OVEREXPRESSION OF HUMAN LECITHIN CHOLESTERYL ACYLTRANSFERASE IN TRANSGENIC MICE

尽管血浆高密度脂蛋白以及载脂蛋白A-I、LCAT浓度增加 转基因(L-TG)小鼠使诱导的饮食增加(高达5倍) 动脉粥样硬化与年龄和性别匹配的对照组比较。去调查 可能解释这种矛盾解离的潜在机制 在我们使用的血浆高密度脂蛋白浓度和动脉粥样硬化之间 体内表达另外两种蛋白的重组腺病毒载体 在高密度脂蛋白新陈代谢中起主要作用。腺病毒载体介导的表达 HL和CETP在对照组和L-TG小鼠中的表达表明，与 对于对照组动物的高密度脂蛋白，L-TG小鼠的载脂蛋白A-I/A-II高密度脂蛋白是 HL的水解性很差，不支持运输 用CETP法将胆固醇酯转化为含载脂蛋白B的脂蛋白。另外， 最有效的新生、前B1-高密度脂蛋白的血浆基线浓度 颗粒对细胞胆固醇的外流有显著的影响 在L-甘油三酯小鼠体内降低。L-甘油三酯小鼠高密度脂蛋白经口服药后的血浆衰减曲线 注射对照高密度脂蛋白-胆固醇醚的放射性标记 而L-甘油三酯组小鼠的高密度脂蛋白表达明显滞后于对照组。 此外，输送到肝脏的总胆固醇醚的百分比，2 注射放射性标记的高密度脂蛋白后数小时， (P&lt；0.001)与对照组(占总数的18%和33%)相比 胆固醇醚)。 这些联合研究表明，在没有CETP的情况下，LCAT 小鼠的过度表达导致高密度脂蛋白颗粒的形成 结构和功能异常，建立了一种潜在的机制 这可能是在这只动物身上观察到的动脉粥样硬化增强的原因。 模特。因此，胆固醇的反向运输过程是一个重要的 高密度脂蛋白调节动脉粥样硬化发展的机制 在L-TG小鼠中被打断。这些研究表明，高密度脂蛋白和 单独的载脂蛋白A-I血浆浓度不能预测 高密度脂蛋白的抗动脉粥样硬化潜力和功能研究需要 确定不同治疗方法是否升高血浆高密度脂蛋白 如果是真的，模式将防止早产儿的发展 心血管疾病。

Despite increased plasma concentrations of HDL, as well as apoA-I, LCAT transgenic (L-tg) mice have enhanced (up to 5-fold) diet induced atherosclerosis compared to age and sex matched controls. To investigate potential mechanisms that may explain this paradoxical dissociation between plasma concentrations of HDL and atherosclerosis we have used recombinant adenovirus vectors to express, in vivo, two other proteins that play a major role in HDL metabolism. Adenovirus-mediated expression of HL and CETP in both control and L-tg mice demonstrated that compared to the HDL in control animals, the apoA-I/A-II HDL in L-tg mice were poorly hydrolyzed by HL and would not support the transport of cholesteryl esters to apoB containing lipoproteins by CETP. Additionally, baseline plasma concentrations of nascent, pre-B1-HDL, the most effector particles for the efflux of cellular cholesterol, were significantly reduced in L-tg mice. The decay plasma curve of L-tg mouse HDL after injection of radiolabelled HDL-cholesterol ether isolated from control and L-tg mice was significantly delayed from that of control mouse HDL. In addition, the % of total cholesterol ether delivered to the liver, two hours after injection of radiolabelled HDL, was significantly reduced (P<0.001) for L-tg mice compared to controls (18% versus 33% of total cholesterol ether). These combined studies indicate that in the absence of CETP, LCAT overexpression in mice leads to the formation of HDL particles with abnormal composition and function, establishing one potential mechanism that may account for the enhanced atherosclerosis observed in this animal model. Thus, the process of reverse cholesterol transport, an important mechanism by which HDL may modulate the development of atherosclerosis is interrupted in L-tg mice. These studies demonstrate that HDL and apoA-I plasma concentrations, alone, are not predictive of the anti-atherogenic potential of HDL and functional studies are required to determine whether increasing plasma HDL by different therapeutic modalities will if fact, protect against the development of premature cardiovascular disease.