Docosahexaenoic acid: A positive modulator of Akt signaling in neuronal survival
Docosahexaenoic acid: A positive modulator of Akt signaling in neuronal survival
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DOI：
10.1073/pnas.0502903102
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发表时间：
2005-08-02
影响因子：
11.1
通讯作者：
Kim, HY
中科院分区：
文献类型：
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作者：
Akbar, M;Calderon, F;Kim, HY
磷脂酰肌醇3-激酶[PI（3）K]/Akt信号通路是细胞存活的关键途径。在这里，我们证明了一种机制，膜改变的n-3脂肪酸状态影响Akt信号，影响神经元的存活。二十二碳六烯酸（DHA）是一种在神经元膜中高度富集的n-3多不饱和脂肪酸，通过其增加磷脂酰丝氨酸（PS）（细胞膜中的主要酸性磷脂）的能力促进Akt的膜移位/活化来促进神经元存活。PI（3）K的活化和磷脂酰肌醇三磷酸的形成不受DHA的影响，表明Akt的膜相互作用是DHA效应的原因。在n-3脂肪酸缺乏期间替代DHA的二十二碳五烯酸在积累PS和易位Akt方面效果较差，因此在预防细胞凋亡方面效果较差。一致，在体内减少DHA的饮食消耗n-3脂肪酸减少海马PS和增加神经元的易感性，细胞凋亡的文化。这种机制可能导致与n-3脂肪酸缺乏相关的神经功能缺损，并支持DHA在脑缺血或阿尔茨海默病等病理模型中的保护作用。
Phosphatidylinositol 3-kinase [PI (3)K]/Akt signaling is a critical pathway in cell survival. Here, we demonstrate a mechanism where membrane alteration by the n-3 fatty acid status affects Akt signaling, impacting neuronal survival. Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid highly enriched in neuronal membranes, promotes neuronal survival by facilitating membrane translocation/activation of Akt through its capacity to increase phosphatidylserine (PS), the major acidic phospholipid in cell membranes. The activation of PI (3)K and phosphatidylsinositol triphosphate formation were not affected by DHA, indicating that membrane interaction of Akt is the event responsible for the DHA effect. Docosapentaenoic acid, which replaces DHA during n-3 fatty acid deficiency, was less effective in accumulating PS and translocating Akt and thus less effective in preventing apoptosis. Consistently, in vivo reduction of DHA by dietary depletion of n-3 fatty acids decreased hippocampal PS and increased neuronal susceptibility to apoptosis in cultures. This mechanism may contribute to neurological deficits associated with n-3 fatty acid deficiency and support protective effects of DHA in pathological models such as brain ischemia or Alzheimer's disease.