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Pharmacy Information

2160-441X

Scientific Research Publishing

10.12677/PI.2013.22005

PI-11870

PI20130200000_48321510.pdf

医药卫生

胆固醇吸收靶点NPC1L1研究进展 Research Progress of Niemann-Pick-C1-Like 1, a Key Target Related to Cholesterol Absorption

方

沐潮

² ¹ 曹

乐

² ¹ 贝

伟剑

² ^*

广东药学院中医药研究院，广州

null

* E-mail: beiwj2000@yahoo.com.cn(贝伟) ;

28 05 2013

02 02 19 26 Mar. 20th, 2013 Apr. 18th, 2013 Apr. 26th, 2013

2014

This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

NPC1L1是近年发现对胆固醇的吸收有调控作用的新靶点。在小肠内NPC1L1蛋白与胆固醇吸收直接相关。NPC1L1蛋白与相关胆固醇转运蛋白Flotillin-1和Flotillin-2相互作用，将胆固醇和其他甾醇转运通过肠上皮细胞刷状缘、运送到肠上皮细胞内。降胆固醇药物Ezetimibe正是阻断了NPC1L1和Flotillin-1和Flotillin-2的相互作用，从而抑制胆固醇吸收。NPC1L1的表达受到多个核因子如PPARs，LXRα，SREBP2，HNF4α的调控；另一方面，NPC1L1又能够通过调节细胞胆固醇水平，进而调控胆固醇代谢相关的SREBP1c、FAS和ABCA1等基因，进一步维持体内胆固醇的动态平衡。多种中药对胆固醇吸收有抑制作用，但是目前尚未发现中药直接作用于NPC1L1而抑制胆固醇吸收的报道。
NPC1L1 is a new found target protein in the regulation of cholesterol absorption. NPC1L1 is directly related to cholesterol absorption in the intestine. By interacting with cholesterol transport protein Flotillin-1 and Flotillin-2, NPC1L1 protein transports the cholesterol and other sterols across the intestinal epithelial brush border membrane into the intestinal epithelial cells. The cholesterol transporter function of NPC1L1 was specifically inhibited by cholesterol- lowering agent Ezetimibe via blocking the interaction. NPC1L1 expression is highly modulated by a variety of nuclear regulators such as PPARs, LXRα, SREBP2, HNF4α. NPC1L1 could otherwise regulate the related downstream genes to maintain cholesterol homeostasis via regulating cholesterol level in the related cells. A variety of traditional Chinese medicine have inhibitory effect on cholesterol absorption. It has not yet reported that Traditional Chinese Medicine could regulate cholesterol absorption by inhibiting NPC1L1.

胆固醇吸收；NPC1L1；中药；依泽麦布, Cholesterol Absorption; Niemann-Pick-C1-Like 1; Traditional Chinese Medicine; Ezetimibe

1. 引言

高胆固醇血症是心脑血管疾病的独立危险因素，可直接引起动脉粥样硬化，最终导致冠心病和脑中风等致死、致残性疾病。阐明胆固醇吸收的分子机制将为防治这类疾病提供重要基础。

体内合成、肠道吸收和肝脏代谢是人体胆固醇动态平衡的三大调节渠道。血浆胆固醇的来源主要有2条途径，一是肝脏和外周组织合成的胆固醇，二是由肠道吸收膳食和胆汁中的胆固醇。

Niemann-Pick-C1-Like 1（NPC1L1）是近年来发现的新基因，主要表达在人、猴子及大、小鼠的小肠和肝脏，可调控胆固醇的吸收^{[

1
]}。蛋白是胆固醇跨膜转运的关键蛋白，在人肠表皮细胞膜和肝实质细胞膜上大量表达，是人体胆固醇代谢调节网络的关键节点之一^[2,3]。大量的细胞及动物实验表明，NPC1L1在肠道胆固醇吸收及代谢过程中发挥重要作用^[4-6]。且近年研究证明NPC1L1在Caco-2细胞中表达促进胆固醇和谷固醇的吸收，并且这种作用能够被ezetimibe所抑制^{[

