Flotillins play an essential role in Niemann-Pick C1-like 1-mediated cholesterol uptake
Flotillins play an essential role in Niemann-Pick C1-like 1-mediated cholesterol uptake
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DOI：
10.1073/pnas.1014434108
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发表时间：
2011-01-11
影响因子：
11.1
通讯作者：
Song, Bao-Liang
中科院分区：
文献类型：
--
作者：
Ge, Liang;Qi, Wei;Song, Bao-Liang
饮食吸收是哺乳动物获取胆固醇的主要途径，NPC1L1通过囊泡内吞作用介导胆固醇的摄取。这个过程中的一个基本问题是，如何通过NPC1L1的内化有效地吸收游离胆固醇。利用外源表达的NPC1L1-EGFP，我们发现脂筏蛋白Flotillins与NPC1L1结合，并且在细胞内转运过程中其定位受到NPC1L1的调节。此外，Flotillins对NPC1L1介导的细胞胆固醇摄取、胆汁胆固醇重吸收和小鼠血脂水平的调节都是必不可少的。它们与NPC1L1一起形成富含胆固醇的膜微域，作为大量胆固醇的载体。降胆固醇药物ezetimibe破坏了NPC1L1和Flotillins之间的联系，从而阻止了富含胆固醇的微域的形成。我们的发现揭示了Foltillins在NPC1L1介导的胆固醇吸收中的功能作用，并阐明了NPC1L1-Foltillins阳性富含胆固醇的膜微域的形成是有效吸收胆固醇的机制。
Dietary absorption is a major way for mammals to obtain cholesterol, which is mediated by Niemann-Pick C1-like 1 (NPC1L1) via vesicular endocytosis. One fundamental question in this process is how free cholesterol is efficiently taken up through the internalization of NPC1L1. Using exogenously expressed NPC1L1-EGFP, we show that the lipid raft proteins flotillins associate with NPC1L1 and their localization is regulated by NPC1L1 during intracellular trafficking. Furthermore, flotillins are essential for NPC1L1-mediated cellular cholesterol uptake, biliary cholesterol reabsorption, and the regulation of lipid levels in mice. Together with NPC1L1, they form cholesterol-enriched membrane microdomains, which function as carriers for bulk of cholesterol. The hypocholesterolemic drug ezetimibe disrupts the association between NPC1L1 and flotillins, which blocks the formation of the cholesterol-enriched microdomains. Our findings reveal a functional role of flotillins in NPC1L1-mediated cholesterol uptake and elucidate the formation of NPC1L1-flotillins-postive cholesterol-enriched membrane microdomains as a mechanism for efficient cholesterol absorption.