姜黄素对肝细胞LDLR表达作用的分子机理研究
|
摘要
血液中胆固醇特别是LDL-C浓度的升高是引起动脉粥样硬化和冠心病的最主要危险因素，降低血液胆固醇浓度可明显减少冠心病的发病率和死亡率。体内大部分胆固醇结合于LDL，经肝细胞表面的LDLR代谢和清除。LDLR是位于细胞表面的跨膜受体，其表达受到胆固醇和其它许多物质在转录水平或转录后水平的调控，上调肝脏LDLR的表达是降低血液胆固醇浓度的最主要手段。目前临床应用最广泛的能上调肝脏LDLR表达的药物是他汀类，他汀类药物能竞争性抑制HMG-CoA还原酶的活性，使细胞内胆固醇合成减少。总体来讲他汀类具有出色的降胆固醇疗效，但是也有部分患者因不良反应(如肝功能损害等)不能耐受其治疗。因此，筛选新型降胆固醇药物一直是调血脂药物的研究重点。
目的：
通过对传统中草药物的筛选，我们发现从活血化瘀药姜黄中提取的姜黄素能显著降低血清胆固醇、LDL-C含量的作用，从而起到降血脂和抗动脉粥样硬化的作用。为了研究姜黄素降胆固醇作用的分子机制，我们设计了一系列实验。本课题就是在以往研究的基础上，拟从基因表达水平和细胞信号调控角度探寻姜黄素与信号调控途径中关键蛋白分子以及基因调控元件间的相互作用关系，从而阐明姜黄素对LDLR表达影响的机理。
方法：
第一部分姜黄素诱导LDLR表达的药效研究
首先利用人肝HepG2细胞作为LDLR基因表达检测系统，经姜黄素干预培养后，利用Western-Blot、Rt-PCR、荧光显微镜和流式细胞仪等技术分析肝细胞内源性LDLR蛋白的表达量及其表达活性，确定姜黄素对LDLR基因表达的影响，从受体蛋白水平阐明姜黄素降胆固醇作用的机理。
第二部分姜黄素诱导LDLR表达的机理研究：
①将绿色荧光蛋白GFP报告基因构建在调控低密度脂蛋白受体基因表达的固醇调控元件SRE-1的下游，经脂质体介导法导入HepG2细胞，建立LDLR基因表达的固醇调控报告系统及其稳定细胞株HepG2／SRE-GFP，通过姜黄素的干预培养，从基因表达调控水平研究姜黄素对启动子SRE-1的影响，探寻姜黄素的作用机理。
②利用脂质体介导法将pCMV-Insig2导入HepG2细胞，建立稳定的细胞株HepG2／Insig2，通过姜黄素的干预培养，研究姜黄素对Insig-2的影响，从信号调控通路水平探寻姜黄素降胆固醇作用可能的分子或基因靶点。
结果：
第一部分研究表明，①姜黄素能够增强HepG2 LDLR对LDL的摄取，具有明显的时间依赖性和剂量依赖性。并且在25μmol／L和作用24小时的时候LDLR的活性最强。②姜黄素能够显著促进HepG2 LDLR的表达量，具有明显的时间依赖性和剂量依赖性。③姜黄素可能通过促进HepG2 LDLR mRNA的转录上调LDLR的表达。
第二部分研究结果表明，①姜黄素能够激活启动子调控元件SRE-1上调LDLR表达。②一定浓度的姜黄素能够通过逆转受Insig2抑制的SREBP通路，上调LDLR的表达。
结论：
综上所述，我们从受体水平、基因表达水平到信号调控通路水平对姜黄素降胆固醇的机理进行了一系列研究。所有证据都证明姜黄素很可能是通过作用于SREBP通路中的某个调节因子，促使LDLR表达起到降胆固醇作用的。但是究竟作用于SCAP还是Insig2或者其它蛋白仍有待进一步研究。
The elevation of serum cholesterol levels, especially LDL-C, is by far one of the mostrelative risk factors that cause atherosclerosis and CHD. Lowering LDL-C levels bymedication can reduce the mortality of CHD significantly. The majority of LDL-C are takenup and cleared by hepatic LDLR. LDLR is a trans-membrane receptor located on cell surface,the expression level of which is tightly regulated by sterols or non-sterols pathway both onthe transcription and post-transcription level. Up-regulation of hepatic LDLR is the mosteffective method to lower serum LDL-C levels. The most widely-used cholesterol-loweringdrug at present is statins. Statins can inhibit the enzymatic activity of HMG-CoA reductasecompetitively, and then inhibit the cellular cholesterol synthesis. In general, statins haveexcellent effect in hypercholesterolemia. However, a small part of patients can not toleratestatins because of adverse effects such as liver function damage. So, the efforts for screeningnew types of LDLR up-regulators have being done for a long time.
Objective:
Based on the traditional Chinese herbal medicine on the screen, we discovered HuoxueHuayu turmeric extract of curcumin could significantly reduce serum cholesterol, LDL-C andplayed the role of hypolipidemic and anti-atherosclerotic effect. In order to study themolecular mechanism of the curcumin effects on cholesterol-lowering, we designed a seriesof experiments. In the basis of previous research, from the level of gene expression and cellsignaling regulation, the issue is order to clarify the mechanism of curcumin on the LDLRexpression and search for the interaction between curcumin and the key protein moleculesand genes in the signal pathway.
Methods:
PartⅠis the effects of curcumin-induced expression of LDLR.
Firstly, using human liver HepG2 cells as LDLR gene expression detection system, aftercurcumin treated, liver cells-derived LDLR protein expression and activity of endocytosis areanalysised by Western-Blot, Rt-PCR, Fluorescence microscopy, flow cytometry and othertechniques. Then the effects of curcumin on LDLR on the gene expression are identified, andthe role of cholesterol-reducing mechanism was clarified from the receptor protein levels.
PartⅡis the mechanism of curcumin-induced expression of LDLR.
①Green fluorescent protein (GFP) reporter gene is constructed in the downstream oflow-density lipoprotein receptor gene control components, SRE-1, and then is transductedinto HepG2 cells by liposome-mediated methods. Then LDLR gene expression regulationreporting system is conducted and the HepG2/SRE-GFP stable cell line is established. Aftercurcumin treated, the mechanism of curcumin on the promoter SRE-1 is explained from the level of gene expression regulation.