7
]}。

本文将就NPC1L1近年来相关胆固醇代谢方面的研究进展做一综述。

2. 胆固醇吸收过程及其抑制剂Ezetimibe

NPC1L1蛋白位于小肠黏膜上皮细胞的刷状缘，是小肠内饮食性胆固醇吸收的转运体。在小肠内饮食胆固醇吸收过程中起关键作用。

先灵葆雅研究院的科学家发现蛋白质NPC1L1在肠道胆固醇吸收机制中扮演重要角色。用免疫组织化学法，分子生物学家Scott Altmann^[8,9]博士等人发现NPC1L1蛋白质位于空肠(jejunum)的肠道细胞。为了确认此新发现蛋白质的作用，Harry Chip Davis博士^[10-12]等通过基因工程发现缺乏NPC1L1蛋白质的老鼠只能吸收较正常老鼠不到70%的胆固醇数量，显示 NPC1L1是胆固醇吸收路径的重要组成之一。

早期研究显示，NPC1L1缺失或ezetimibe治疗可以减少血液中胆固醇含量，在此基础上的进一步研究确定NPC1L1是强效胆固醇吸收抑制剂ezetimibe的作用靶点^[7,13]。ezetimibe在临床使用中用来治疗高胆固醇血症，也用来预防饮食所导致的脂肪肝和肥胖症。同时，研究结果表明降低NPC1L1基因的表达可减少因高脂饮食所致的肝脏脂肪性变^[14,15]。

胆固醇吸收过程可分为三个阶段^[16,17]：1) 初始阶段(the initial or intraluminal phase)：亦称管腔内过程，是一系列理化过程，主要为在混合胶束(mixed micelles)中的甾醇被转运到肠上皮细胞刷状缘(BBM，brush border membrane)上的过程。2) BBM阶段(brush border membrane phase)：NPC1L1和其他相关胆固醇转运蛋白将胆固醇与其他甾醇跨膜转运通过BBM。3) 细胞内阶段(intracellular phase)：包含了数个复杂过程，比如大多数胆固醇进入上皮细胞后的再酯化，胆固醇与其他脂类随载脂蛋白B48组成乳糜微粒等过程。本综述重点在第二阶段，即BBM阶段中NPC1L1与胆固醇相互作用^[18,19]。

在初始阶段，胆固醇吸收过程从消化液中各种酶与食物在口腔中混合开始。食物进入胃部与胃蛋白酶等消化液混合，胃蠕动将食物加工成糜状。食物乳糜从胃进入十二指肠，在十二指肠中食物乳糜与胆汁和胰液混合后，进入小肠中。脂肪水解酶将脂类水解成包括胆固醇在内的不溶于水相的各种脂类，其中胆汁酸与胆固醇结合成胆酸盐，胆酸盐可以增加胆固醇在水相中溶解度。BBM阶段，即胶束穿过小肠腔膜上的一层可以改变胆固醇吸收动力学的屏障。小肠腔中胆固醇与胆固醇转运体结合通过上皮细胞刷状缘。胆固醇在小肠上皮细胞被迅速加工并转运至淋巴液中。进入上皮细胞后，即为细胞内阶段，一半的胆固醇被转移至内质网，胆固醇在内质网被ACAT (acyl CoA: cholesterol acyltransferase脂肪酰转移酶)催化，聚合成乳糜微粒。乳糜微粒从淋巴液分泌至血液中。乳糜微粒通过血管脂蛋白脂肪酶lipoprotein lipase (LPL)的水解作用向外周组织转运甘油三酯，水解残留部分含有丰富的胆固醇，肝脏吸收之。在肝脏，胆固醇去路有两条：合成胆汁酸，再次与VLDL结合进入全身循环。与脂蛋白和载脂蛋白相关的蛋白质，作为脂质受体，酶的辅助因子或受体介导的细胞摄取的配体。

Altmann等^{[

1
]}在2004年发表的文章中称NPC1L1是食物与胆汁中胆固醇吸收的重要蛋白。2005年，Garcia-Calov等^{[

7
]}发表论文宣布NPC1L1为ezetimibe的作用靶点。Hawes等^{[

13
]}发现，ezetimibe体内实验表明，其作用于NPC1L1的亲和力直接相关。有研究表明NPC1L1敲除小鼠中，胆固醇吸收显著下降。ezetimibe可抑制食物胆固醇从小肠管腔转运至小肠细胞中。其他领域研究开始向NPC1L1在人类中表达的遗传多样性和此特性与人类个体血浆LDL-C水平相关性研究^[6,20-22]。

