Direct evidence in vivo of impaired macrophage-specific reverse cholesterol transport in ATP-binding cassette transporter A1-deficient mice
Direct evidence in vivo of impaired macrophage-specific reverse cholesterol transport in ATP-binding cassette transporter A1-deficient mice
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DOI：
10.1016/j.bbalip.2005.11.012
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发表时间：
2005-12-30
影响因子：
4.8
通讯作者：
Escolà-Gil, JC
中科院分区：
文献类型：
--
作者：
Calpe-Berdiel, L;Rotllan, N;Escolà-Gil, JC
ATP结合盒转运蛋白A1（ABCA 1）是高密度脂蛋白（HDL）代谢的关键调节因子。有强有力的证据表明ABCA 1是胆固醇逆向转运（RCT）的关键调节因子。然而，由于ABCA 1缺陷小鼠（ABCA 1-/-）的肝胆胆固醇转运未发生变化，因此无法在体内证明这一点。我们使用ABCA 1-/-小鼠来检验ABCA 1是巨噬细胞特异性RCT的关键决定因素这一假设。虽然这种细胞特异性RCT仅占总RCT的一小部分，但它被广泛认为可能对动脉粥样硬化易感性有重要影响。将[H-3]胆固醇标记的内源性巨噬细胞腹膜内注射到维持普通饲料的野生型ABCA 1 +/+、ABCA 1 +/-和ABCA 1-/-小鼠中。在小鼠体内注射示踪剂后24和48 h，ABCA 1基因剂量与血浆[H-3]胆固醇之间观察到直接关系。注射后48小时，ABCA 1-/-小鼠肝脏（2.8倍）、小肠肠上皮细胞（1.7倍）和粪便（2倍）中的[H-3]胆固醇显著降低。据我们所知，这是第一个直接的体内定量证据表明ABCA 1是巨噬细胞特异性RCT的关键决定因素。(c)2005 Elsevier B.V保留所有权利。
The ATP-binding cassette transporter A1 (ABCA1) is a key regulator of high-density lipoprotein (HDL) metabolism. There is strong evidence that ABCA1 is a key regulator of reverse cholesterol transport (RCT). However, this could not be proved in vivo since hepatobiliary cholesterol transport was unchanged in ABCA1-deficient mice (ABCA1-/-). We used ABCA1-/- mice to test the hypothesis that ABCA1 is a critical determinant of macrophage-specific RCT. Although this cell-specific RCT only accounts for a tiny part of total RCT, it is widely accepted that it may have a major impact on atherosclerosis susceptibility. [H-3]cholesterol-labeled endogenous macrophages were injected intraperitoneally into wild-type ABCA1+/+, ABCA1+/- and ABCA1-/- mice maintained on a chow diet. A direct relationship was observed between ABCA1 gene dose and plasma [H-3]cholesterol at 24 and 48 h after the injection of tracer into the mice. Forty-eight hours after this injection, ABCA1-/- mice had significantly reduced [H-3]cholesterol in liver (2.8-fold), small intestine enterocytes (1.7-fold) and feces (2-fold). To our knowledge, this is the first direct in vivo quantitative evidence that ABCA1 is a critical determinant of macrophage-specific RCT. (c) 2005 Elsevier B.V All rights reserved.