②The CMV-Insig2 plasmid is also transducted into HepG2 cells by liposome-mediatedmethods and then constructs the stable cell lines, HepG2/Insig2. After curcumin treated, themechanism of curcumin on the Insig2 is revealed from the level of gene expression regulation.And the possible molecular or genetic target of curcumin in the role of cholesterol lowering isexplored.
Results:
PartⅠresults showed that,①curcumin can enhance HepG2 LDLR uptake of LDL,Obviously with the time-dependent and dose-dependent manner. And the 25μmol/L and the24-hour time LDLR have the strongest endocytosis activity.②Curcumin can significantlypromote the expression in HepG2 LDLR, with obvious time-dependent and dose-dependentmanner.③Curcumin can up-regulate the expression of LDLR mRNA to a significant extentin the human hepatoma cell line HepG2.
PartⅡresults showed that,①Curcumin can activate the promoter element SRE-1 toincrease LDLR expression.②Certain concentration of curcumin can reverse and restore theSREBP pathway inhibited by the Insig2 and up-regulate the expression of LDLR.
Conclusion:
In summary, from the receptor level, gene expression levels and the signal regulationpathway level, we discussed the mechanism of the curcumin on the cholesterol-lowering by aseries of studies. All the evidence proved that curcumin, as a cholesterol-lowering drug, canpromote the LDLR expression by acting with some regulational molecular in the SREBPpathway. But which step the curcumin acts on remains to be further studied.
目的：
通过对传统中草药物的筛选，我们发现从活血化瘀药姜黄中提取的姜黄素能显著降低血清胆固醇、LDL-C含量的作用，从而起到降血脂和抗动脉粥样硬化的作用。为了研究姜黄素降胆固醇作用的分子机制，我们设计了一系列实验。本课题就是在以往研究的基础上，拟从基因表达水平和细胞信号调控角度探寻姜黄素与信号调控途径中关键蛋白分子以及基因调控元件间的相互作用关系，从而阐明姜黄素对LDLR表达影响的机理。
方法：
第一部分姜黄素诱导LDLR表达的药效研究
首先利用人肝HepG2细胞作为LDLR基因表达检测系统，经姜黄素干预培养后，利用Western-Blot、Rt-PCR、荧光显微镜和流式细胞仪等技术分析肝细胞内源性LDLR蛋白的表达量及其表达活性，确定姜黄素对LDLR基因表达的影响，从受体蛋白水平阐明姜黄素降胆固醇作用的机理。
第二部分姜黄素诱导LDLR表达的机理研究：
①将绿色荧光蛋白GFP报告基因构建在调控低密度脂蛋白受体基因表达的固醇调控元件SRE-1的下游，经脂质体介导法导入HepG2细胞，建立LDLR基因表达的固醇调控报告系统及其稳定细胞株HepG2／SRE-GFP，通过姜黄素的干预培养，从基因表达调控水平研究姜黄素对启动子SRE-1的影响，探寻姜黄素的作用机理。
②利用脂质体介导法将pCMV-Insig2导入HepG2细胞，建立稳定的细胞株HepG2／Insig2，通过姜黄素的干预培养，研究姜黄素对Insig-2的影响，从信号调控通路水平探寻姜黄素降胆固醇作用可能的分子或基因靶点。
结果：
第一部分研究表明，①姜黄素能够增强HepG2 LDLR对LDL的摄取，具有明显的时间依赖性和剂量依赖性。并且在25μmol／L和作用24小时的时候LDLR的活性最强。②姜黄素能够显著促进HepG2 LDLR的表达量，具有明显的时间依赖性和剂量依赖性。③姜黄素可能通过促进HepG2 LDLR mRNA的转录上调LDLR的表达。
第二部分研究结果表明，①姜黄素能够激活启动子调控元件SRE-1上调LDLR表达。②一定浓度的姜黄素能够通过逆转受Insig2抑制的SREBP通路，上调LDLR的表达。
结论：
综上所述，我们从受体水平、基因表达水平到信号调控通路水平对姜黄素降胆固醇的机理进行了一系列研究。所有证据都证明姜黄素很可能是通过作用于SREBP通路中的某个调节因子，促使LDLR表达起到降胆固醇作用的。但是究竟作用于SCAP还是Insig2或者其它蛋白仍有待进一步研究。
The elevation of serum cholesterol levels, especially LDL-C, is by far one of the mostrelative risk factors that cause atherosclerosis and CHD. Lowering LDL-C levels bymedication can reduce the mortality of CHD significantly. The majority of LDL-C are takenup and cleared by hepatic LDLR. LDLR is a trans-membrane receptor located on cell surface,the expression level of which is tightly regulated by sterols or non-sterols pathway both onthe transcription and post-transcription level. Up-regulation of hepatic LDLR is the mosteffective method to lower serum LDL-C levels. The most widely-used cholesterol-loweringdrug at present is statins. Statins can inhibit the enzymatic activity of HMG-CoA reductasecompetitively, and then inhibit the cellular cholesterol synthesis. In general, statins haveexcellent effect in hypercholesterolemia. However, a small part of patients can not toleratestatins because of adverse effects such as liver function damage. So, the efforts for screeningnew types of LDLR up-regulators have being done for a long time.
Objective:
Based on the traditional Chinese herbal medicine on the screen, we discovered HuoxueHuayu turmeric extract of curcumin could significantly reduce serum cholesterol, LDL-C andplayed the role of hypolipidemic and anti-atherosclerotic effect. In order to study themolecular mechanism of the curcumin effects on cholesterol-lowering, we designed a seriesof experiments. In the basis of previous research, from the level of gene expression and cellsignaling regulation, the issue is order to clarify the mechanism of curcumin on the LDLRexpression and search for the interaction between curcumin and the key protein moleculesand genes in the signal pathway.
Methods:
PartⅠis the effects of curcumin-induced expression of LDLR.