3. NPC1L1转运胆固醇及Ezetimibe抑制 NPC1L1的分子机制

NPC1L1为治疗高胆固醇血症的药物靶点，对该基因的研究有助于在分子水平上深入理解胆固醇吸收过程，有助于加速在分子水平开发调节胆固醇代谢的药物。

“NPC1L1”蛋白质和两个名为“Flotillin-1”和“Flotillin-2”的同源蛋白相互作用，形成一个含有高浓度胆固醇的特殊膜结构域，将人们饮食中所含的大量胆固醇高效摄取进入细胞^{[

23
]}。这个过程依赖于细胞内的微丝系统和Clathrin/AP2蛋白复合体^{[

24
]}。

该膜结构域在小肠上皮细胞膜表面组装。其中，蛋白质NPC1L1为转运体，同源蛋白Flotillin-1和Flotillin-2结合细胞外的大量游离胆固醇，该结构域在一个Clathrin/AP2的蛋白复合体共同作用下，通过细胞的微丝，将大量胆固醇运送到细胞内^{[

23
]}。

Ge等^{[

25
]}报道了在肝脏和小肠细胞中，NPC1L1控制胆固醇在细胞表面和细胞内循环转运，并鉴定出这个过程依赖于细胞内的微丝系统和Clathrin/AP2蛋白复合体。进一步研究证明新近上市的降胆固醇药物ezetimibe的作用机制，证明该药物通过抑制NPC1L1蛋白，从而抑制细胞对胆固醇的吸收。

宋保亮研究组^[26,27]进一步阐明了降胆固醇类药物Ezetimibe的作用机制，证明该药物通过抑制NPC1L1蛋白，从而抑制细胞对胆固醇的吸收。研究还发现，降胆固醇药物益适纯的作机理在于该药物阻断了NPC1L1和Flotillin-1和Flotillin-2之间的作用关系，让NPC1L1不能发挥运送胆固醇进入细胞内部的功效。Smart等研究发现^{[

28
]}，ezetimibe能够作用于胆固醇转运复合物，随后小凹蛋白1 (caveolin-1)从该复合物释放出来。胆固醇和植物固醇在肠上皮细胞的吸收都需要NPC1L1蛋白，植物固醇同胆固醇竞争使用NPC1L1蛋白^[23,29-30]。

4. NPC1L1上游调控因子

NPC1L1基因表达在转录水平受多种转录调节因子的调控。近年研究显示，过氧化物酶增殖体激活受体(peroxisome proliferator activated receptor, PPAR)，肝脏X受体(Liver X receptor, LXR)，甾体调节原件结合蛋白2 (sterol regulatory element binding protein 2，SREBP2)，肝核因子1α、4α (hepatocyte nuclear factor 1α/4α, HNF1α/4α)是细胞内调节胆固醇代谢的重要转录调节因子。上述调控因子受到药物等因素刺激，在细胞内被激活或抑制，进而调控NPC1L1的表达，从而维持细胞内胆固醇含量稳定。

4.1. PPARs

激活PPARδ，可下调NPC1L1基因的表达，抑制肠道胆固醇吸收。Oliver等^{[

31
]}使用PPARδ激动剂GW501516对肥胖恒河猴进行4周治疗后，发现NPC1L1表达下调，胆固醇吸收减少。并且其血脂谱明显改善：血清高密度脂蛋白胆固醇(HDL-C)上升79%，低密度脂蛋白胆固醇(LDL-C)下降29%，甘油三酯下降56%，血清中与HDL-C相关的载脂蛋白apoA和apoC水平升高。Van der Veen^{[

32
]}等用GW 610742激动PPARδ，在肥胖和非肥胖的小鼠模型上也得到相似的结果。

PPARα和PPARδ均能下调肠内NPC1L1表达，抑制肠内胆固醇吸收。其可能机制如下。PPARα和δ激动剂可增加肌肉中氧化型纤维比例与含量，提高琥珀酸脱氢酶活性；上调心肌脂肪酸氧化相关基因或阻滞核转录因子对心肌脂肪酸氧化的抑制，进而促进心肌脂肪酸氧化，从而有效促进骨骼肌、心肌、脂肪组织的脂肪酸摄取、β氧化和能量耗散等体内脂肪酸代谢去路而调节血脂，如可显著升高血HDL-C，促进血中apoA Ⅰ/Ⅱ增加，体内巨噬细胞、肠细胞以及纤维细胞中ABCA1的表达；进而调节NPC1L1的表达^[33-35]。

