Phillips Michael C
Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, 11-130 Translational Research Center, Philadelphia, PA, USA.
IUBMB Life. 2014 Sep;66(9):616-23. doi: 10.1002/iub.1314.
Apolipoprotein (apo) E is a 299-residue protein which functions as a key regulator of plasma lipid levels. Human apoE exists as three common isoforms and the parent form, apoE3, operates optimally in promoting clearance of triglyceride (TG)-rich lipoproteins and is associated with normal plasma lipid levels. This result occurs because apoE3 possesses both the requisite lipid-binding ability and affinity for the low density lipoprotein receptor (LDLR) to mediate appropriate lipolytic processing and endocytosis of TG-rich lipoprotein remnant particles. ApoE2 which differs from apoE3 by the single amino acid substitution Arg158Cys located near the LDLR recognition site exhibits impaired binding to the receptor and an inability to promote clearance of TG-rich lipoprotein remnant particles; this isoform is associated with Type-III hyperlipoproteinemia. ApoE4 which differs from apoE3 by the single amino acid substitution Cys112Arg is also associated with dyslipidemia although binding of this isoform to the LDLR is unaffected. The amino acid substitution affects the organization and stability of both the N-terminal helix bundle domain and separately folded C-terminal domain so that apoE4 has enhanced lipid binding ability. As a consequence, apoE4 binds better than apoE3 to the surface of very low density lipoprotein (VLDL) particles and impairs their lipolytic processing in the circulation so that apoE4 is associated with a more pro-atherogenic lipoprotein-cholesterol distribution (higher VLDL-cholesterol/high density lipoprotein-cholesterol ratio). This review summarizes current understanding of the structural differences between apoE2, apoE3, and apoE4, and the molecular mechanisms responsible for the alterations in lipoprotein metabolism resulting from this polymorphism of apoE. Detailed knowledge of how expression of structurally distinct apoE variants modifies lipoprotein metabolism provides a basis for developing ways to manipulate the functionality of apoE in vivo.
载脂蛋白（apo）E是一种由299个氨基酸残基组成的蛋白质，它是血浆脂质水平的关键调节因子。人类载脂蛋白E以三种常见的异构体形式存在，其原始形式载脂蛋白E3在促进富含甘油三酯（TG）的脂蛋白清除方面发挥着最佳作用，并与正常的血浆脂质水平相关。出现这种结果是因为载脂蛋白E3既具备必要的脂质结合能力，又对低密度脂蛋白受体（LDLR）具有亲和力，从而介导富含TG的脂蛋白残余颗粒进行适当的脂解处理和内吞作用。载脂蛋白E2与载脂蛋白E3的区别在于位于LDLR识别位点附近的单个氨基酸替换，即精氨酸158被半胱氨酸取代，它与受体的结合受损，无法促进富含TG的脂蛋白残余颗粒的清除；这种异构体与III型高脂蛋白血症有关。载脂蛋白E4与载脂蛋白E3的区别在于单个氨基酸替换，即半胱氨酸112被精氨酸取代，尽管这种异构体与LDLR的结合不受影响，但它也与血脂异常有关。氨基酸替换影响了N端螺旋束结构域和单独折叠的C端结构域的组织和稳定性，使得载脂蛋白E4具有增强的脂质结合能力。因此，载脂蛋白E4比载脂蛋白E3更能与极低密度脂蛋白（VLDL）颗粒表面结合，并损害其在循环中的脂解处理，从而使载脂蛋白E4与更具促动脉粥样硬化的脂蛋白胆固醇分布（更高的VLDL胆固醇/高密度脂蛋白胆固醇比率）相关。本综述总结了目前对载脂蛋白E2、载脂蛋白E3和载脂蛋白E4之间结构差异的理解，以及由载脂蛋白E这种多态性导致的脂蛋白代谢改变的分子机制。关于结构不同的载脂蛋白E变体的表达如何改变脂蛋白代谢的详细知识，为开发在体内操纵载脂蛋白E功能的方法提供了基础。