Firstly, using human liver HepG2 cells as LDLR gene expression detection system, aftercurcumin treated, liver cells-derived LDLR protein expression and activity of endocytosis areanalysised by Western-Blot, Rt-PCR, Fluorescence microscopy, flow cytometry and othertechniques. Then the effects of curcumin on LDLR on the gene expression are identified, andthe role of cholesterol-reducing mechanism was clarified from the receptor protein levels.
PartⅡis the mechanism of curcumin-induced expression of LDLR.
①Green fluorescent protein (GFP) reporter gene is constructed in the downstream oflow-density lipoprotein receptor gene control components, SRE-1, and then is transductedinto HepG2 cells by liposome-mediated methods. Then LDLR gene expression regulationreporting system is conducted and the HepG2/SRE-GFP stable cell line is established. Aftercurcumin treated, the mechanism of curcumin on the promoter SRE-1 is explained from the level of gene expression regulation.
②The CMV-Insig2 plasmid is also transducted into HepG2 cells by liposome-mediatedmethods and then constructs the stable cell lines, HepG2/Insig2. After curcumin treated, themechanism of curcumin on the Insig2 is revealed from the level of gene expression regulation.And the possible molecular or genetic target of curcumin in the role of cholesterol lowering isexplored.
Results:
PartⅠresults showed that,①curcumin can enhance HepG2 LDLR uptake of LDL,Obviously with the time-dependent and dose-dependent manner. And the 25μmol/L and the24-hour time LDLR have the strongest endocytosis activity.②Curcumin can significantlypromote the expression in HepG2 LDLR, with obvious time-dependent and dose-dependentmanner.③Curcumin can up-regulate the expression of LDLR mRNA to a significant extentin the human hepatoma cell line HepG2.
PartⅡresults showed that,①Curcumin can activate the promoter element SRE-1 toincrease LDLR expression.②Certain concentration of curcumin can reverse and restore theSREBP pathway inhibited by the Insig2 and up-regulate the expression of LDLR.
Conclusion:
In summary, from the receptor level, gene expression levels and the signal regulationpathway level, we discussed the mechanism of the curcumin on the cholesterol-lowering by aseries of studies. All the evidence proved that curcumin, as a cholesterol-lowering drug, canpromote the LDLR expression by acting with some regulational molecular in the SREBPpathway. But which step the curcumin acts on remains to be further studied.
引文
[1] 王鸣瑞，韩明向．高脂血证脏腑病机的研究进展[J]．中国中医基础医学杂志，2005，11(4)：316-319．
[2] 孙丽英，焦亚斌，康广盛．高脂血症的病因病机研究进展[J]．中医药学报，2004，32(2)：70-71．
[3] 刘红跃．高脂血症的中医药治疗研究进展[J]．吉林中医药，2004，24(8)：56-57．
[4] 宋剑南．中医药防治动脉粥样硬化研究进展[J]．中国中医基础医学杂志，2003，9(11)：71-75．
[5] 叶世龙，谢为民，丁文，等．中药治疗高脂血症探讨[J]．中西医结合心脑血管病杂志，2004，2(12)：727-729．
[6] 陆岩．动脉粥样硬化的中医药防治进展[J]．中医研究，2005，18(3)：61-63．
[7] 陈伯钧，潘宗奇，苏学旭．高血脂症的中西医结合治疗进展[J]．现代中西医结合杂志．2005，14(21)：2882-2884．
[8] 杨红．高脂血症的中药研究概况[J]．中西医结合心脑血管病杂志．2004，2(1)：47-48．
[9] 陈可冀．实用中西医结合内科学[M]．北京：北京医科大学，中国协和医科大学，联合出版社，1999．
[10] 沃兴德，洪行球，赵革平，等．脂可平姜黄素对低密度蛋白和脂蛋白a代谢的影响[J]．中华医学信息导报．2005，20(22)：15-16．
[11] 杜宝俊，涂秀华，李立志．脂可平软胶囊治疗高脂血症临床研究[J]．中国中医药信息杂志．2004．11(9)：757-759．
[12] 周俊琴，夏先明，薛志权，等．丹参黄芪配伍对家兔低密度脂蛋白受体的影响．中药药理与临床[J]．2004，20(5)：5-7．
[13] 薛智权，关胜江，张江华，等．芪丹煎对动脉粥样硬化家兔载脂蛋白的影响[J]．中华实用中西医杂志，2004，4(17)：3177-3178．
[14] 闫玉慧．复方降脂茶的制备与临床疗效观察[J]．实用中西医结合临床，2003，3(2)：52-53．
[15] 才向军．化浊降脂汤治疗高脂血症80例[J]．陕西中医，2004，25(2)：135-136．
[16] 李映红，李湘楚，郑红花，等．加味复方血脂清对高脂血症家兔的降脂及抗动脉粥样硬化作用的研究[J]．湖北中医杂志，2003，25(5)：8-10．
[17] 祁长荣，姬生国．降脂通脉汤防治动脉粥样硬化作用机理研究[J]．中华实用中西医杂志，2004，4(17)：1631-1632．
[18] 韩桂英，祁长荣．通脉降脂汤对高脂血症鹌鹑血脂及内皮功能的影响[J]．中国临床康复，2005，9(31)：134-135．
[19] 金智生，何建成．健脾降脂灵对高脂血症大鼠血脂的影响[J]．中国中西医结合急救杂志，2002，9(1)：41．
[20] 王敏，雷桂华，王青．复方丹茶胶囊降血脂作用的实验研究[J]．中药材，2004，27(9)：671．
[21] 魏巍，霍江林，左云飞，等．芪参降脂饮对血脂的调节作用[J]．中药药理与临床，2001，17(3)：30．
[22] 李佃淳，张红，张福海，等．复方芪参降脂饮对高胆固醇血症大鼠主动脉壁细胞间黏附分子_1表达量的影响[J]．中国临床药学杂志，2005，14(5)：282-284．
[23] 李林，李祖贵．复方泽丹活血降脂胶囊的制备及临床观察[J]．时珍国医国药，2003，14(11)：676-677．
[24] 贺圣文，贺圣光，赵仁宏，等．复方马齿苋对高脂血症患者血脂、载脂蛋白及血液流变学的影响[J]．中国临床康复，2005，9(31)：164-166．
[25] 刘萍，张静生，张兴中．冠心康对高脂血症大鼠肝低密度脂蛋白受体基因表达的影响[J]．中医药学刊，2003，21(9)：1516-1517．
[26] 唐可欣，王金光，王凤斌．胸痹通胶囊对高脂血症大鼠肝低密度脂蛋白受体基因表达的影响[J]．中西医结合心脑血管病杂志，2004，2(8)：464-465．
[27] 陈运中，陈春艳，张声华．红曲有效成分洛伐他汀对高脂小鼠血脂代谢及脂蛋白脂酶mRNA表达的作用[J]．中草药，2005，36(5)：713-717．
[28] 王虎根，周淡宜，徐水祥，等．复方红曲制剂调节血脂作用的实验研究[J]．中国卫生检验杂志，2005，15(5)：540-541．
[29] 寇文镕．血脂康基础与临床研究现况概述[J]．中国处方药，2005(7)：52-57．
[30] 严瑾，沃兴德，范春雷，等．山楂叶总黄酮对PPAR γ-PPRE信号调控系统的影响[J]．中国药学杂志，2005，40(8)：625-628．
[31] Park MY, Lee KS,Sung MK.Effects of dietary mulberry, Korean red ginseng, and banaba on glucose homeostasis in relation to PPAR-alpha, PPAR-gamma, and LPL mRNA expressions[J]. Life Sci, 2005,77(26):3344-54.