4.2. LXRα

激活LXRα，可下调NPC1L1基因的表达，抑制肠道胆固醇吸收。

LXR属于核受体超家族，是细胞核的胆固醇感受器，可调节外周组织胆固醇逆转运、胆酸形成和胆固醇分泌过程中相关基因的表达。其在调节细胞内胆固醇、脂肪酸、葡萄糖的动态平衡中发挥了重要作用。在维持体内胆固醇的动态平衡方面，激活LXRα，可上调三磷酸腺苷结合盒转运体(ABC)中ABCA1和ABCG5/8异二聚体的表达，增加细胞内胆固醇逆转运至肝和肠腔，促进体内胆固醇清除。同时，可通过调控NPC1L1，使NPC1L1调节摄取固醇类脂质，然而具体机制仍不清楚。

NPC1L1蛋白的细胞表达和活性受到一些因素的调节，目前证实胆固醇浓度是最主要的调节因子。Repa的体内外实验发现，当食物中胆固醇含量高时，小鼠的小肠上皮细胞NPC1L1蛋白的表达较正常饮食的小鼠下调^{[

36
]}；当细胞内胆固醇浓度升高时，LXRα激活并导致小肠上皮细胞的NPC1L1 mRNA和蛋白表达下调^[37,38]。Duval等^{[

37
]}研究发现，在人肠上皮细胞株Caco2/TC7内，LXR激动剂T0901317则下调NPC1L1 mRNA的表达。用同样方法处理过的小鼠十二指肠NPC1L1降低30%给予小鼠单剂量LXR激动剂(T0901317) 6h后，NPC1L1 mRNA表达水平显著降低，表明NPC1L1是LXR的靶点基因^[39,40]。

4.3. 其他调控因子

NPC1L1与转录调节因子甾醇调节元件结合蛋白2 (sterol regulatory element binding protein 2, SREBP2) 基因表达呈正相关，提示NPC1L1的转录表达可能受到SREBP2的调控。Horton^{[

41
]}等实验研究发现，在Caco-2细胞中，应用洛伐他汀导致细胞内胆固醇水平降低时，通过激活SREBP2，可以上调细胞NPC1L1 mRNA和蛋白的表达^{[

13
]}。Pramfalk等通过构建NPC1L1启动子荧光素酶报告基因，染色质免疫沉淀和凝胶迟滞电泳等方法，在人肝细胞HuH7实验证实，NPC1L1基因主要受两个肝脏核受体SREBP2和肝细胞核因子1α (HNF1α)的转录调节^[42,43]。

SREBP2是细胞内调节胆固醇代谢的重要转录调节因子，Goldstein^{[

44
]}等发现，在Caco-2细胞内SREBP2能增进人体NPC1L1启动子的转录活性。上海瑞金医院与瑞典Karolinska医学院的合作研究后亦证实，人体肝细胞NPC1L1基因受SREBP2以及肝核因子1的转录调控^{[

43
]}。

研究这些转录因子对表达调节的意义在于，有可能采用特定药物调控基因表达及其功能，进而改变小肠细胞和肝细胞对胆固醇的摄取，调节胆固醇代谢以及胆汁胆固醇含量。

肝细胞核因子4 (HNF4)是核受体超家族中一种孤儿受体，广泛表达于人体各个器官，是脂质和糖代谢的关键调节因子。体外实验研究发现，HNF4直接作用于NPC1L1启动子区，与SREBP2协同上调NPC1L1的转录水平，增加NPC1L1蛋白的表达，增加肠道对胆固醇的吸收。敲除HNF4基因小鼠NPC1L1 mRNA的表达显著减少^{[

45
]}。

近期研究显示胆石患者空肠黏膜NPC1L1基因表达显著增加，同时ACAT2基因表达也增加^{[

46
]}。

5. NPC1L1的下游调控靶点

NPC1L1不但是胆固醇跨膜转运的关键蛋白，还对全身的胆固醇动态平衡的调控起关键作用。通过细胞内吞作用的循环途径，NPC1L1蛋白在细胞浆膜和细胞内结构间的分布可以转换，药物刺激、胆固醇水平变化等因素可引起NPC1L1蛋白在细胞膜上分布的变化，进而影响NPC1L1蛋白于细胞膜上突起的子区域数量的增减，从而增加或减少游离胆固醇的摄取^{[

