飲食中大量膽固醇的攝取已經(jīng)成為心血管疾病的主要誘因之一,，其相關(guān)疾病如動(dòng)脈粥樣硬化,、冠心病以及腦中風(fēng)也越來(lái)越威脅人們的健康。Niemann-Pick Type C1-Like 1 (NPC1L1)蛋白是介導(dǎo)飲食膽固醇吸收的關(guān)鍵蛋白質(zhì),。該蛋白質(zhì)通過(guò)和其它蛋白質(zhì)相互配合形成一類(lèi)富含膽固醇的膜結(jié)構(gòu)域,，高效介導(dǎo)膽固醇的吸收。先前的研究雖然一定程度上揭示了NPC1L1蛋白介導(dǎo)膽固醇吸收的分子機(jī)制,，但是還有很多問(wèn)題沒(méi)有解答,。比如說(shuō)，NPC1L1蛋白各個(gè)結(jié)構(gòu)域的功能并不清楚,；人體對(duì)膽固醇的吸收效率遠(yuǎn)大于植物性甾醇,，其分子機(jī)理還不明確。
5月20日,，《生物化學(xué)期刊》（The Journal of Biological Chemistry）在線發(fā)表了中科院上海生命科學(xué)研究院生化與細(xì)胞所宋保亮研究組關(guān)于NPC1L1蛋白N-端結(jié)構(gòu)域結(jié)合膽固醇并促進(jìn)膽固醇吸收的最新研究結(jié)果,。該研究工作發(fā)現(xiàn)，NPC1L1蛋白N-端結(jié)構(gòu)域直接結(jié)合膽固醇,，其中L216等氨基酸突變后影響該蛋白與膽固醇的結(jié)合,，進(jìn)而在細(xì)胞及小鼠模型上影響膽固醇的吸收。
進(jìn)一步地,，N-端結(jié)構(gòu)域結(jié)合膽固醇的能力決定了富含膽固醇的膜結(jié)構(gòu)域的形成和膽固醇的吸收效率,，解釋了N-端結(jié)構(gòu)域促進(jìn)膽固醇吸收的分子機(jī)制。有趣的是,，NPC1L1蛋白N-端結(jié)構(gòu)域并不結(jié)合植物甾醇,，揭示了腸道特異性吸收膽固醇的分子機(jī)制。在該研究工作中,，25-羥基膽固醇能夠競(jìng)爭(zhēng)性抑制NPC1L1蛋白對(duì)膽固醇的吸收,，而已有的膽固醇吸收抑制劑Ezatamibe則作用在NPC1L1蛋白的另一位點(diǎn)，提示NPC1L1蛋白N-端結(jié)構(gòu)域可以作為篩選新型膽固醇吸收抑制劑的靶點(diǎn),。
宋保亮研究組圍繞膽固醇吸收已進(jìn)行了一系列系統(tǒng)的研究,，該工作進(jìn)一步揭示了NPC1L1蛋白介導(dǎo)的膽固醇吸收的分子機(jī)制，并為篩選膽固醇吸收抑制劑提供了新的策略,。
本論文主要是由博士研究生張錦輝和葛亮完成的,。該研究課題獲得國(guó)家科技部973項(xiàng)目、國(guó)家自然科學(xué)基金委、中國(guó)科學(xué)院和上海市科委的經(jīng)費(fèi)資助,。（生物谷Bioon.com）
生物谷推薦原文出處：
The Journal of Biological Chemistry DOI:10.1074/jbc.M111.244475
The N-terminal domain of NPC1L1 binds cholesterol and plays essential roles in cholesterol uptake
Jin-Hui Zhang, Liang Ge, Wei Qi, Liqing Zhang, Hong-Hua Miao, Bo-Liang Li, Maojun Yang and Bao-Liang Song
Niemann-Pick C1 Like 1 (NPC1L1) is a multi-transmembrane protein playing a crucial role in dietary and biliary cholesterol absorption. Cholesterol promotes the formation and endocytosis of NPC1L1-flotillin-cholesterol membrane microdomains, which is an early step in cholesterol uptake. How cholesterol is sensed in this step is unknown. Here, we find that the N-terminal domain (NTD) of NPC1L1 binds cholesterol. Mutation of residue L216 in NPC1L1-NTD eliminates cholesterol binding, decreases the formation of NPC1L1-flotillin-cholesterol membrane microdomains, and prevents NPC1L1-mediated cholesterol uptake in culture cells and mice livers. NPC1L1-NTD specifically binds cholesterol but not plant sterols, which may account for the selective cholesterol absorption in intestine. Furthermore, 25- or 27-hydroxycholesterol competes with cholesterol to bind NPC1L1-NTD and inhibits the cholesterol induced endocytosis of NPC1L1. Together, these results demonstrate that plasma membrane-localized NPC1L1 binds exogenous cholesterol via its NTD, and facilitates the formation of NPC1L1-flotillin-cholesterol membrane microdomains that are then internalized into cells through clathrin-AP2 pathway. Our study uncovers the mechanism of cholesterol sensing by NPC1L1 and proposes a mechanism for selective cholesterol absorption.
