OVEREXPRESSION OF HUMAN LECITHIN CHOLESTERYL ACYLTRANSFERASE IN TRANSGENIC MICE

为了评价LCAT在HDL代谢中的作用， 动脉粥样硬化，我们已经产生过表达hLCAT的转基因小鼠 血浆水平比对照组（1微克/毫升）高100倍。相比 对于24个年龄和性别匹配的兄弟姐妹，转基因小鼠的血浆 TC（NL的133-237%）、CE（NL的141-267%）和HDL-C（NL的123-209%），但 甘油三酯、PL、含B脂蛋白 apoA-I和apoA-II。hLCAT TG血浆的FPLC分析显示， 富含CE和PL的尺寸的HDL颗粒。因此，LCAT调节 组成和异质性以及HDL的浓度， 小鼠 年龄/性别匹配的转基因动物（M=7，F=8）和对照动物（M=14，F=13） 高胆脂饲料喂养21 d， LCAT在调节饮食反应中的潜在作用。饲喂前 对照组的血脂值（mg/dl）为TC=97+/-11，HDL=72+/-10， 转基因组TC=121 +/-16，HDL-C=84 +/-17。饮食后血脂值 对照组的TC=290+/-55，HDL= 85+/-15，转基因组的TC = 290 +/-55，HDL= 85+/-15， TC=313+/-83，HDL=115+/-27。因此，在HF饮食中，转基因小鼠 HDL-C显著升高（p<0.05），TC/HDL比值降低 与对照相比，Tg、PL、CE、LCAT质量和 活动转基因小鼠血浆的FPLC分析显示显著性差异。 HDL-C、CE和PL升高，IDL/LDL-C反向降低， CE和PL，证明LCAT介导的血脂调节， 应对饮食挑战。 为了评估过表达人LCAT基因的效果， 饮食诱导的动脉粥样硬化对照组（N=19）和LCAT转基因组（N=18） 在开始高脂肪饮食后16周分析C57 B1小鼠。 平均主动脉病变尺寸分析显示， 对照和转基因小鼠。这些发现表明，在这种动物中， 在CETP缺乏的模型中，LCAT过表达不能保护 防止饮食引起的动脉粥样硬化的发展。

In order to evaluate the role of LCAT in HDL metabolism, and atherosclerosis we have generated transgenic mice overexpressing hLCAT at plasma levels 100 fold higher than control (1 ug/ml) mice. Compared to 24 age and sex-matched siblings, transgenic mice had elevated plasma TC (133-237% of NL), CE (141-267% of NL) and HDL-C (123-209% of NL) but similar plasma levels of triglycerides, PL, B-containing lipoproteins, apoA-I and apoA-II. FPLC analysis of hLCAT TG plasma revealed larger sized HDL particles enriched in CE and PL. Thus, LCAT modulates the composition and heterogeneity as well as the concentrations of HDL in mice. Age/sex matched transgenic (M=7, F=8) and control (M=14, F=13) animals were then placed on a high chol-fat (HF) diet for 21 d to investigate the potential role of LCAT in modulating dietary responses. Pre-diet lipid values (mg/dl) in controls were TC=97+/-11, HDL=72+/-10 and in transgenics were TC=121 +/-16, HDL-C=84 +/-17. Post-diet lipid values in controls were TC=290+/-55, HDL= 85+/-15, and in transgenics were TC=313+/-83, HDL=115+/-27. Thus, on the HF diet transgenic mice had significantly higher (p<0.05) HDL-C as well as reduced TC/HDL ratios than controls, without differences in Tg, PL, CE, LCAT mass and activity. FPLC analysis of transgenic mouse plasma revealed significant increases in HDL-C, CE and PL with reciprocal decreases in IDL/LDL-C, CE and PL, demonstrating LCAT-mediated modulation of plasma lipids in response to a dietary challenge. In order to evaluate the effect of overexpressing the human LCAT gene on diet-induced atherosclerosis control (N=19)and LCAT transgenic (N=18) C57Bl mice were analyzed 16 weeks after initiation of a high fat-diet. Analysis of mean aortic lesion size revealed no differences between control and transgenic mice. These findings indicate that in this animal model with a deficiency of CETP, LCAT overexpression does not protect against the development of diet-induced atherosclerosis.