Hughes S D, Rouy D, Navaratnam N, Scott J, Rubin E M
Lawrence Berkeley Laboratory, University of California, Berkeley 94720, USA.
Hum Gene Ther. 1996 Jan;7(1):39-49. doi: 10.1089/hum.1996.7.1-39.
Apolipoprotein (apo) B100 is an essential component of low-density lipoproteins (LDL) and lipoprotein(a) [Lp(a)]. In mammals, apoB can be edited post-transcriptionally to encode a truncated form of apoB (apoB48) that is unable to form either of these atherogenic lipoproteins. To study the effect of increasing hepatic apoB editing activity on formation of Lp(a), a recombinant adenovirus encoding rat apoBEC-1, the cytidine deaminase component of the apoB mRNA editing complex, was administered to human apoB/apo(a) transgenic mice. This resulted in expression of apoBEC-1 in hepatocytes of these mice, increased hepatic editing of human apoB mRNA, and decreased plasma levels of human apoB100 and Lp(a). The apoBEC-1 recombinant adenovirus was also administered to rabbits, an animal which, like humans, naturally lacks hepatic apoB editing. Expression of the exogenous apoBEC-1 in rabbit liver resulted in editing of up to 10% of apoB mRNA. Hepatic apoB editing was associated with lower LDL levels in these rabbits relative to those treated with a control adenovirus. However, LDL levels were elevated significantly in both animals as a result of adenovirus injection. These studies demonstrate that introduction of the cytidine deaminase apoBEC-1 is sufficient to induce hepatic apoB editing in an animal lacking this activity, and that induction of editing could serve as a novel approach for lowering plasma concentrations of the atherogenic lipoproteins Lp(a) and LDL.
载脂蛋白（apo）B100是低密度脂蛋白（LDL）和脂蛋白（a）[Lp（a）]的重要组成部分。在哺乳动物中，apoB可在转录后进行编辑，以编码一种截短形式的apoB（apoB48），这种截短形式无法形成这两种致动脉粥样硬化脂蛋白中的任何一种。为了研究增加肝脏apoB编辑活性对Lp（a）形成的影响，将编码大鼠apoBEC-1（apoB mRNA编辑复合物的胞苷脱氨酶成分）的重组腺病毒给予人apoB/apo（a）转基因小鼠。这导致这些小鼠的肝细胞中apoBEC-1表达，人apoB mRNA的肝脏编辑增加，以及人apoB100和Lp（a）的血浆水平降低。apoBEC-1重组腺病毒也被给予兔子，兔子是一种像人类一样天然缺乏肝脏apoB编辑的动物。外源apoBEC-1在兔肝脏中的表达导致高达10%的apoB mRNA被编辑。相对于用对照腺病毒处理的兔子，这些兔子的肝脏apoB编辑与较低的LDL水平相关。然而，由于注射腺病毒，两种动物的LDL水平均显著升高。这些研究表明，引入胞苷脱氨酶apoBEC-1足以在缺乏这种活性的动物中诱导肝脏apoB编辑，并且诱导编辑可作为降低致动脉粥样硬化脂蛋白Lp（a）和LDL血浆浓度的一种新方法。