[32] 沃兴德，崔小强，唐利华．姜黄素对食饵性高脂血症大鼠血浆脂蛋白代谢相关酶活性的影响[J]．中国动脉硬化杂志，2003(11)：223-226．
[33] 窦晓兵，范春雷，洪行球，等．姜黄素对人淋巴细胞低密度脂蛋白受体表达影响的研究[J]．中国药学杂志，2005，40(13)：980-982．
[34] 范春雷，沃兴德，罗艳，等．姜黄素对爪蟾卵母细胞人LDL受体表达的影响[J]．中国中西医结合杂志，2005，25：432-435．
[35] Chunlei Fan, Xingde Wo, Ying Qian,et al. Effect of curcumin on the expression of LDL receptor in mouse macrophages[J].J Ethnopharmacol, 2006,105:251-254.
[36] 钱颖，范春雷，窦晓兵，等．姜黄素对293细胞固醇调控报告系统的作用[J]．中国药理学通报，2006，22：257-260．
[37] Weijia Kong, Jing Wei, et al.Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins [J].Nat.Med, 2004(10): 1345-1351.
[38] Bursill CA, Roach PD. Modulation of cholesterol metabolism by the green tea polyphenol(-)-epigallocatechin gallate in cultured human liver (HepG2) cells[J]. J Agric Food Chem, 2006, 54(5): 1621-1626.
[39] Ricketts ML, Moore DD, Banz WJ, et al.Molecular mechanisms of action of the soy isoflavones includes activation of promiscuous nuclear receptors[J]. Journal of Nutritional Biochemistry, 2005, 6(16):321-330.
[40] 范春雷，高丽萍，沃兴德，严瑾，宋家梁．川芎嗪对爪蟾卵母细胞外源清道夫受体基因调控表达的研究[J]．中国药理学通报，2005，21(6)：841-846．
[41] Niu XL, Ichimori K, Yang X, et al.Tanshinone Ⅱ-A inhibits low density lipoprotein oxidation in vitro[J].Free Radic Res, 2000,33(3):305-12.
[42] 霍伟琪．中药治疗动脉粥样硬化作用的研究进展[J]．2005，11(11)：64-66．
[1] Innes C.Long-term results show superiority of rosuvastatin [J].Inpharma, 2001, 13(8): 10.
[2] Prescott D L. Rosuvastatin provides superior benefits in lipid therapy [J]. Inpharma, 2001,(1282):6.
[3] Brown W V, Bays H E, Hassman D R, et al.Efficacy and safety of rosuvastatin compared with pravastatin and simvastatin in patients with hypercholesterolemia:a randomized, double-blind,52-week trial [J]. Am Heart J, 2002, 144(6): 1036.
[4] 张印俊．降血脂药物的研究进展[J]．国外医药抗生素分册，2003，24(6)：241．
[5] 黄力．罗伐他汀[J]．国外医学药学分册，2003，30(3)：1561．
[6] 董祝斌，张学农．他汀类药物的研究进展[J]．中国新医药，2003，2(10)：481．
[7] 陈碧珊，苏丽华．他汀类药物的研究进展[J]．中国药房 2005，16(7)：545-546．
[8] Prasad K. Hypocholesterolemic and antiatherosclerotic effect of flax lignan complex isolated from flaxseed [J]. Atherosclerosis.2005, 179(2):269-275.
[9] Raederstorff D, Elste V, Aebischer C, et al. Effect of either gamma-tocotrienol or a tocotrienol mixture on the plasma lipid profile in hamsters [J]. Ann Nutr Metab. 2002; 46(1):17-23.
[10] Baumgart E, Stegmeier K, Schmidt FH,et al.Proliferation of peroxisomes in pericentral hepatocytes of rat liver after administration of a new hypocholesterolemic agent (BM 15766) [J].Lab Invest. 1987,56(5):554-64.
[11] Chen TH, Liu JC, Chang J J, et al. The in vitro inhibitory effect of flavonoid astilbin on 3-hydroxy-3-methylglutaryl coenzyme A reductase on Vero cells [J]. Zhonghua Yi Xue Za Zhi (Taipei). 2001,64(7):382-7.
[12] Roitelman J, Masson D, Avner R,et al. Apomine, a novel hypocholesterolemic agent, accelerates degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and stimulates low density lipoprotein receptor activity [J].J Biol Chem. 2004, 279(8):6465-73.
[13] Homma Y, Kobayashi T, Yamaguchi H,et al.Specific reduction of plasma large, light low-density lipoprotein by a bile acid sequestering resin, cholebine (MCI-196) in type Ⅱ hyperlipoproteinemia [J].Atherosclerosis. 1997, 129(2):241-8.
[14] Meng CQ. Ezetimibe [J].Curr Opin Investig Drugs, 2002, 3(3):427-432.