47
]}。Duval等^{[

37
]}NPC1L1蛋白通过调节细胞内胆固醇的浓度，进而调节其他基因的活性，来维持胆固醇在体内的动态平衡，如3-羟基-3-甲基戊二酰辅酶A还原酶(3-hydroxy-3-methyl glutaryl coenzyme A reductase, HMGR)、胆固醇酰基转移酶(acyl-coenzyme A cholesterol acyltransferase, ACAT)等。在肝脏表达的几种调控脂肪生成的基因，如SREBP1c、FAS和ABCA1基因等，抑或与NPC1L1的下游调控有关，它们的转录激活及表达紊乱可能参与肝脏脂肪性变性^[48,49]。

5.1. NPC1L1与ACAT、HMGR和SREBP2

NPC1L1表达下调能够抑制游离胆固醇和脂酰CoA向胆固醇酯的转变，促进体内胆固醇合成，从而在体内胆固醇代谢平衡中起到重要的调控作用。当小鼠NPC1L1基因敲除时，肝细胞和小肠上皮细胞中的胆固醇合成限速酶(HMGR)活性增加。NPC1L1−/−小鼠肝细胞的HMGR的基因表达是正常NPC1L1+/+小鼠的35倍，显示NPC1L1基因敲除小鼠通过增加体内胆固醇的合成来代偿肠道吸收减少的胆固醇^{[

50
]}。同时，对胆固醇饲养的野生型小鼠的研究发现，其肠道NPC1L1的mRNA表达量下调，肠道HMG-CoA合成酶的mRNA和胆固醇合成酶的mRNA表达上调。

Sane等研究表明，NPC1L1表达下调，可抑制胆固醇酰基转移酶(ACAT)活性，同时促进HMG-CoA还原酶活性和SREBP2 RNA水平的提高^{[

51
]}。

5.2. NPC1L1与ABC家族

ATP结合盒转运子(ATP-binding cassette, ABC) A1 (ABCA1)基因调节胆固醇逆向转运，它由高密度脂蛋白(HDL)介导，从肝外组织将胆固醇转运至肝脏进行代谢，通过这种机制，机体可将外周组织细胞中的胆固醇转运至肝脏代谢。

有研究表明，肠道NPC1L1对胆固醇的吸收是由雌激素受体介导的，同时，跨膜蛋白ATP结合盒转运子G5和G8 (ABCG5和ABCG8)参与了其中的过程^{[

52
]}。但是，对胆固醇饲养的野生型小鼠的研究发现，肝脏NPC1L1表达增加，ABCA1表达降低。同时，在NPC1L1缺失的小鼠体内，ABCA1的mRNA的表达下调，但是ABCG5和ABCG8的mRNA并没有改变，说明NPC1L1对于调节肠道内胆固醇和植物甾醇类的摄取有重要的作用^{[

1
]}。

魏长林^{[

53
]}等研究则发现，肝脏过表达人NPC1L1的转基因小鼠(L1Tg)给予LXR激动剂(T0901317) 7天后，发现其与相同处理的野生小鼠对比，粪便核心甾醇降低并升高了血浆游离胆固醇。其表明肝脏过表达人NPC1L1能够下调由LXR诱导的小鼠肝脏ABCG5和ABCG8的mRNA水平。

有实验表明，用ezetimibe处理小鼠，可以发现小鼠肠内ABCA1的mRNA表达量下调，但是ABCG5和ABCG8的mRNA表达量并没有改变，说明ezetimibe通过NPC1L1抑制胆固醇的吸收，可能同这些胆固醇跨膜转运蛋白有关的^[54-56]。

NPC1L1对胆固醇跨膜转运的调节作用是与ABCA1的相互调节来实现的。ABCA1和SR-B在胆固醇的跨膜转运中起重要的作用，ABCA1的mRNA在NPC1L1+/+和NPC1L1−/−的小鼠体内都有表达，但在这些基因未被激活的小鼠体内，它们对胆固醇的吸收并没有影响，说明在这种情况下，胆固醇的跨膜转运是通过另一种信号通路来实现的。在胆固醇食物喂养的NPC1L1缺失小鼠中可以发现，肠道ABCA1的mRNA的表达和下调，这种现象说明了NPC1L1对胆固醇的吸收调节作用有可能是通过ABCA1或者是SR-B实现的^[57-60]。

