Altered glycogen metabolism in cultured astrocytes from mice with chronic glutathione deficit; relevance for neuroenergetics in schizophrenia.
Altered glycogen metabolism in cultured astrocytes from mice with chronic glutathione deficit; relevance for neuroenergetics in schizophrenia.
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DOI：
10.1371/journal.pone.0022875
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Magistretti PJ
中科院分区：
文献类型：
--
作者：
Lavoie S;Allaman I;Petit JM;Do KQ;Magistretti PJ
神经退行性和精神疾病，包括阿尔茨海默病、帕金森病或亨廷顿病和精神分裂症，都与谷胱甘肽（GSH）缺乏有关。特别是谷氨酸半胱氨酸连接酶调节亚基（GCLM）基因的多态性与精神分裂症有关。GSH是最重要的细胞内抗氧化剂，并且对于去除利用葡萄糖提供能量所产生的反应性副产物是必需的。此外，通过戊糖磷酸途径的葡萄糖代谢是NADPH的主要来源，NADPH是还原型谷胱甘肽再生所必需的辅因子。本研究的目的是研究培养的GCLM基因敲除小鼠的星形胶质细胞中的葡萄糖代谢，其显示GSH水平降低。在野生型和敲除细胞之间没有观察到葡萄糖基础代谢的差异。相反，糖原水平较低，其营业额较高敲除星形胶质细胞。这些变化伴随着参与其合成和降解的基因表达的减少，包括靶向糖原的蛋白质。在由叔丁基过氧化氢诱导的氧化挑战期间，野生型细胞增加了它们的糖原动员和葡萄糖摄取。然而，敲除星形胶质细胞在相同的应激后不能动员糖原，并且它们只能在主要氧化损伤后增加它们的葡萄糖利用。总之，这些结果表明，葡萄糖代谢和糖原利用失调的星形胶质细胞表现出慢性赤字的GSH，这表明脑能量代谢的一个基本方面的改变是由GSH赤字引起的，因此可能与精神分裂症中观察到的代谢功能障碍。
Neurodegenerative and psychiatric disorders including Alzheimer's, Parkinson's or Huntington's diseases and schizophrenia have been associated with a deficit in glutathione (GSH). In particular, a polymorphism in the gene of glutamate cysteine ligase modulatory subunit (GCLM) is associated with schizophrenia. GSH is the most important intracellular antioxidant and is necessary for the removal of reactive by-products generated by the utilization of glucose for energy supply. Furthermore, glucose metabolism through the pentose phosphate pathway is a major source of NADPH, the cofactor necessary for the regeneration of reduced glutathione. This study aims at investigating glucose metabolism in cultured astrocytes from GCLM knockout mice, which show decreased GSH levels. No difference in the basal metabolism of glucose was observed between wild-type and knockout cells. In contrast, glycogen levels were lower and its turnover was higher in knockout astrocytes. These changes were accompanied by a decrease in the expression of the genes involved in its synthesis and degradation, including the protein targeting to glycogen. During an oxidative challenge induced by tert-Butylhydroperoxide, wild-type cells increased their glycogen mobilization and glucose uptake. However, knockout astrocytes were unable to mobilize glycogen following the same stress and they could increase their glucose utilization only following a major oxidative insult. Altogether, these results show that glucose metabolism and glycogen utilization are dysregulated in astrocytes showing a chronic deficit in GSH, suggesting that alterations of a fundamental aspect of brain energy metabolism is caused by GSH deficit and may therefore be relevant to metabolic dysfunctions observed in schizophrenia.
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影响因子：
2.3
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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通讯作者：
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影响因子：
2.9
作者：
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通讯作者：
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作者：
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