Kozarsky K F, Bonen D K, Giannoni F, Funahashi T, Wilson J M, Davidson N O
Institute for Human Gene Therapy, University of Pennsylvania, Philadelphia 19104, USA.
Hum Gene Ther. 1996 May 20;7(8):943-57. doi: 10.1089/hum.1996.7.8-943.
Apolipoprotein (apo) B48, a protein contained in intestinally derived lipoprotein particles, is synthesized by post-transcriptional editing of apoB100 mRNA. This reaction is mediated by an enzyme complex that includes the catalytic subunit, apobec-1. The liver of most mammals, by contrast, contains only unedited apoB mRNA and secretes apoB100, the major protein component of plasma low-density lipoprotein (LDL). Because rabbits, like humans, fail to edit hepatic apoB100 mRNA, we introduced a recombinant adenovirus encoding apobec-1 into the livers of LDL receptor-defective rabbits to determine the impact on lipoprotein metabolism of hepatic apoB48 secretion. Transgene expression was mainly confined to the liver and was sustained for up to 3 weeks following virus administration, as evidenced by the presence of apobec-1 mRNA and the ability of hepatic S100 extracts to edit a synthetic apoB RNA template in vitro. The transient induction of hepatic apoB mRNA editing accompanied alterations in very-low-density lipoprotein (VLDL) size, the presence of apoB48 in fractions spanning the VLDL and LDL range, and modest reductions in total plasma cholesterol levels.
载脂蛋白（apo）B48是肠道源性脂蛋白颗粒所含的一种蛋白质，它通过apoB100 mRNA的转录后编辑合成。该反应由一种酶复合物介导，该酶复合物包括催化亚基载脂蛋白B mRNA编辑酶1（apobec-1）。相比之下，大多数哺乳动物的肝脏只含有未编辑的apoB mRNA，并分泌血浆低密度脂蛋白（LDL）的主要蛋白质成分apoB100。由于兔子与人类一样，无法编辑肝脏中的apoB100 mRNA，我们将编码apobec-1的重组腺病毒导入低密度脂蛋白受体缺陷兔子的肝脏，以确定肝脏分泌apoB48对脂蛋白代谢的影响。转基因表达主要局限于肝脏，并且在病毒给药后持续长达3周，这可通过apobec-1 mRNA的存在以及肝脏S100提取物在体外编辑合成apoB RNA模板的能力得以证明。肝脏apoB mRNA编辑的短暂诱导伴随着极低密度脂蛋白（VLDL）大小的改变、在跨越VLDL和LDL范围的组分中存在apoB48以及血浆总胆固醇水平的适度降低。
