Liver ABCA1 deletion in LDLrKO mice does not impair macrophage reverse cholesterol transport or exacerbate atherogenesis.
Liver ABCA1 deletion in LDLrKO mice does not impair macrophage reverse cholesterol transport or exacerbate atherogenesis.
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DOI：
10.1161/atvbaha.112.301110
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发表时间：
2013-10
期刊：
影响因子：
--
通讯作者：
Parks JS
中科院分区：
文献类型：
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作者：
Bi X;Zhu X;Duong M;Boudyguina EY;Wilson MD;Gebre AK;Parks JS
肝脏 ATP 结合盒转运蛋白 A1 (ABCA1) 的表达对于维持血浆 HDL 浓度至关重要，但其在巨噬细胞逆转胆固醇转运 (RCT) 和动脉粥样硬化中的作用尚不完全清楚。我们在 LDL 受体敲除 (LDLrKO) C57BL/6 背景下研究了肝细胞特异性 ABCA1 敲除 (HSKO) 小鼠的动脉粥样硬化发展和随机对照试验。雄性和雌性 LDLrKO 和 HSKO/LDLrKO 小鼠在 8 周龄时从饮食改为致动脉粥样硬化饮食（10% 棕榈油，0.2% 胆固醇），持续 16 周。饲料喂养的 HSKO/LDLrKO 小鼠的 HDL 浓度是 LDLrKO 小鼠的 10-20%，但 VLDL 和 LDL 浓度相似。令人惊讶的是，与 LDLrKO 小鼠相比，饲喂致动脉粥样硬化饮食的 HSKO/LDLrKO 小鼠的 VLDL、LDL 和 HDL 浓度 (50%) 显着降低 (40-60%)。两种基因型小鼠的主动脉表面病变面积和胆固醇含量相似，但 HSKO/LDLrKO 小鼠的主动脉根部内膜面积显着较低（20-40%）。尽管与 LDLrKO 小鼠相比，致动脉粥样硬化饮食喂养的 HSKO/LDLrKO 小鼠的巨噬细胞 3H-胆固醇流出到 apoB 脂蛋白耗尽的血浆中要低 24%，但与血浆 HDL 浓度的 10 倍变化相比，个体小鼠之间流出百分比的变化小于 2 倍，这表明 HDL 水平本身并不是血浆流出能力的主要决定因素。两种基因型小鼠的体内随机对照试验、腹腔巨噬细胞甾醇含量、胆汁脂质成分和粪便胆固醇质量相似。 HSKO/LDLrKO 小鼠血浆 HDL 池显着减少，足以维持巨噬细胞 RCT，加上血浆 VLDL 和 LDL 浓度降低，防止了预期的动脉粥样硬化增加。
Hepatic ATP binding cassette transporter A1 (ABCA1) expression is critical for maintaining plasma HDL concentrations, but its role in macrophage reverse cholesterol transport (RCT) and atherosclerosis is not fully understood. We investigated atherosclerosis development and RCT in hepatocyte specific ABCA1 knockout (HSKO) mice in the LDL receptor knockout (LDLrKO) C57BL/6 background. Male and female LDLrKO and HSKO/LDLrKO mice were switched from chow at 8 wks of age to an atherogenic diet (10% palm oil, 0.2% cholesterol) for 16 wks. Chow-fed HSKO/LDLrKO mice had HDL concentrations 10–20% of LDLrKO mice, but similar VLDL and LDL concentrations. Surprisingly, HSKO/LDLrKO mice fed the atherogenic diet had significantly lower (40–60%) VLDL, LDL, and HDL concentrations (50%) compared to LDLrKO mice. Aortic surface lesion area and cholesterol content were similar for both genotypes of mice, but aortic root intimal area was significantly lower (20–40%) in HSKO/LDLrKO mice. Although macrophage 3H-cholesterol efflux to apoB lipoprotein-depleted plasma was 24% lower for atherogenic diet-fed HSKO/LDLrKO vs. LDLrKO mice, variation in percentage efflux among individual mice was <2-fold compared to a 10-fold variation in plasma HDL concentrations, suggesting that HDL levels, per se, were not the primary determinant of plasma efflux capacity. In vivo RCT, resident peritoneal macrophage sterol content, biliary lipid composition, and fecal cholesterol mass were similar between both genotypes of mice. The markedly reduced plasma HDL pool in HSKO/LDLrKO mice is sufficient to maintain macrophage RCT, which, along with reduced plasma VLDL and LDL concentrations, prevented the expected increase in atherosclerosis.