EXPRESSION OF HUMAN APOLIPOPROTEIN-A-I IN TRANSGENIC MICE RESULTS IN REDUCED PLASMA-LEVELS OF MURINE APOLIPOPROTEIN-A-I AND THE APPEARANCE OF 2 NEW HIGH-DENSITY-LIPOPROTEIN SIZE SUBCLASSES
EXPRESSION OF HUMAN APOLIPOPROTEIN-A-I IN TRANSGENIC MICE RESULTS IN REDUCED PLASMA-LEVELS OF MURINE APOLIPOPROTEIN-A-I AND THE APPEARANCE OF 2 NEW HIGH-DENSITY-LIPOPROTEIN SIZE SUBCLASSES
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DOI：
10.1073/pnas.88.2.434
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发表时间：
1991-01-01
影响因子：
11.1
通讯作者：
KRAUSS, RM
中科院分区：
文献类型：
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作者：
RUBIN, EM;ISHIDA, BY;KRAUSS, RM
在西方社会，高密度脂蛋白（HDL）水平与冠心病风险成反比。 人类和小鼠 HDL 的主要蛋白质成分是载脂蛋白 A-I (apoAI)，其包含 > 70% 的 HDL 蛋白质和 30% 的 HDL 质量。 人类 HDL 包含多个不同大小亚群的颗粒，而来自近交 C57BL/6 小鼠的 HDL 则包含单一颗粒群。 为了研究apoAI表达的调节及其在HDL组装中的作用，我们创建了含有人类apoAI基因的转基因C57BL/6小鼠。 研究了两个独立品系的转基因小鼠，它们的总apoAI血浆水平约为正常血浆水平的两倍。 小鼠 apoAI 水平在两个转基因系中均降低了 4 倍以上，其中一个转基因系中仅占总血浆 apoAI 水平的 4%，而另一个转基因系中则占 13%。 我们证明导致小鼠 apoAI 减少的机制是转录后的。 与用人 apoAI 替代小鼠平行，通常存在于 C57BL/6 血浆中的单一 HDL 种类被大小与人 HDL2b 和 HDL3a 相似的两个 HDL 亚类替代。 小鼠载脂蛋白水平和高密度脂蛋白亚类大小的变化由两种创始动物的所有转基因后代遗传。 这些结果表明apoAI在确定HDL粒度分布中起主导作用，以及涉及人类apoAI转基因表达改变小鼠apoAI血浆水平的机制。
In Western societies high density lipoprotein (HDL) levels correlate inversely with the risk for coronary heart disease. The primary protein component of both human and mouse HDL is apolipoprotein A-I (apoAI), which comprises > 70% of HDL protein and 30% of HDL mass. Human HDLs include particles of several distinct size subpopulations, whereas HDLs from inbred C57BL/6 mice contain a single population of particles. To study the regulation of apoAI expression and its role in HDL assembly, we created transgenic C57BL/6 mice containing the human apoAI gene. Two independent lines of transgenic mice with approximately twice the normal plasma levels of total apoAI were studied. The level of mouse apoAI is reduced > 4-fold in both transgenic lines, comprising only 4% of total plasma apoAI levels in one transgenic line and 13% in the other. We demonstrate that the mechanism responsible for the decrease in mouse apoAI is posttranscriptional. Parallel to the replacement of mouse with human apoAI, the single HDL species normally present in the plasma of C57BL/6 is replaced by two HDL subclasses similar in size to human HDL2b and HDL3a. The changes in murine apolipoprotein levels and HDL subclass size are inherited by all transgenic offspring of the two founder animals. These results suggest a dominant role of apoAI in determining the HDL particle size distribution and a mechanism involving expression of human apoAI transgenes that alters the plasma levels of mouse apoAI.