van den Maagdenberg A M, Hofker M H, Krimpenfort P J, de Bruijn I, van Vlijmen B, van der Boom H, Havekes L M, Frants R R
MGC-Department of Human Genetics, Leiden University, The Netherlands.
J Biol Chem. 1993 May 15;268(14):10540-5.
Apolipoprotein (apo) E3-Leiden, described in a large Dutch family, is associated with a dominantly inherited form of familial dysbetalipoproteinemia. To study the effect of the APOE3-Leiden mutation in vivo, transgenic mice were generated using a genomic 27-kilobase DNA construct isolated from the APOE3-Leiden proband. This construct carried the APOE gene, the APOC1 gene, and all known regulatory elements including an element that mediates liver expression. Three strains were generated that showed human APOE and APOC1 expression. All strains had significantly elevated levels of total plasma cholesterol and triglycerides on a regular diet. When mice of one strain were fed a semisynthetic cholesterol-rich diet, total plasma cholesterol and triglyceride levels increased dramatically. This increase was observed mainly in the very low density lipoprotein (VLDL)- and low density lipoprotein (LDL)-sized fractions. In cholesterol-fed mice, the apoE3-Leiden protein became equally distributed between the VLDL/LDL and HDL-sized fractions, while in mice kept on a regular diet, apoE3-Leiden protein was mainly associated with HDL-sized fractions. The presence of hyperlipoproteinemia in the APOE*3-Leiden-expressing transgenic mice supports our finding that the apoE3-Leiden variant behaves like a dominant trait in the expression of familial dysbetalipoproteinemia. ApoE3-Leiden transgenic mice may serve as a model to elucidate additional factors involved in the metabolism of apoE containing remnant lipoproteins in general and the etiology of familial dysbetalipoproteinemia in particular.
在一个荷兰大家族中发现的载脂蛋白（apo）E3-莱顿与家族性异常β脂蛋白血症的显性遗传形式相关。为了在体内研究APOE3-莱顿突变的作用，使用从APOE3-莱顿先证者分离的27千碱基基因组DNA构建体生成了转基因小鼠。该构建体携带APOE基因、APOC1基因以及所有已知的调控元件，包括一个介导肝脏表达的元件。产生了三个显示人APOE和APOC1表达的品系。所有品系在常规饮食下总血浆胆固醇和甘油三酯水平均显著升高。当给一个品系的小鼠喂食半合成富含胆固醇的饮食时，总血浆胆固醇和甘油三酯水平急剧增加。这种增加主要在极低密度脂蛋白（VLDL）和低密度脂蛋白（LDL）大小的组分中观察到。在喂食胆固醇的小鼠中，apoE3-莱顿蛋白在VLDL/LDL和HDL大小的组分中均匀分布，而在维持常规饮食的小鼠中，apoE3-莱顿蛋白主要与HDL大小的组分相关。表达APOE*3-莱顿的转基因小鼠中存在高脂蛋白血症支持了我们的发现，即apoE3-莱顿变体在家族性异常β脂蛋白血症的表达中表现为显性性状。apoE3-莱顿转基因小鼠可作为一个模型，用于阐明一般情况下参与含apoE的残余脂蛋白代谢的其他因素，特别是家族性异常β脂蛋白血症的病因。
