Recycling of Apolipoprotein(a) After PlgRKT-Mediated Endocytosis Lipoprotein(a)
Recycling of Apolipoprotein(a) After PlgRKT-Mediated Endocytosis Lipoprotein(a)
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DOI：
10.1161/circresaha.116.310272
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发表时间：
2017-03-31
影响因子：
20.1
通讯作者：
McCormick, Sally P. A.
中科院分区：
文献类型：
--
作者：
Sharma, Monika;Redpath, Gregory M.;McCormick, Sally P. A.
基本原理：脂蛋白(a) [Lp(a)]是一种低密度脂蛋白样脂蛋白，是重要的心血管危险因素，其同源受体和细胞内命运仍未知。目的：我们的研究旨在确定 Lp(a) 的细胞内运输途径以及负责其在肝细胞中摄取的受体。方法和结果：用从人血浆中纯化的 Lp(a) 处理人肝癌细胞，并使用蛋白质印迹分析和研究 Lp(a) 的摄取。通过共聚焦显微镜进行 Lp(a) 的细胞内定位。 Lp(a) 在 2 小时内最大内化，并通过抗 apo(a) 抗体检测到定位于 Rab5 阳性早期内体、跨高尔基体网络，以及随后的 Rab11 阳性再循环内体。在人肝癌细胞中，内化 Lp(a) 中的 apo(a) 成分重新分泌回细胞介质中，而低密度脂蛋白成分则定位于溶酶体区室。 Lp(a) 内化在 HAP1 中减少 0.35 倍，在纤溶酶原受体 (KT) 被敲除的人肝癌细胞中减少 0.33 倍。相反，Lp(a) 内化在 HAP1 中增强 2 倍，在纤溶酶原受体 (KT) 过表达的人肝癌细胞中增强 1.6 倍，首次显示特定纤溶酶原受体在 Lp(a) 摄取中的作用。结论：Lp(a) 被纤溶酶原受体、纤溶酶原受体 (KT) 和 apo(a) 成分内化的新发现是回收可能对 Lp(a) 的分解代谢和功能具有重要影响。
Rationale: Lipoprotein(a) [Lp(a)] is a low-density lipoprotein-like lipoprotein and important cardiovascular risk factor whose cognate receptor and intracellular fate remains unknown.Objective: Our study aimed to determine the intracellular trafficking pathway for Lp(a) and the receptor responsible for its uptake in liver cells.Methods and Results: Human hepatoma cells were treated with Lp(a) purified from human plasma and Lp(a) uptake studied using Western blot analysis and intracellular localization of Lp(a) by confocal microscopy. Lp(a) was maximally internalized by 2 hours and was detected by an antiapo(a) antibody to be localized to Rab5-positive early endosomes, the trans-Golgi network, and subsequently Rab11-positive recycling endosomes. In human hepatoma cells, the apo(a) component from the internalized Lp(a) was resecreted back into the cellular media, whereas the low-density lipoprotein component was localized to the lysosomal compartment. Lp(a) internalization was reduced 0.35-fold in HAP1 and 0.33-fold in human hepatoma cells in which the plasminogen receptor (KT) was knocked out. Conversely, Lp(a) internalization was enhanced 2-fold in HAP1 and 1.6-fold in human hepatoma cells in which plasminogen receptor (KT) was overexpressed, showing for the first time the role of a specific plasminogen receptor in Lp(a) uptake.Conclusions: The novel findings that Lp(a) is internalized by the plasminogen receptor, plasminogen receptor (KT), and the apo(a) component is recycled may have important implications for the catabolism and function of Lp(a).