[15] Dujovne C A,Ettinger M P,McNeer J F,et al. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia [J]. Am Cardiol,2002,90(10): 1092
[16] Calpe-Berdiel L,Escola-Gil JC, Ribas V, et al. Changes in intestinal and liver global gene expression in response to a phytosterol-enriched diet [J].Atherosclerosis. 2005, (1):75-85.
[17] Hui DY, Howles PN. Molecular mechanisms of cholesterol absorption and transport in the intestine [J]. Semin Cell Dev Biol. 2005,16(2): 183-192.
[18] Margarita Garcia-Calvoa, b,c, JeanMarie Lisnocka,c, Herbert G. et al. The target of ezetimibe is Niemann-Pick Cl-Like 1 (NPC1L1) [J].Proc Natl Acad Sci U S A. 2005, 102(23):8132-7.
[19] Sudhop T, Lutjohann D, von Bergmann K. Sterol transporters: targets of natural sterols and new lipid lowering drugs. Pharmacol Ther. 2005 Mar;105(3):333-41.
[20] Vermaak W, Pionto X, Ponsonnet D, et al. Heterozygous familial hypercholesterolemia: coadministration of ezetimibe plus atorvastatin [J]. Atherosclerosis, 2002; 3(suppl 2):230-231
[21] Gagne C, Gaudet D,Bruckert E,et al. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia [J]. Circulation, 2002,105 (21): 2469-2475.
[22] Ouguerram K, Lutton C, Delhon A, et al. Effects ofF2833 on cholesterol metabolism in the genetically hyperlipidemic rat [J]. Eur J Pharmacol. 2001 415(2-3):293-299.
[23] Gallaher DD, Gallaher CM, Mahrt GJ, et al. A glucomannan and chitosan fiber supplement decreases plasma cholesterol and increases cholesterol excretion in overweight normocholesterolemic humans [J]. J Am Coll Nutr. 2002, 21(5):428-433.
[24] Janowski BA. The hypocholesterolemic agent LY295427 up-regulates INSIG-1, identifying the INSIG-1 protein as a mediator of cholesterol homeostasis through SREBP [J]. Proc Natl Acad Sci U S A. 2002,99(20): 12675-80.
[25] Grand-Perret T, Bouillot A, Perrot A, et al. SCAP ligands are potent new lipid -lowering drugs [J]. Nat Med, 2001,7(12): 1332.
[26] Jingwen Liu; Fang Zhang; Cong Li; Synergistic Activation of Human LDL Receptor Expression by SCAP Ligand and Cytokine Oncostatin M [J]. Arteriosclerosis, Thrombosis, and Vascular Biology. 2003; 23:90.
[27] Jessie Zhang, Nicole Dudley-Rucker, Jan R,et al. The steroidal analog GW707 activates the SREBP pathway through disruption of intracellular cholesterol trafficking [J].Journal of Lipid Research, 2004,45:223-231.
[28] 范春雷，沃兴德，罗艳，等．姜黄素对爪蟾卵母细胞表达LDLR的影响[J]．中国中西医结合杂志，2005，25(5)：435．
[29] 窦晓兵，范春雷，洪行球，等．姜黄素对人淋巴细胞LDLR表达影响的研究[J]．中国药学杂志，2005，40(13)：52．
[30] Junquero D, Bruniquel F.Soy isoflavones affect sterol regulatory element binding proteins (SREBPs) and SREBP-regulated genes in HepG2 cells [J]. J Nutr. 2004, 134(11):2942.
[31] Cong Li, Fredric B. Kraemer, et al.Induction of Low Density Lipoprotein Receptor (LDLR) Transcription by Oncostatin M Is Mediated by the Extracellular Signal-regulated Kinase Signaling Pathway and the Repeat 3 Element of the LDLR Promoter [J].The Journal of Biological Chemistry. 1999, 274(10):6747-6753.
[32] Weijia Kong, Parveen Abidi, Fredric B, et al. In vivo activities of cytokine oncostatin M in the regulation of plasma lipid levels [J]. J. Lipid Res., 2005,46: 1163 -1171.
[33] Insull WJ ,Koren M,Davignon J,et al. Efficacy and short - term safety of a new ACAT inhibitor, avasimibe, on lipids, lipoproteins,and apolipoproteins , in patients with combied hyperlipidemia [J]. Atherosclerosis, 2001,157(1): 137.
[34] Junquero D, Bruniquel F, N'Guyen X, et al. F12511, a novel ACAT inhibitor, and atorvastatin regulate endogenous hypercholesterolemia in a synergistic manner in New Zealand rabbits fed a casein-enriched diet [J]. Atherosclerosis. 2001,155(1):131-42.
[35] Miyazaki A, Horiuchi S. ACAT inhibitors [J].Nippon Rinsho.2001, 59(3):675.
[36] Ohishi K, Aiyama R, Hatano H,et al. Structure-activity relationships of N- (3,5 -dimethoxy-4-n-octyloxycinnamoyl)-N'-(3,4-dimethylphenyl) piperazine and analogues as inhibitors of acyl-CoA: cholesterol O-acyltransferase [J]. Chem Pharm Bull (Tokyo). 2001,49(7):830-839.
[37] Matsuyama N, Kosaka T, Fukuhara M, et al. Polyunsaturated fatty acid anilides as inhibitors of acyl-coA: cholesterol acyltransferase (ACAT) [J]. Bioorg Med Chem Lett. 1999, 9(14):2039-42.
[38] Umeda Y, Hirano T, Kako Y, Kamagata K, Okuyama K, Suzuki K A selective inhibitor of intestinal ACAT, EAB309 suppresses both intestinal and hepatic cholesterol output and stimulates chylomicron removal [J]. Life Sci. 1998, 63(13):187-95.
[39] Prasad K. Hypocholesterolemic and antiatherosclerotic effect of flax lignan complex isolated from flaxseed [J]. Atherosclerosis,2005, 179(2):269-75. .
[40] Yokozawa T, Nakagawa T, Kitani K. Antioxidative activity of green tea polyphenol in cholesterol-fed rats [J].J Agric Food Chem. 2002,50(12):3549-52.
[41] Fuhrman B, Volkova N, Kaplan M, et al.Antiatherosclerotic effects of licorice extract supplementation on hypercholesterolemic patients: increased resistance of LDL to atherogenic modifications, reduced plasma lipid levels, and decreased systolic blood pressure [J]. Nutrition, 2002,18(3):268-273.
