Effect of apolipoprotein M on high density lipoprotein metabolism and atherosclerosis in low density lipoprotein receptor knock-out mice
Effect of apolipoprotein M on high density lipoprotein metabolism and atherosclerosis in low density lipoprotein receptor knock-out mice
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DOI：
10.1074/jbc.m704576200
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发表时间：
2008-01-25
影响因子：
4.8
通讯作者：
Nielsen, Lars Bo
中科院分区：
文献类型：
--
作者：
Christoffersen, Christina;Jauhiainen, Matti;Nielsen, Lars Bo
为了研究载脂蛋白M（apoM）在高密度脂蛋白（HDL）代谢和动脉粥样硬化形成中的作用，我们建立了人apoM转基因（apoM-Tg）和apoM缺陷（apoM（-/-））小鼠。血浆apoM主要与10-12 nm的α-迁移HDL颗粒相关。人apoM过表达（11倍）使血浆胆固醇浓度增加13- 22%，而apoM缺乏使其降低17- 21%。载脂蛋白A-I的HDL在apoM-Tg或apoM（-/-）小鼠血浆中的大小和电荷没有改变。然而，在37 ℃孵育的血浆中，apoM-Tg小鼠中α-HDL向前α-迁移HDL的卵磷脂：胆固醇酰基转移酶依赖性转化延迟。此外，卵磷脂：与对照组（1.8 +/-0.05%）相比，apoM-Tg小鼠血浆中含前β-迁移apoA-I颗粒的胆固醇酰基转移酶非依赖性生成增加（4.2 +/-1.1%，p = 0.06），apoM（-/-）小鼠血浆中含前β-迁移apoA-I颗粒的胆固醇酰基转移酶非依赖性生成减少（0.5 +/-0.3%，p = 0.03）。在低密度脂蛋白受体缺乏的情况下，血浆apoM浓度增加约2倍的apoM-Tg小鼠的动脉粥样硬化病变比对照组小。载脂蛋白M对动脉粥样硬化的影响可能是通过血浆HDL颗粒的酶促调节、泡沫细胞胆固醇流出增加以及含载脂蛋白M的HDL的抗氧化作用来促进的。
To investigate the role of apoM in high density lipoprotein (HDL) metabolism and atherogenesis, we generated human apoM transgenic (apoM-Tg) and apoM-deficient ( apoM(-/-)) mice. Plasma apoM was predominantly associated with 10-12-nm alpha-migrating HDL particles. Human apoM overexpression (11-fold) increased plasma cholesterol concentration by 13-22%, whereas apoM deficiency decreased it by 17-21%. The size and charge of apoA-I-containing HDL in plasma were not changed in apoM-Tg or apoM(-/-) mice. However, in plasma incubated at 37 C, lecithin: cholesterol acyltransferase-dependent conversion of alpha- to pre-alpha-migrating HDL was delayed in apoM-Tg mice. Moreover, lecithin: cholesterol acyltransferase-independent generation of pre-beta-migrating apoA-I-containing particles in plasma was increased in apoM-Tg mice (4.2 +/- 1.1%, p = 0.06) and decreased in apoM(-/-) mice (0.5 +/- 0.3%, p = 0.03) versus controls ( 1.8 +/- 0.05%). In the setting of low density lipoprotein receptor deficiency, apoM-Tg mice with similar to 2-fold increased plasma apoM concentrations developed smaller atherosclerotic lesions than controls. The effect of apoM on atherosclerosis may be facilitated by enzymatic modulation of plasma HDL particles, increased cholesterol efflux from foam cells, and an antioxidative effect of apoM-containing HDL.