State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):551-6. doi: 10.1073/pnas.1014434108. Epub 2010 Dec 27.
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.
饮食吸收是哺乳动物获取胆固醇的主要途径，胆固醇通过 NPC1 样蛋白 1（NPC1L1）通过囊泡内吞作用进行介导。该过程中的一个基本问题是游离胆固醇如何通过 NPC1L1 的内化被有效地摄取。利用外源表达的 NPC1L1-EGFP，我们表明脂筏蛋白 flotillins 与 NPC1L1 结合，并且它们的定位在 NPC1L1 细胞内运输过程中受到调节。此外， flotillins 对于 NPC1L1 介导的细胞胆固醇摄取、胆汁胆固醇重吸收以及小鼠脂质水平的调节是必不可少的。它们与 NPC1L1 一起形成富含胆固醇的膜微区，作为胆固醇的载体。降胆固醇药物依折麦布会破坏 NPC1L1 和 flotillins 之间的关联，从而阻止富含胆固醇的微区的形成。我们的研究结果揭示了 flotillins 在 NPC1L1 介导的胆固醇摄取中的功能作用，并阐明了 NPC1L1-flotillins-阳性胆固醇富集膜微区的形成是有效胆固醇吸收的一种机制。
