早年毕业于南京大学的宋保亮博士2005年被作为“百人计划”人才引进，近年来其研究组主要对*代谢的两个重要方面－*合成及吸收进行研究，获得了不少新成果。

在长久的进化选择过程中，人类获得了吸收食物中营养的能力，用以应对当初食物来源的不足，当然对于*的吸收也不例外。饮食中大于50%的*将被人体所吸收。然而在现代社会，随着人们生活水平的提高和饮食结构的改变，的*摄取反而成为导致高*血症发病率提高的直接因素，也是相关的严重疾病，如动脉粥样硬化、冠心病和脑中风等发病的重要病因。阐明饮食*吸收效率的分子机制，将为研发新型的降*药物提供靶点，为防治高*血症以及相关严重代谢疾病提供重要理论基础。

宋保亮博士研究组发现一个名叫NPC1L1的蛋白质和两个名叫Flotillin-1和Flotillin-2的同源蛋白相互作用形成一个含有高浓度*的特殊膜结构域，犹如载有大量*的卡车一般。该结构域通过膜泡内吞，将大量*摄取进入细胞。这是饮食*吸收的重要原因之一。进一步研究发现降*药物“益适纯”（Ezetimibe，先灵葆雅公司）是通过阻断这种特殊膜结构域的形成，抑制*的吸收。

这一研究成果不仅进一步揭示了NPC1L1蛋白的作用机制和降*药物“益适纯”的作用原理，而且为筛选新型*吸收抑制剂提供了新的分子靶点、理论依据和实验基础。

另外这一研究组还揭示了人群中*吸收效率差异的分子机制，为相关疾病的临床诊断提供重要基础。

随着人们生活水平的提高，目前从食物中摄取的过多*已成为诱发各种心脑血管疾病，如高*血症、动脉粥样硬化、冠心病和脑中风等的主要致病因素。食物中*在流经肠道时大约有50%会被吸收，但由于个体的遗传差异，*实际上的吸收效率变动从29%到80%不等。并且这种*高吸收或低吸收的现象在人群中是可遗传的。

Niemann-Pick Type C1-Like 1 （NPC1L1）是近年来发现的介导饮食和胆汁中*吸收的关键蛋白，也是降*药物“益适纯”的直接作用靶点。宋保亮组的博士生王丽娟等人通过对在*低吸收人群中天然存在的多个NPC1L1 蛋白单氨基酸突变体进行了深入的分析和研究，揭示了其中多种单氨基酸突变直接影响了NPC1L1 蛋白的翻译后修饰、折叠和蛋白稳定性，导致其功能丧失和快速降解。同时，他们在小鼠模型上的相关研究结果也进一步表明这些NPC1L1 蛋白的突变是导致人群中*低吸收的主要原因。这些工作将为相关疾病的临床诊断提供重要基础。

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.

来源：生物通