Central Nervous System Lipoproteins: ApoE and Regulation of Cholesterol Metabolism.
Central Nervous System Lipoproteins: ApoE and Regulation of Cholesterol Metabolism.
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DOI：
10.1161/atvbaha.116.307023
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发表时间：
2016-07
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影响因子：
--
通讯作者：
Mahley RW
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作者：
Mahley RW
高密度脂蛋白的APOE主要负责中枢神经系统（CNS）中的脂质转运和胆固醇稳态。通常主要由星形胶质细胞产生，APOE也由神经元在神经病理条件下产生。高密度脂蛋白的APOE对于重新分布胆固醇和磷脂以进行膜修复和重塑至关重要。 3个主要的结构同工型在其有效性上有所不同。与APOE2和APOE3不同，APOE4明显改变了中枢神经系统代谢，与阿尔茨海默氏病和其他神经退行性疾病有关，并且在脑和脑脊液中较低水平表达。表达APOE4的培养的星形胶质细胞和神经元降低了胆固醇和磷脂分泌，脂质结合能力降低，并增加了细胞内降解。两种结构特征导致APOE4功能障碍：域相互作用，其中精氨酸61与谷氨酸-255与APOE3和APOE2相比，精氨酸61与谷氨酸-255相互作用且稳定构象不那么稳定。通过基因靶向（用苏氨酸代替精氨酸-61）或通过小分子结构校正器来阻断结构域的相互作用，从而增加了CNS APOE4水平和脂质结合能力，并降低了细胞内降解。破坏结构域相互作用的小分子（药物），即所谓的结构校正器，可以通过阻止神经毒性片段的形成来防止与APOE4相关的神经病理学。了解如何调节中枢神经系统胆固醇的运输和代谢正在为中枢神经系统健康和疾病提供重要的见解。
ApoE on high-density lipoproteins is primarily responsible for lipid transport and cholesterol homeostasis in the central nervous system (CNS). Normally produced mostly by astrocytes, apoE is also produced under neuropathologic conditions by neurons. ApoE on high-density lipoproteins is critical in redistributing cholesterol and phospholipids for membrane repair and remodeling. The 3 main structural isoforms differ in their effectiveness. Unlike apoE2 and apoE3, apoE4 has markedly altered CNS metabolism, is associated with Alzheimer disease and other neurodegenerative disorders, and is expressed at lower levels in brain and cerebrospinal fluid. ApoE4-expressing cultured astrocytes and neurons have reduced cholesterol and phospholipid secretion, decreased lipid-binding capacity, and increased intracellular degradation. Two structural features are responsible for apoE4 dysfunction: domain interaction, in which arginine-61 interacts ionically with glutamic acid-255, and a less stable conformation than apoE3 and apoE2. Blocking domain interaction by gene targeting (replacing arginine-61 with threonine) or by small-molecule structure correctors increases CNS apoE4 levels and lipid-binding capacity and decreases intracellular degradation. Small molecules (drugs) that disrupt domain interaction, so-called structure correctors, could prevent the apoE4-associated neuropathology by blocking the formation of neurotoxic fragments. Understanding how to modulate CNS cholesterol transport and metabolism is providing important insights into CNS health and disease.