The Glia-Neuron Lactate Shuttle and Elevated ROS Promote Lipid Synthesis in Neurons and Lipid Droplet Accumulation in Glia via APOE/D.
The Glia-Neuron Lactate Shuttle and Elevated ROS Promote Lipid Synthesis in Neurons and Lipid Droplet Accumulation in Glia via APOE/D.
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DOI：
10.1016/j.cmet.2017.08.024
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发表时间：
2017-11-07
期刊：
影响因子：
29
通讯作者：
Bellen HJ
中科院分区：
文献类型：
--
作者：
Liu L;MacKenzie KR;Putluri N;Maletić-Savatić M;Bellen HJ
活性氧簇(ROS)的升高诱导神经元中脂质的形成，这些脂质被转移到胶质细胞，在那里它们形成脂滴(LD)。我们发现，胶质和神经元单羧酸转运蛋白(MCTs)、脂肪酸转运蛋白(FATP)和载脂蛋白对胶质细胞LD的形成至关重要。MCT使胶质细胞分泌，神经元吸收乳酸，乳酸在神经元中转化为丙酮酸和乙酰辅酶A。乳酸代谢产物为脂肪酸的合成提供了底物，脂肪酸被FATP和载脂蛋白加工并转移到胶质细胞。在高ROS存在的情况下，抑制乳酸转移或降低FATP或载脂蛋白水平都会减少果蝇和原代小鼠神经胶质细胞培养中胶质细胞LD的积累。我们发现，人类APOE可以替代苍蝇胶质载脂蛋白，而APOE4，一种阿尔茨海默病的易感等位基因，在脂质运输方面受到损害，并促进神经退化，为疾病机制提供了见解。刘等人。解开一种进化上保守的机制，使神经元-胶质细胞代谢合作循环完整。他们表明，胶质乳酸可以刺激神经元的脂肪生成，以响应ROS；反过来，神经元的脂质以脂滴的形式在胶质细胞中运输和储存。在应激状态下，由于不能将脂质运输到神经胶质细胞形成脂滴，导致神经加速变性。
Elevated reactive oxygen species (ROS) induce the formation of lipids in neurons that are transferred to glia where they form lipid droplets (LD). We show that glial and neuronal monocarboxylate transporters (MCTs), fatty acid transport proteins (FATP), and apolipoproteins are critical for glial LD formation. MCTs enable glia to secrete and neurons to absorb lactate, which is converted to pyruvate and acetyl-CoA in neurons. Lactate metabolites provide a substrate for synthesis of fatty acids, which are processed and transferred to glia by FATP and apolipoproteins. In the presence of high ROS, inhibiting lactate transfer or lowering FATP or apolipoprotein levels all decrease glial LD accumulation in flies and in primary mouse glial-neuronal cultures. We show that human APOE can substitute for a fly glial apolipoprotein and that APOE4, an Alzheimer’s Disease susceptibility allele, is impaired in lipid transport and promotes neurodegeneration, providing insights into disease mechanisms. Liu et al. unravel an evolutionarily conserved mechanism which brings neuron-glia metabolic cooperation full circle. They show that glial lactate can fuel neuronal lipogenesis in response to ROS; in turn, neuronal lipids are transported and stored in glia as lipid droplets. The inability to transport lipids to glia for lipid droplet formation leads to accelerated neurodegeneration under stress.
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