Transbilayer phospholipid movements in ABCA1-deficient cells.
Transbilayer phospholipid movements in ABCA1-deficient cells.
复制标题
ABCA1缺陷型细胞中的经贝贝磷脂运动。
DOI：
10.1371/journal.pone.0000729
复制
发表时间：
2007-08-15
期刊：
影响因子：
3.7
通讯作者：
Schlegel, Robert A.
中科院分区：
文献类型：
--
作者：
Williamson, Patrick;Halleck, Margaret S.;Malowitz, Jonathan;Ng, Susan;Fan, Xiaoxuan;Krahling, Stephen;Remaley, Alan T.;Schlegel, Robert A.
丹吉尔病是一种遗传性疾病，导致循环中HDL水平不足。虽然已知该疾病是由ABCA 1基因突变引起的，但ABCA 1 ATP酶损伤影响该结果的机制尚不清楚。ABCA 1基因敲除小鼠（ABCA 1 −/−）无法将胆固醇和磷脂加载到apoA 1上，这导致了一种假设，即ABCA 1介导磷脂的跨双层外化，这种活性不仅与HDL颗粒的形成有关，而且与另一个不同的过程有关：巨噬细胞识别和清除凋亡细胞。表达的磷脂酰丝氨酸（PS）的表面上的巨噬细胞和它们的凋亡目标是必需的凋亡细胞的有效吞噬，它已被提出，ABCA 1是所需的PS的transbilayer externalization到两种细胞类型的表面。为了确定ABCA 1是否负责已知控制跨双层磷脂运动的任何催化活性，在ABCA 1 −/−小鼠和丹吉尔个体的细胞以及表达ABCA 1的HeLa细胞中测量了这些活性。磷脂运动在正常或凋亡的淋巴细胞或巨噬细胞中没有被抑制时，细胞从敲除和野生型小鼠或永生化细胞从丹吉尔个人与正常人进行了比较。PS暴露在正常胸腺细胞，凋亡胸腺细胞和引起的野生型和敲除小鼠或B淋巴细胞从正常和丹吉尔个人的表面上，作为测量膜联蛋白V结合，也没有变化。没有证据表明，ABCA 1刺激的主动PS出口，和自发PS运动的外叶中存在或不存在的apoA 1的存在或不存在的ABCA 1的影响。在凋亡细胞清除试验中，正常或Tangier B淋巴细胞和巨噬细胞作为靶细胞或吞噬细胞的能力也是相同的。没有发现证据支持ABCA 1参与膜联蛋白I和II转运至巨噬细胞表面的建议，已知膜联蛋白I和II增强凋亡细胞的吞噬作用。这些结果表明，ABCA 1的突变不会显著降低吞噬巨噬细胞或凋亡靶细胞中磷脂的跨双层运动速率，因此不考虑作为ABCA 1促进磷脂和胆固醇加载到apoA 1上的机制的磷脂的跨双层运动的催化作用。
Tangier disease is an inherited disorder that results in a deficiency in circulating levels of HDL. Although the disease is known to be caused by mutations in the ABCA1 gene, the mechanism by which lesions in the ABCA1 ATPase effect this outcome is not known. The inability of ABCA1 knockout mice (ABCA1−/−) to load cholesterol and phospholipids onto apoA1 led to a proposal that ABCA1 mediates the transbilayer externalization of phospholipids, an activity integral not only to the formation of HDL particles but also to another, distinct process: the recognition and clearance of apoptotic cells by macrophages. Expression of phosphatidylserine (PS) on the surface of both macrophages and their apoptotic targets is required for efficient engulfment of the apoptotic cells, and it has been proposed that ABCA1 is required for transbilayer externalization of PS to the surface of both cell types. To determine whether ABCA1 is responsible for any of the catalytic activities known to control transbilayer phospholipid movements, these activities were measured in cells from ABCA1−/− mice and from Tangier individuals as well as ABCA1-expressing HeLa cells. Phospholipid movements in either normal or apoptotic lymphocytes or in macrophages were not inhibited when cells from knockout and wildtype mice or immortalized cells from Tangier individuals vs normal individuals were compared. Exposure of PS on the surface of normal thymocytes, apoptotic thymocytes and elicited peritoneal macrophages from wildtype and knockout mice or B lymphocytes from normal and Tangier individuals, as measured by annexin V binding, was also unchanged. No evidence was found of ABCA1-stimulated active PS export, and spontaneous PS movement to the outer leaflet in the presence or absence of apoA1 was unaffected by the presence or absence of ABCA1. Normal or Tangier B lymphocytes and macrophages were also identical in their ability to serve as targets or phagocytes, respectively, in apoptotic cell clearance assays. No evidence was found to support the suggestion that ABCA1 is involved in transport to the macrophage cell surface of annexins I and II, known to enhance phagocytosis of apoptotic cells. These results show that mutations in ABCA1 do not measurably reduce the rate of transbilayer movements of phospholipids in either the engulfing macrophage or the apoptotic target, thus discounting catalysis of transbilayer movements of phospholipids as the mechanism by which ABCA1 facilitates loading of phospholipids and cholesterol onto apoA1.
登录
查看更多内容
影响因子：
20.3
作者：
Albrecht, C;McVey, JH;Higgins, CF
通讯作者：
Higgins, CF
影响因子：
4.8
作者：
Chambenoit, O;Hamon, Y;Chimini, G
通讯作者：
Chimini, G
影响因子：
3.3
作者：
Fan, XX;Krahling, S;Schlegel, RA
通讯作者：
Schlegel, RA
影响因子：
30.8
作者：
Bodzioch, M;Orsó, E;Schmitz, G
通讯作者：
Schmitz, G
影响因子：
12.4
作者：
Krahling, S;Callahan, MK;Schlegel, RA
通讯作者：
Schlegel, RA