Rubin E M, Ishida B Y, Clift S M, Krauss R M
Division of Research Medicine and Radiation Biophysics, Lawrence Berkeley Laboratory, University of California, Berkeley 94720.
Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):434-8. doi: 10.1073/pnas.88.2.434.
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 greater than 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 greater than 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.
在西方社会，高密度脂蛋白（HDL）水平与冠心病风险呈负相关。人和小鼠HDL的主要蛋白质成分都是载脂蛋白A-I（apoAI），它占HDL蛋白质的70%以上，占HDL质量的30%。人类HDL包括几个不同大小亚群的颗粒，而近交C57BL/6小鼠的HDL包含单一颗粒群体。为了研究apoAI表达的调控及其在HDL组装中的作用，我们构建了携带人类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，其总apoAI的血浆水平约为正常水平的两倍。在两个转基因品系中，小鼠apoAI的水平均降低了4倍以上，在一个转基因品系中仅占血浆总apoAI水平的4%，在另一个品系中占13%。我们证明，导致小鼠apoAI减少的机制是转录后机制。与用人apoAI替代小鼠apoAI并行的是，C57BL/6血浆中通常存在的单一HDL种类被两种大小与人类HDL2b和HDL3a相似的HDL亚类所取代。两种奠基动物的所有转基因后代都继承了小鼠载脂蛋白水平和HDL亚类大小的变化。这些结果表明apoAI在决定HDL颗粒大小分布中起主导作用，以及一种涉及人类apoAI转基因表达的机制，该机制改变了小鼠apoAI的血浆水平。
