AN INTERACTION BETWEEN THE HUMAN CHOLESTERYL ESTER TRANSFER PROTEIN (CETP) AND APOLIPOPROTEIN-A-I GENES IN TRANSGENIC MICE RESULTS IN A PROFOUND CETP-MEDIATED DEPRESSION OF HIGH-DENSITY-LIPOPROTEIN CHOLESTEROL LEVELS
AN INTERACTION BETWEEN THE HUMAN CHOLESTERYL ESTER TRANSFER PROTEIN (CETP) AND APOLIPOPROTEIN-A-I GENES IN TRANSGENIC MICE RESULTS IN A PROFOUND CETP-MEDIATED DEPRESSION OF HIGH-DENSITY-LIPOPROTEIN CHOLESTEROL LEVELS
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DOI：
10.1172/jci115887
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发表时间：
1992-08-01
影响因子：
15.9
通讯作者：
BRESLOW, JL
中科院分区：
文献类型：
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作者：
HAYEK, T;CHAJEKSHAUL, T;BRESLOW, JL
我们之前已经描述了两种转基因小鼠系，一种是人类载脂蛋白a - i基因的杂合，另一种是由小鼠金属硫蛋白i基因启动子驱动的人类胆固醇酯转移蛋白（CETP）的杂合。在本研究中，我们将这两个品系杂交产生对照小鼠、huicetptg、huicetptg和huicetptg，研究CETP对小鼠和类人HDL动物中HDL胆固醇水平、粒度分布和代谢的影响。在huetptg和huicetptg动物中，锌诱导的血浆CETP活性大约增加了一倍，而对照组和huicetptg动物的血浆中没有活性。CETP对脂蛋白亚组分胆固醇浓度的唯一显著影响是对HDL-C。与对照动物相比，HuCETPTg动物的HDL-C降低了20%，锌诱导后降低了35%；与huitg动物相比，huetftg动物的HDL-C降低了35%，锌诱导后降低了66%。对照组和HuCETPTg HDL主要由单一大小的种群组成，平均直径分别为10.00+/-0.10 nm和9.71+/-0.05 nm。HuAITg HDL主要由三个不同大小的HDL亚群组成，其峰直径分别为10.35+/-0.08 nm、8.80+/-0.06 nm、7.40+/-0.10 nm； HuAICETPTg HDL也主要由三个不同大小的HDL亚群组成，其峰直径分别为9.87+/-0.05 nm、8.60+/-0.10 nm、7.30+/-0.15 nm，锌诱导后分别为9.71+/-0.08 nm、8.50+/-0.11 nm、7.27+/-0.15 nm。用CETP单克隆抗体对血浆非变性梯度凝胶进行Western blotting分析表明，在HuCETPTg和huicetptg小鼠中，CETP与HDL相关的比例分别为22%和100%。用I-125载脂蛋白A-I和H-3胆固醇亚油酸双标记的HDL转换研究表明，在没有和存在人类载脂蛋白A-I的情况下，cetp诱导的HDL-c下降与HDL-胆固醇酯部分分解代谢率的增加有关，这表明cetp介导的HDL-胆固醇酯向载脂蛋白b的转移。综上所述，这些研究表明CETP对表达人类载脂蛋白a - i的转基因动物的高密度脂蛋白胆固醇水平有更深远的影响。这可能是由于与小鼠载脂蛋白A-I或它们产生的高密度脂蛋白颗粒相比，CETP与人的相互作用增强。
We have previously described two transgenic mouse lines, one heterozygous for the human apo A-I gene and the other heterozygous for a human cholesteryl ester transfer protein (CETP) minigene driven by the mouse metallothionein-I gene promoter. In the current study, these two lines were crossed producing control, HuCETPTg, HuAITg, and HuAICETPTg mice to study the influence of CETP on HDL cholesterol levels, particle size distribution, and metabolism in animals with mouse and human-like HDL. In the HuCETPTg and HuAICETPTg animals, zinc induction approximately doubled plasma CETP activity, with no activity in plasma from the control and HuAITg animals. The only significant effect of CETP on lipoprotein subfraction cholesterol concentrations was for HDL-C. Compared to control animals, HuCETPTg animals had lower HDL-C, 20% before and 35% after Zn induction, and compared to HuAITg animals, HuAICETFTg animals had lower HDL-C, 35% before and 66% after Zn induction. Control and HuCETPTg HDL consist primarily of a single size population with a mean diameter of 10.00+/-0.10 nm and 9.71+/-0.05 nm, respectively. HuAITg HDL consists primarily of three distinct HDL size subpopulations with peak diameters of 10.35+/-0.08 nm, 8.80+/-0.06 nm, 7.40+/-0.10 nm, and HuAICETPTg HDL also consists primarily of three distinct HDL size subpopulations with peak diameters of 9.87+/-0.05 nm, 8.60+/-0.10 nm, 7.30+/-0.15 nm before, and 9.71+/-0.08 nm, 8.50+/-0.11 nm, 7.27+/-0.15 nm after zinc induction, respectively. Western blotting analysis of nondenaturing gradient gels of plasma with a monoclonal antibody to CETP indicated that in HuCETPTg and HuAICETPTg mice, 22 and 100%, respectively, of the CETP was HDL associated. Turnover studies with HDL doubly labeled with I-125 apo A-I and H-3 cholesteryl linoleate indicated that the CETP-induced fall in HDL-C was associated with increased HDL-cholesterol ester fractional catabolic rate in both the absence and presence of human apo A-I, suggesting CETP-mediated transfer of HDL-cholesterol ester to apo B-containing lipoproteins. In summary, these studies suggest that CETP has a much more profound effect on HDL cholesterol levels in transgenic animals expressing human apo A-I. This may be due to an enhanced interaction of CETP with human compared to mouse apo A-I or to the HDL particles they produce.