[42] Chen TH, Liu JC, Chang JJ, et al. The in vitro inhibitory effect of flavonoid astilbin on 3-hydroxy-3-methylglutaryl coenzyme A reductase on Vero cells [J]. Zhonghua Yi Xue Za Zhi (Taipei). 2001, 64(7):382-387.
[43] Ricketts ML, Moore DD, Banz WJ, et al. Molecular mechanisms of action of the soy isoflavones includes activation of promiscuous nuclear receptors [J]. Journal of Nutritional Biochemistry, 2005, (16):321-330.
[44] Lovati MR, Manzoni C, Gianazza E, Arnoldi A, Kurowska E, Carroll KK, Sirtori CR.Soy protein peptides regulate cholesterol homeostasis in Hep G2 cells [J]. J Nutr. 2000, 130(10):2543-2549.
[45] 刘浩然，田育望．中药降脂活性成分药理作用研究概述[J]．湖南中医药导报，2002，8(12)：742-745．
[46] 王宇辉，周超凡．中药降脂研究进展[J]．中国中药杂志，1999，24(3)：184-186．
[47] 楼锦英，中药降脂研究现状[J]．浙江中医学院学报，2002，26(5)：79-80．
[48] 李贵海，孙敬勇，张希林，等．山楂降血脂有效成分的实验研究[J]．中草药，2002，33(1)： 50-52．
[49] 沃兴德，唐利华，李万里，等．姜黄醇提取物对食饵性高脂血症家兔抗氧化和促纤溶作用的研究[J]．浙江中医学院学报，1999，23(2)：25-26．
[50] 沃兴德，洪行球，高承贤，等．姜黄醇提取物、舒降之和血脂康对大鼠食饵性高脂血症脂代谢影响的对比分析[J]．浙江中医学院学报，1998，22(6)：18～20．
[51] 杜军，陈长雄，邵洪．天然降脂红曲的有效成分及毒性成分研究简介[J]．安徽中医临床杂志，2003，15(1)：74-75．
[52] 刘奕琼，张灏，田丰伟．微生物降胆固醇作用研究进展(J]．食品与机械，2003(1)：6-9．
[53] Zhou YF, Mori T, Nagasawa H, et al. Probucol, a hypocholesterolemic agent, prevents the development of uterine adenomyosis induced by pituitary grafting in mice [J]. Anticancer Res. 2004.24(4):2209-2212.
[54] 杜宝俊，涂秀华，李立志．脂可平软胶囊治疗高脂血症临床研究[J]．中国中医药信息杂志．2004，11(9)：757-759．
[55] Rashid S, Curtis DE, Garuti R, et al. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9 [J]. Proc Natl Acad Sci U S A. 2005, 102(15):5374-9.
[56] Weijia Kong, Jing Wei, Parveen Abi,et al. Berberineisa novel cholesterol lowering drug working through a unique mechanism distinct from statins [J]. Nature Medicine 2004 (10):1345-51.
[57] Kuivenhoven JA, Klerkx AH, et al. Role of CETP inhibitors in the treatment of dyslipidemia [J]. Curr Opin Lipidol. 2004, 15(6):631-636.
[1] Soutar AK.Intracellular transport of the low-density lipoprotein receptor [J]. Bioch Soci Tran,1996,34(8):547-552.
[2] 陈碧珊，苏丽华．他汀类药物的研究进展[J]．中国药房，2005，16(7)：545-546．
[3] Garcia-Calvo M,Lisnock J,Bull HG,et al.The target of ezetimibe is Niemann - Pick C1- Like 1 (NPC1L1) [J]. Proc Natl Acad Sci U S A. 2005,102(23):8132-8137.
[4] Grand-Perret T, Bouillot A, Perrot A, et al. SCAP ligands are potent new lipid-lowering drugs [J]. Nat Med,2001,7(12): 1332.
[5] Jessie Zhang, Nicole Dudley-Rucker, Jan R. Crowley, et al. The steroidal analog GW707 activates the SREBP pathway through disruption of intracellular cholesterol trafficking[J]. Journal of Lipid Research, 2004,45:223-231.
[6] Janowski BA. The hypocholesterolemic agent LY295427 up-regulates INSIG-1, identifying the INSIG-1 protein as a mediator of cholesterol homeostasis through SREBP [J]. Proc Natl Acad Sci U S A. 2002 99(20):12675-80.
[7] Eimear Mullen, Rachel M. Brown, Timothy F, et al. Soy isoflavones affect sterol regulatory element binding proteins (SREBPs) and SREBP- regulated genes in HepG2 cells [J]. J Nutr. 2004,134(11):2942-7.
[8] Weijia Kong, Parveen Abidi, Fredric B.,et al. In vivo activities of cytokine oncostatin M in the regulation of plasma lipid levels [J]. J. Lipid Res., 2005; 46:1163-1171.
[9] 沃兴德，唐利华，李万里等．姜黄醇提取物对食饵性高脂血症家兔抗氧化和促纤溶作用的研究[J]．浙江中医学院学报，1999，23(2)：25-26．
[10] 窦晓兵，范春雷，洪行球，等．姜黄素对人淋巴细胞低密度脂蛋白受体表达影响的研究[J]，中国药学杂志 2005；40(13)：980-982．
[11] Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis [J]. Science, 1986:232-234.
[12] Soutar AK & Knight BL. Structure and regulation of the LDL-receptor and its gene [J]. British Medical Bulletin, 1990,46(4): 891-916.
[13] Brown M.S. & Goldstein J.L.The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor [J]. Cell, 1997,89:331-340.
[14] Wang X, Sato R, Brown MS, et al.SREBP-1, a membrane-bound transcription factor released by sterol regulated proteolysis [J]. Cell, 1994, 77(1): 53-62.
[14] Adams CM, Goldstein JL&Brown MS. Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles [J]. Proc Natl Acad Sci, 2003, 100(19): 10647-10652.
[15] Brown MS& Goldstein JL. A proteolytic pathway that controls the cholesterol content of membranes,cells, and blood [J]. Proc Natl Acad Sci, 1999, 96(10): 11041-11048.
