LIPOPROTEIN METABOLISM IN TRANSGENIC MICE OVEREXPRESSING APOA-II

载脂蛋白A-II和载脂蛋白E是两种重要的载脂蛋白 血浆高密度脂蛋白。过表达apoA-II的转基因小鼠增加了 有动脉粥样硬化的风险，其特征是血浆水平升高 甘油三酯、高密度脂蛋白与一种独特的富载脂蛋白的形成 (LPE)在HDL1粒子的大小范围内。过度表达的小鼠 与对照组相比，载脂蛋白A-II出现自发性早期脂肪酸条纹 小鼠，即使保持在食物饮食中。血浆载脂蛋白A-II(152- 312 mg/dl)和apoE(6-10 mg/dl)与对照组相比增加 小鼠分别为34+/-16 mg/dl和6.8+/-0.7 mg/dl。 了解含有高密度脂蛋白和低密度脂蛋白的载脂蛋白A-II的形成 我们在体内进行了~(125)I-apoE和~(131)I-apoA-II的体内动力学研究。 A-II转基因小鼠(n=8)和年龄匹配的对照组(n=8)。血脂 A-II转基因水平(mg/dl)为TC=291-454 mg/dl，TG=83-279 mg/dl 对照组TC=128+/-29 mg/dl，TG=84+/-38 mg/dl。这个 A-II转基因小鼠的载脂蛋白E分解代谢明显延迟 与部分分解代谢率(FCR)为6.98+/-的正常人相比 2.18d-1和12.11+/-1.32d-1。A-II中的载脂蛋白A-II 当FCR=1.15时，转基因小鼠的分解代谢也比正常小鼠慢 +/-0.13d-1，生产效率(PR)=19.91+/-1.89 mg/g-d，FCR=1.85 +/-0.17d-1，PR=5.48+/-2.16 mg/g-d。载脂蛋白E和载脂蛋白A-II 在老鼠体内分解代谢的速度比人类快9倍和8倍。浅谈FPLC 分析对照组小鼠的载脂蛋白E主要存在于高密度脂蛋白上，而在 A-II转基因小鼠中，大部分载脂蛋白E都是对独特的富含载脂蛋白E 脂蛋白，HDL1中的LPE。 我们在A-II转基因小鼠中的研究表明，apoE是分解代谢的 比对照组小鼠慢2倍。A-II患者高密度脂蛋白水平升高 转基因小鼠是由于合成增加和 载脂蛋白A-II的延迟分解代谢。LPE的血浆水平升高 颗粒主要是由于apoE分解代谢降低所致。LPE 颗粒可能在A-AS患者动脉粥样硬化风险增加中发挥作用 转基因小鼠。

ApoA-II and apoE are two important apolipoproteins associated with plasma HDL. Transgenic mice overexpressing apoA-II have an increased risk of atherosclerosis and are characterized by elevated plasma triglycerides, HDL and the development of a unique apoE rich lipoprotein (LpE) in the size range of the HDL1 particle. Mice overexpressing mouse apoA-II develop spontaneous early fatty acid streaks compared to control mice even when maintained on a chow diet. Plasma levels of apoA-II (152- 312 mg/dl) and apoE (6-10 mg/dl) were increased when compared to control mice levels of 34 +/- 16 mg/dl and 6.8 +/- 0.7 mg/dl, respectively. To gain insight into the formation of the apoA-II containing HDL and LpE we performed in vivo kinetic studies of 125I-apoE and 131I-apoA-II in A-II transgenic mice (n=8) and age matched controls (n=8). Plasma lipid levels (mg/dl) in A-II transgenic were TC=291-454 mg/dl, Tg=83-279 mg/dl and in control mice TC=128 +/- 29 mg/dl, Tg=84 +/- 38 mg/dl. The catabolism of apoE in A-II transgenic mice was markedly delayed when compared to normals with fractional catabolic rates (FCR) of 6.98 +/- 2.18 d -1 and 12.11 +/- 1.32 d -1, respectively. ApoA-II in A-II transgenic mice was also catabolized slower than normals with FCR=1.15 +/- 0.13d -1, production rate (PR)=19.91 +/- 1.89 mg/g-d and FCR=1.85 +/- 0.17d -1, PR=5.48 +/- 2.16 mg/g-d, respectively. ApoE and apoA-II are catabolized 9 fold and 8 fold faster in mice than humans. On FPLC analysis apoE in control mice was present predominantly on HDL while in A-II transgenic mice the majority of apoE was on the unique apoE rich lipoprotein, LpE in HDL1. Our studies in A-II transgenic mice indicate that apoE is catabolized 2 fold slower than in control mice. The elevated HDL level in A-II transgenic mice is due to a combination of increased synthesis and delayed catabolism of apoA-II. The elevated plasma level of the LpE particle is due predominantly to decreased catabolism of apoE. The LpE particle may play a role in the increased risk of atherosclerosis in A- II transgenic mice.