5.3. NPC1L1与SREBP1c和FAS

SREBP1c的功能是加强LDL受体的转录，介导胆固醇从血浆脂蛋白的吸收，促进胆固醇的合成。而脂肪酸合成酶(fatty acid synthetase, FAS)的体内平衡是由上游刺激因子和SREBP1c进行转录调控，以对进食行为和胰岛素做出反应。对胆固醇饲养的野生型小鼠的研究发现，肝脏NPC1L1表达增加，同时脂肪及胆固醇代谢调节基因SREBP1c和FAS基因表达明显增高。NPC1L1可以调节胞内胆固醇浓度，SREBP裂解激活蛋白(SREBP cleavage activating protein, SCAP)对此信号——胆固醇浓度——敏感。故NPC1L1可对SREBP1c和FAS的表达进行调控^[61,62]。

人类的NPC1L1的跨膜转运区域中具有一个分泌性信号区，跨膜转运的N端糖基化位点定位在该蛋白的细胞小凹的结构处，该蛋白还有一个固醇敏感的区域，Davies等研究证实该区域可调节调节包括HMGCoA还原酶、SREBP-1的激活蛋白SCAP、PATCHED和NPC1在内的胆固醇平衡调节部位^[63-65]。

6. 影响胆固醇吸收的中药

目前还未见中药作用于NPC1L1靶点而抑制胆固醇吸收的报道。但许多中药对胆固醇吸收有抑制作用。这类中药主要是抑制机体对外源性脂类的吸收，同时，在肝肠循环中减少胆酸重吸收的数量，从而达到降血脂的目的。外源性胆固醇经过小肠的消化吸收而进入到人体内，摄入的胆固醇在肠黏膜细胞经酶作用重新酯化成胆固醇酯，再进入淋巴管，淋巴管和血液中的胆固醇大部分以胆固醇酯的形式存在^[66-69]。

含三萜类化合物的中药，如泽泻能影响脂肪分解，使合成胆固醇的原料减少而起到降血脂、防止动脉粥样硬化和脂肪肝的功效；含甾醇类植物能与动物性固醇的化学本质一样，如豆类、蒲黄、海藻等含有谷甾醇、豆甾醇、菜油甾醇等植物甾醇，在肠道中可以与动物性固醇竞争，从而减少胆固醇的吸收；何首乌、草决明、虎杖、大黄等含有蒽醌类化合物及其衍生物，能促进肠的蠕动，减少脂类在肠道停留时间，从而减少胆固醇在肠道的吸收。荷叶能使肠道形成一层膜，阻止脂类进入小肠黏膜细胞，减少吸收。中药影响胆汁酸的肠肝循环。胆盐为胆固醇的转化物，在胆汁酸的肝肠循环中，有些植物中的纤维素、果胶等和胆盐结合形成复合物，阻断胆汁酸的肝肠循环，减少胆汁酸重吸收的数量，不仅增加胆汁酸及其衍生物的排泄量，还能通过反馈机制增加胆汁酸合成限速酶活性，促进胆固醇转化为胆汁酸，从而达到降胆固醇的目的。甘薯中的黏蛋白、决明子蛋白质、大豆蛋白等这类活性蛋白质，能与胆汁酸相结合，减少肝肠循环中胆汁酸重吸收量，达到降胆固醇的目的；枸杞多糖、海带多糖、魔芋中所含的葡甘聚糖等都有类似的功效^[70-77]。

7. 展望

NPC1L1作为一个体内调节胆固醇的新节点，为调脂中药活性成分筛选提供了新靶标。调脂中药是否具有调节NPC1L1的具体机制仍不清楚，中药中何种成分调节NPC1L1的表达也不清楚。深入研究调脂中药或其活性成分对NPC1L1的调控作用及其分子机制，有望为中药调节血脂平衡提供科学内涵，并为中药防治高脂血症提供新策略。

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[ 74 ] 彭罡, 覃冬云. 岩豇豆脂肪酸对高脂血症小鼠动脉粥样硬化的治疗作用[J]. 中国现代医药杂志, 2009, 10: 13-16.

[ 75 ] 粟时颖. 山(金)银花有效成分的分析和提取以及抑制巨噬细胞胆固醇蓄积作用的研究[D]. 南华大学, 2011.

[ 76 ] 王春艳. 普洱茶抑制膳食脂肪吸收功效的研究[D]. 吉林大学, 2011.

[ 77 ] 夏晓凯, 童希琼, 张庭廷等. 柚肉黄酮降脂作用研究[J]. 中国中医药现代远程教育, 2008, 10: 1164-1165.

NOTES

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