[16] Arun Radhakrishnan,Yukio Ikeda,Hyock Joo Kwon,et al. Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi:Oxysterols block transport by binding to Insig [J]. Proc Natl Acad Sci,2007, 104(16):6511-6518.
[17] 严瑾，沃兴德，范春雷，等．山楂叶总黄酮对PPAR γ-PPRE信号调控系统的影响[J]．中国药学杂志，2005，40(8)：625-628．
[18] 唐建华，高小平，张义正．低密度脂蛋白受体／报告基因系统建立及中药降脂药物的筛选[J]．天然产物研究与开发[J]．2005，17(3)：316-319．
[19] Dou Xiaobing, Fan Chunlei, Hong Xingqiu, et al. Effect of curcumin on expression of LDL-R in human lymphocytes [J]. Chin Pharmaceu J. 2005, 40(13): 980-982
[20] Qian Ying, Fan Chunlei, Dou Xiaobing,et al. Effect of curcumin on sterol regulatory report system in HEK-293 [J]. Chin Pharmacol Bull. 2006,22(7):257-260.
[21] Fan Chunlei, Qian Ying, Lu Dezhao, et al. Establishing Sterol Regulatory Report System in Xenopus Oocytes and its Application for Screening of Lipid-lowering Drugs.Chin Pharmaceu J [J]. 2006(41)9:664-668.
[22] Fan CL,Wo XD, Qian Y, et al. Effect of curcumin on the expression of LDL receptor in mouse macrophages [J]. J Ethnopharmacol. 2006,105(1-2):251-254.
[23] Fan CL,Wo XD,Luo Y, et al. Effect of Curcumin on Expression of Human Low Density Lipoprotein Receptors in Xenopus Laevis Oocytes [J]. Chin J Inte Trad West Med, 2005,25(5):432-435.
[24] Grundy SM. Pathogenesis of hyperlipoproteinemia [J]. J Lip Res,1994,35(5):1611-1618.
[25] Salleh MN, et al, Inhibition of low-density lipoprotein oxidation and up-regulation of low-density lipoprotein receptor in HepG2 cells by tropical plant extracts [J]. J Agric Food Chem 2002, 50(13): 3693-3697.
[26] Lian Xin,Lin Jie, Wang Lvya,et al. One Sample of Familial Hypemholesterolemia [J]. Chinese Journal of Laboratory Medicine,2005,28(5):548.
[27] Knight BL, Patel DD, Soutar AK. Regulation of synthesis and cell content of the low- density-lipoprotein receptor protein in cultured fibroblasts from normal and familial hypercholesterolaemic subjects [J]. Eur J Biochem. 1987,163(1):189-196.
[28] Brown MS, Goldstein JL. Regulation of the activity of the low density lipoprotein receptor in human fibroblasts [J]. Cell. 1975,6(3):307-316.
[29] Golstein,J.L., Brown M.S., Anderson,R.G.W.,et al. Receptor-mediated endocytosis: Concepts emerging from the LDL receptor system [J]. Ann. Rev. Cell Biol. 1985,1:1-39.
[30] Briggers, M.R, Yokoyama C, Brown, M S, et al. Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter [J]. J Biol Chem. 1993. 268(19): 14490-14496.
[31] Brown M S, Goldstein J L. A receptor-mediated pathway for cholesterol homeostasis [J]. Science. 1986,232:234.
[32] Mcpherson R,Gauthier A.Molecular regulation of SREBP function:the Insig-SCAP connection and isoform specific modulation of lipid sythesis [J].Biochem Cell Biol,2004,82:201-211.
[33] Weijia Kong, Jing Wei, Parveen Abidi, et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins [J]. Nature Medicine, 2004 (10):1345-1351.
[34] 宋剑南．从生物化学角度看痰及痰癖相关．中国中医基础医学杂志[J]，2000，6(3)：40-43．
[35] 王东生，袁肇凯，余亚明．痰疲与动脉粥样硬化相关性探讨[J]．山东中医药大学学报，2003．27 C3)：162-164．
[36] 王鸣瑞，韩明向．高脂血证脏腑病机的研究进展[J]．中国中医基础医学杂志，2005，11(4)：316-319．
[37] 孙丽英，焦亚斌，康广盛．高脂血症的病因病机研究进展[J]．中医药学报，2004，32(2)：70-71．
[38] 刘红跃．高脂血症的中医药治疗研究进展[J]．吉林中医药，2004，24(8)：56-57．
[39] 陈伯钧，潘宗奇，苏学旭．高血脂症的中西医结合治疗进展[J]．现代中西医结合杂志．2005，14(21)：2882-2884．
[40] 杨永宗．动脉粥样硬化性心血管病基础与临床[M]．科学出版社．2004，62-90．
[41] 叶平．血脂的基础与临床．人民军医出版社[M]，2002年，117-171．
[42] Grand-Perret T, Bouillot A,Perrot A,et al.SCAP ligands are potent new lipid-lowering drugs.Nat Med,2001,7:1332-1338.
