The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1
The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1
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胆固醇吸收抑制剂依折麦布通过阻断甾醇诱导的 NPC1L1 内化发挥作用
DOI：
10.1016/j.cmet.2008.04.001
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发表时间：
2008-06-01
期刊：
影响因子：
29
通讯作者：
Song, Bao-Liang
中科院分区：
文献类型：
--
作者：
Ge, Liang;Wang, Jing;Song, Bao-Liang
Niemann-Pick C1-like 1 （NPC1L1）是一种多聚跨膜蛋白，在胆固醇吸收中起关键作用。Ezetimibe是一种降胆固醇药物，据报道可结合NPC1L1并阻断胆固醇吸收。然而，npc1l1介导的胆固醇摄取的分子机制以及依折替米贝如何抑制这一过程尚不清楚。在这里，我们发现胆固醇特异性地促进了NPC1L1的内化，而这一过程需要微丝和网格蛋白/AP2复合物。阻断NPC1L1的内吞作用可显著降低胆固醇内化，表明NPC1L1通过其囊泡内吞作用介导胆固醇摄取。依折替米可阻止NPC1L1与网格蛋白包被的囊泡结合，从而抑制胆固醇的摄取。总之，我们的数据表明，胆固醇通过网格蛋白/ ap2介导的内吞作用被内化到具有NPC1L1的细胞中，依泽替米贝通过阻断NPC1L1的内化来抑制胆固醇的吸收。
Niemann-Pick C1-like 1 (NPC1L1) is a polytopic transmembrane protein that plays a critical role in cholesterol absorption. Ezetimibe, a hypocholesterolemic drug, has been reported to bind NPC1L1 and block cholesterol absorption. However, the molecular mechanism of NPC1L1-mediated cholesterol uptake and how ezetimibe inhibits this process are poorly defined. Here we find that cholesterol specifically promotes the internalization of NPC1L1 and that this process requires microfilaments and the clathrin/AP2 complex. Blocking NPC1L1 endocytosis dramatically decreases cholesterol internalization, indicating that NPC1L1 mediates cholesterol uptake via its vesicular endocytosis. Ezetimibe prevents NPC1L1 from incorporating into clathrin-coated vesicles and thus inhibits cholesterol uptake. Together, our data suggest a model wherein cholesterol is internalized into cells with NPC1L1 through clathrin/AP2-mediated endocytosis and ezetimibe inhibits cholesterol absorption by blocking the internalization of NPC1L1.