早年畢業(yè)于南京大學(xué)的宋保亮博士2005年被作為“百人計(jì)劃”人才引進(jìn)，近年來(lái)其研究組主要對(duì)*代謝的兩個(gè)重要方面－*合成及吸收進(jìn)行研究，獲得了不少新成果。

在長(zhǎng)久的進(jìn)化選擇過(guò)程中，人類獲得了吸收食物中營(yíng)養(yǎng)的能力，用以應(yīng)對(duì)當(dāng)初食物來(lái)源的不足，當(dāng)然對(duì)于*的吸收也不例外。飲食中大于50%的*將被人體所吸收。然而在現(xiàn)代社會(huì)，隨著人們生活水平的提高和飲食結(jié)構(gòu)的改變，的*攝取反而成為導(dǎo)致高*血癥發(fā)病率提高的直接因素，也是相關(guān)的嚴(yán)重疾病，如動(dòng)脈粥樣硬化、冠心病和腦中風(fēng)等發(fā)病的重要病因。闡明飲食*吸收效率的分子機(jī)制，將為研發(fā)新型的降*藥物提供靶點(diǎn)，為防治高*血癥以及相關(guān)嚴(yán)重代謝疾病提供重要理論基礎(chǔ)。

宋保亮博士研究組發(fā)現(xiàn)一個(gè)名叫NPC1L1的蛋白質(zhì)和兩個(gè)名叫Flotillin-1和Flotillin-2的同源蛋白相互作用形成一個(gè)含有高濃度*的特殊膜結(jié)構(gòu)域，猶如載有大量*的卡車一般。該結(jié)構(gòu)域通過(guò)膜泡內(nèi)吞，將大量*攝取進(jìn)入細(xì)胞。這是飲食*吸收的重要原因之一。進(jìn)一步研究發(fā)現(xiàn)降*藥物“益適純”（Ezetimibe，先靈葆雅公司）是通過(guò)阻斷這種特殊膜結(jié)構(gòu)域的形成，抑制*的吸收。

這一研究成果不僅進(jìn)一步揭示了NPC1L1蛋白的作用機(jī)制和降*藥物“益適純”的作用原理，而且為篩選新型*吸收抑制劑提供了新的分子靶點(diǎn)、理論依據(jù)和實(shí)驗(yàn)基礎(chǔ)。

另外這一研究組還揭示了人群中*吸收效率差異的分子機(jī)制，為相關(guān)疾病的臨床診斷提供重要基礎(chǔ)。

隨著人們生活水平的提高，目前從食物中攝取的過(guò)多*已成為誘發(fā)各種心腦血管疾病，如高*血癥、動(dòng)脈粥樣硬化、冠心病和腦中風(fēng)等的主要致病因素。食物中*在流經(jīng)腸道時(shí)大約有50%會(huì)被吸收，但由于個(gè)體的遺傳差異，*實(shí)際上的吸收效率變動(dòng)從29%到80%不等。并且這種*高吸收或低吸收的現(xiàn)象在人群中是可遺傳的。

Niemann-Pick Type C1-Like 1 （NPC1L1）是近年來(lái)發(fā)現(xiàn)的介導(dǎo)飲食和膽汁中*吸收的關(guān)鍵蛋白，也是降*藥物“益適純”的直接作用靶點(diǎn)。宋保亮組的博士生王麗娟等人通過(guò)對(duì)在*低吸收人群中天然存在的多個(gè)NPC1L1 蛋白單氨基酸突變體進(jìn)行了深入的分析和研究，揭示了其中多種單氨基酸突變直接影響了NPC1L1 蛋白的翻譯后修飾、折疊和蛋白穩(wěn)定性，導(dǎo)致其功能喪失和快速降解。同時(shí)，他們?cè)谛∈竽Ｐ蜕系南嚓P(guān)研究結(jié)果也進(jìn)一步表明這些NPC1L1 蛋白的突變是導(dǎo)致人群中*低吸收的主要原因。這些工作將為相關(guān)疾病的臨床診斷提供重要基礎(chǔ)。

原文摘要：

Flotillins play an essential role in Niemann-Pick C1-like 1-mediated cholesterol uptake.

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.

Molecular characterization of the NPC1L1 variants identified from cholesterol low absorbers

Niemann-Pick C1-like 1 （NPC1L1） is an essential protein for dietary cholesterol absorption. Nonsynonymous （NS） variants of NPC1L1 in humans are suggested to associate with cholesterol absorption variations. However, information concerning the characteristics and mechanism of these variants in cholesterol uptake are limited. In this study, we analyzed the cholesterol uptake ability of the 19 reported NS variants of NPC1L1 identified from cholesterol low absorbers. Among these variants, L110F, R306C, A395V, G402S, T413M, R693C, R1214H and R1268H could partially mediate cellular cholesterol uptake and were categorized as the partially dysfunctional variants. The other 11 variants including T61M, N132S, D398G, R417W, G434R, T499M, S620C, I647N, G672R, S881L and R1108W could barely facilitate cholesterol uptake, and were classified into the severely dysfunctional group. The partially dysfunctional variants showed mild defects on one or multiple aspects of cholesterol-regulated recycling, subcellular localization, glycosylation and protein stability. The severely dysfunctional ones displayed remarkable defects on all these aspects and were rapidly degraded through ER-associated degradation （ERAD） pathway. In vivo analyses using adenovirus-mediated expression in mice liver confirmed that the S881L variant failed to localize to liver canalicular membrane and the mice showed defect in biliary cholesterol re-absorption, while the G402S variant appeared to be similar to wild-type NPC1L1 in mice liver. This study suggests that the dysfunction of the 19 variants on cholesterol absorption is due to the impairment of recycling, subcellular localization, glycosylation, or stability of NPC1L1.

來(lái)源：生物通