Nakamuta M, Taniguchi S, Ishida B Y, Kobayashi K, Chan L
Department of Cell Biology, Baylor College of Medicine, Houston, Tex 77030, USA.
Arterioscler Thromb Vasc Biol. 1998 May;18(5):747-55. doi: 10.1161/01.atv.18.5.747.
Apolipoprotein (apo) B mRNA editing determines the amount of apoB-100 and apoB-48 produced. Surprisingly, apobec-1 knockout mice, which do not edit apoB, have an essentially normal lipoprotein phenotype. By selected cross-breeding of mice of different genotypes, we show in this report that inactivation of editing produces profound phenotypic effects in cholesteryl ester transfer protein (CETP) transgenic mice and in apoE and low density lipoprotein receptor (LDLR) knockout mice. Compared with mice with an apobec-1+/+ background, CETP expression in apobec-1-/- mice caused a doubling of the plasma apoB-100 concentration (from 3.5+/-0.6 to 8.8+/-1.9 mg/dL, P<.01) and a much greater shift of plasma cholesterol from HDL to IDL/LDL as assayed by fast protein liquid chromatography analysis; the ratio of non-HDL to HDL cholesterol was 0.47, 0.46, 0.76, and 1.43 in apobec-1(+/+)/CETP-/-, apobec-1(-/-)/CETP-/-, apobec-1(+/+)/CETP+/-, and apobec-1(-/-)/CETP+/- animals, respectively. Feeding of a Western-type diet further exaggerated the shift in this ratio. In LDLR-/- mice, inactivation of apobec-1 caused an approximately 200% rise in plasma apoB-100 concentration, an approximately 60% increase in apoE concentration, and a 70% increase in total plasma cholesterol, which resulted exclusively from an increase in non-HDL cholesterol. The exaggerated hypercholesterolemia involving the VLDL+LDL fractions was further enhanced by a Western-type diet. In contrast, in apoE-/- mice, inactivation of apobec-1 caused a massive increase (from <0.5 to 55.5+/-16.4 mg/dL) in plasma apoB-100 concentration but an approximately 55% reduction in hypercholesterolemia due to partial amelioration of the marked VLDL+IDL elevation. However, the difference in lipid profiles between apobec-1(+/+)/apoE-/- and apobec-1(-/-)/apoE-/- mice was abolished in a time-dependent manner as further increases in total plasma cholesterol were induced by a Western-type diet. Whereas apobec-1 inactivation in wild-type mice produced little or no change in lipoprotein phenotype, giving rise to speculation that apoB mRNA editing does not have significant effect on lipoprotein dynamics, we show herein that there is important gene-gene interaction between apobec-1 and the CETP, LDLR, and apoE loci, which is subject to further substantial modulation by environmental factors such as a Western-type diet in mice.
载脂蛋白（apo）B信使核糖核酸（mRNA）编辑决定了所产生的apoB - 100和apoB - 48的量。令人惊讶的是，不编辑apoB的载脂蛋白B mRNA编辑酶1（apobec - 1）基因敲除小鼠具有基本正常的脂蛋白表型。通过对不同基因型小鼠进行选择性杂交繁殖，我们在本报告中表明，编辑功能的失活在胆固醇酯转运蛋白（CETP）转基因小鼠以及载脂蛋白E（apoE）和低密度脂蛋白受体（LDLR）基因敲除小鼠中产生了深刻的表型效应。与具有apobec - 1 +/+背景的小鼠相比，apobec - 1 -/-小鼠中的CETP表达导致血浆apoB - 100浓度翻倍（从3.5±0.6增至8.8±1.9毫克/分升，P<0.01），并且通过快速蛋白质液相色谱分析测定，血浆胆固醇从高密度脂蛋白（HDL）向中间密度脂蛋白（IDL）/低密度脂蛋白（LDL）的转移幅度更大；在apobec - 1(+/+)/CETP -/-、apobec - 1(-/-)/CETP -/-、apobec - 1(+/+)/CETP +/ -和apobec - 1(-/-)/CETP +/ -动物中，非HDL与HDL胆固醇的比率分别为0.47、0.46、0.76和1.43。喂食西式饮食进一步加剧了该比率的变化。在LDLR -/-小鼠中，apobec - 1失活导致血浆apoB - 100浓度升高约200%，apoE浓度升高约60%，血浆总胆固醇升高70%，这完全是由于非HDL胆固醇增加所致。涉及极低密度脂蛋白（VLDL）+LDL部分的过度高胆固醇血症通过西式饮食进一步加剧。相比之下，在apoE -/-小鼠中，apobec - 1失活导致血浆apoB - 100浓度大幅增加（从<0.5增至55.5±16.4毫克/分升），但由于显著升高的VLDL + IDL部分得到部分改善，高胆固醇血症降低了约55%。然而，随着西式饮食诱导血浆总胆固醇进一步升高，apobec - 1(+/+)/apoE -/-和apobec - 1(-/-)/apoE -/-小鼠之间的脂质谱差异以时间依赖性方式消失。虽然在野生型小鼠中apobec - 1失活在脂蛋白表型上产生很小或没有变化，这引发了关于apoB mRNA编辑对脂蛋白动力学没有显著影响的推测，但我们在此表明，apobec - 1与CETP、LDLR和apoE基因座之间存在重要的基因 - 基因相互作用，并且在小鼠中这种相互作用会受到诸如西式饮食等环境因素的进一步显著调节。
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