induced stress did not involve translational reprogramming by activation transcription factor 4 (ATF4) dependent induction of the eIF2α-P phosphatase subunit GADD34. Instead, ammonia increased expression of the leucine/glutamine exchanger SLC7A5, L-leucine uptake and intracellular L-leucine levels, the latter not being sufficient to rescue the inhibition of protein synthesis, due to potentially enhanced mitochondrial sequestration of L-leucine. L-leucine supplementation rescued protein synthesis inhibition caused by hyperammonemia. Response to hyperammonemia is reminiscent of the cellular response to amino acid starvation, but lacks the adaptive ATF4 dependent integrated stress response (ISR). Instead, hyperammonemia-induced L-leucine uptake was an adaptive response to the GCN2-mediated decreased protein synthesis.
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影响因子：
21.3
作者：
通讯作者：
--
影响因子：
16
作者：
Harding, HP;Novoa, I;Ron, D
通讯作者：
Ron, D
影响因子：
25.7
作者：
Chatauret, Nicolas;Desjardins, Paul;Butterworth, Roger F.
通讯作者：
Butterworth, Roger F.
DOI：
10.1083/jcb.153.5.1011
发表时间：
2001-05-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Novoa I;Zeng H;Harding HP;Ron D
通讯作者：
Ron D
影响因子：
3.5
作者：
Atherton, Philip J.;Smith, Ken;Rennie, Michael J.
通讯作者：
Rennie, Michael J.