Greeve J, Jona V K, Chowdhury N R, Horwitz M S, Chowdhury J R
Medizinische Klinik, Universitäts-Krankenhaus Eppendorf, Hamburg, Germany.
J Lipid Res. 1996 Sep;37(9):2001-17.
Apolipoprotein (apo) B exists in two forms, the full length protein apoB-100 and the carboxyterminal-truncated apoB-48 that is synthesized in the intestine due to editing of the apoB mRNA which generates a premature stop codon. To determine whether gene transfer of the catalytic subunit of the apoB mRNA editing enzyme APOBEC-1 (apoB mRNA editing enzyme catalytic polypeptide 1) into the liver of rabbits reconstitutes hepatic apoB mRNA editing and how this affects the plasma levels of apoB-containing lipoproteins, we constructed an APOBEC-1 recombinant adenovirus (Ad APOBEC-1). After injection of Ad APOBEC-1 into normal New Zealand White (NZW) or Watanabe heritable hyperlipidemic (WHHL) rabbits, up to 50% of the hepatic apoB mRNA was edited and freshly isolated hepatocytes secreted predominantly apoB-48-containing lipoproteins. VLDL isolated from Ad APOBEC-1-treated NZW and WHHL rabbits contained both apoB-100 and apoB-48, whereas that from control rabbits infected with a beta-galactosidase recombinant adenovirus (Ad LacZ) contained exclusively apoB-100. VLDL from WHHL rabbits treated with Ad APOBEC-1 had the same particle size, lipid composition, and content of apolipoprotein E as VLDL from Ad LacZ-infected control animals. An increase of VLDL was observed in NZW and WHHL rabbits after infection with Ad APOBEC-1 as well as Ad LacZ. After injection of Ad APOBEC-1, LDL became undetectable in the plasma of NZW rabbits and was reduced by an average of 65% in the plasma of WHHL rabbits compared to Ad LacZ-infected controls. LDL from Ad APOBEC-1-infected WHHL rabbits contained only apoB-100. VLDL isolated from Ad APOBEC-1-infected WHHL rabbits were rapidly cleared from the circulation after injection into NZW rabbits. These results provide further evidence that the switch in the hepatic synthesis from exclusively apoB-100 to partly apoB-48 can result in a reduction of LDL formation that requires the full-length apoB-100.
载脂蛋白（apo）B 以两种形式存在，即全长蛋白 apoB-100 和在肠道中因 apoB mRNA 编辑而合成的羧基末端截短的 apoB-48，这种编辑产生了一个提前终止密码子。为了确定将 apoB mRNA 编辑酶 APOBEC-1（apoB mRNA 编辑酶催化多肽 1）的催化亚基基因转移到兔肝脏中是否能重建肝脏 apoB mRNA 编辑，以及这如何影响含 apoB 脂蛋白的血浆水平，我们构建了一种 APOBEC-1 重组腺病毒（Ad APOBEC-1）。将 Ad APOBEC-1 注射到正常新西兰白兔（NZW）或渡边遗传性高脂血症（WHHL）兔体内后，高达 50%的肝脏 apoB mRNA 被编辑，新鲜分离的肝细胞主要分泌含 apoB-48 的脂蛋白。从经 Ad APOBEC-1 处理的 NZW 和 WHHL 兔分离的极低密度脂蛋白（VLDL）同时含有 apoB-100 和 apoB-48，而从感染β-半乳糖苷酶重组腺病毒（Ad LacZ）的对照兔分离的 VLDL 仅含有 apoB-100。用 Ad APOBEC-1 处理的 WHHL 兔的 VLDL 与来自 Ad LacZ 感染对照动物体内的 VLDL 具有相同的粒径、脂质组成和载脂蛋白 E 含量。NZW 和 WHHL 兔感染 Ad APOBEC-1 以及 Ad LacZ 后均观察到 VLDL 增加。注射 Ad APOBEC-之后，NZW 兔血浆中低密度脂蛋白（LDL）无法检测到，与 Ad LacZ 感染的对照相比，WHHL 兔血浆中 LDL 平均降低了 65%。来自 Ad APOBEC-1感染的 WHHL 兔的 LDL 仅含有 apoB-100。将从 Ad APOBEC-1 感染的 WHHL 兔分离的 VLDL 注射到 NZW 兔体内后，能迅速从循环中清除。这些结果进一步证明，肝脏合成从仅产生 apoB-100 转变为部分产生 apoB-48 可导致需要全长 apoB-100 的 LDL 生成减少。