[2] 孙丽英，焦亚斌，康广盛．高脂血症的病因病机研究进展[J]．中医药学报，2004，32(2)：70-71．
[3] 刘红跃．高脂血症的中医药治疗研究进展[J]．吉林中医药，2004，24(8)：56-57．
[4] 宋剑南．中医药防治动脉粥样硬化研究进展[J]．中国中医基础医学杂志，2003，9(11)：71-75．
[5] 叶世龙，谢为民，丁文，等．中药治疗高脂血症探讨[J]．中西医结合心脑血管病杂志，2004，2(12)：727-729．
[6] 陆岩．动脉粥样硬化的中医药防治进展[J]．中医研究，2005，18(3)：61-63．
[7] 陈伯钧，潘宗奇，苏学旭．高血脂症的中西医结合治疗进展[J]．现代中西医结合杂志．2005，14(21)：2882-2884．
[8] 杨红．高脂血症的中药研究概况[J]．中西医结合心脑血管病杂志．2004，2(1)：47-48．
[9] 陈可冀．实用中西医结合内科学[M]．北京：北京医科大学，中国协和医科大学，联合出版社，1999．
[10] 沃兴德，洪行球，赵革平，等．脂可平姜黄素对低密度蛋白和脂蛋白a代谢的影响[J]．中华医学信息导报．2005，20(22)：15-16．
[11] 杜宝俊，涂秀华，李立志．脂可平软胶囊治疗高脂血症临床研究[J]．中国中医药信息杂志．2004．11(9)：757-759．
[12] 周俊琴，夏先明，薛志权，等．丹参黄芪配伍对家兔低密度脂蛋白受体的影响．中药药理与临床[J]．2004，20(5)：5-7．
[13] 薛智权，关胜江，张江华，等．芪丹煎对动脉粥样硬化家兔载脂蛋白的影响[J]．中华实用中西医杂志，2004，4(17)：3177-3178．
[14] 闫玉慧．复方降脂茶的制备与临床疗效观察[J]．实用中西医结合临床，2003，3(2)：52-53．
[15] 才向军．化浊降脂汤治疗高脂血症80例[J]．陕西中医，2004，25(2)：135-136．
[16] 李映红，李湘楚，郑红花，等．加味复方血脂清对高脂血症家兔的降脂及抗动脉粥样硬化作用的研究[J]．湖北中医杂志，2003，25(5)：8-10．
[17] 祁长荣，姬生国．降脂通脉汤防治动脉粥样硬化作用机理研究[J]．中华实用中西医杂志，2004，4(17)：1631-1632．
[18] 韩桂英，祁长荣．通脉降脂汤对高脂血症鹌鹑血脂及内皮功能的影响[J]．中国临床康复，2005，9(31)：134-135．
[19] 金智生，何建成．健脾降脂灵对高脂血症大鼠血脂的影响[J]．中国中西医结合急救杂志，2002，9(1)：41．
[20] 王敏，雷桂华，王青．复方丹茶胶囊降血脂作用的实验研究[J]．中药材，2004，27(9)：671．
[21] 魏巍，霍江林，左云飞，等．芪参降脂饮对血脂的调节作用[J]．中药药理与临床，2001，17(3)：30．
[22] 李佃淳，张红，张福海，等．复方芪参降脂饮对高胆固醇血症大鼠主动脉壁细胞间黏附分子_1表达量的影响[J]．中国临床药学杂志，2005，14(5)：282-284．
[23] 李林，李祖贵．复方泽丹活血降脂胶囊的制备及临床观察[J]．时珍国医国药，2003，14(11)：676-677．
[24] 贺圣文，贺圣光，赵仁宏，等．复方马齿苋对高脂血症患者血脂、载脂蛋白及血液流变学的影响[J]．中国临床康复，2005，9(31)：164-166．
[25] 刘萍，张静生，张兴中．冠心康对高脂血症大鼠肝低密度脂蛋白受体基因表达的影响[J]．中医药学刊，2003，21(9)：1516-1517．
[26] 唐可欣，王金光，王凤斌．胸痹通胶囊对高脂血症大鼠肝低密度脂蛋白受体基因表达的影响[J]．中西医结合心脑血管病杂志，2004，2(8)：464-465．
[27] 陈运中，陈春艳，张声华．红曲有效成分洛伐他汀对高脂小鼠血脂代谢及脂蛋白脂酶mRNA表达的作用[J]．中草药，2005，36(5)：713-717．
[28] 王虎根，周淡宜，徐水祥，等．复方红曲制剂调节血脂作用的实验研究[J]．中国卫生检验杂志，2005，15(5)：540-541．
[29] 寇文镕．血脂康基础与临床研究现况概述[J]．中国处方药，2005(7)：52-57．
[30] 严瑾，沃兴德，范春雷，等．山楂叶总黄酮对PPAR γ-PPRE信号调控系统的影响[J]．中国药学杂志，2005，40(8)：625-628．
[31] Park MY, Lee KS,Sung MK.Effects of dietary mulberry, Korean red ginseng, and banaba on glucose homeostasis in relation to PPAR-alpha, PPAR-gamma, and LPL mRNA expressions[J]. Life Sci, 2005,77(26):3344-54.
[32] 沃兴德，崔小强，唐利华．姜黄素对食饵性高脂血症大鼠血浆脂蛋白代谢相关酶活性的影响[J]．中国动脉硬化杂志，2003(11)：223-226．
[33] 窦晓兵，范春雷，洪行球，等．姜黄素对人淋巴细胞低密度脂蛋白受体表达影响的研究[J]．中国药学杂志，2005，40(13)：980-982．
[34] 范春雷，沃兴德，罗艳，等．姜黄素对爪蟾卵母细胞人LDL受体表达的影响[J]．中国中西医结合杂志，2005，25：432-435．
[35] Chunlei Fan, Xingde Wo, Ying Qian,et al. Effect of curcumin on the expression of LDL receptor in mouse macrophages[J].J Ethnopharmacol, 2006,105:251-254.
[36] 钱颖，范春雷，窦晓兵，等．姜黄素对293细胞固醇调控报告系统的作用[J]．中国药理学通报，2006，22：257-260．
[37] Weijia Kong, Jing Wei, et al.Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins [J].Nat.Med, 2004(10): 1345-1351.
[38] Bursill CA, Roach PD. Modulation of cholesterol metabolism by the green tea polyphenol(-)-epigallocatechin gallate in cultured human liver (HepG2) cells[J]. J Agric Food Chem, 2006, 54(5): 1621-1626.
[39] Ricketts ML, Moore DD, Banz WJ, et al.Molecular mechanisms of action of the soy isoflavones includes activation of promiscuous nuclear receptors[J]. Journal of Nutritional Biochemistry, 2005, 6(16):321-330.
[40] 范春雷，高丽萍，沃兴德，严瑾，宋家梁．川芎嗪对爪蟾卵母细胞外源清道夫受体基因调控表达的研究[J]．中国药理学通报，2005，21(6)：841-846．
[41] Niu XL, Ichimori K, Yang X, et al.Tanshinone Ⅱ-A inhibits low density lipoprotein oxidation in vitro[J].Free Radic Res, 2000,33(3):305-12.
[42] 霍伟琪．中药治疗动脉粥样硬化作用的研究进展[J]．2005，11(11)：64-66．
[1] Innes C.Long-term results show superiority of rosuvastatin [J].Inpharma, 2001, 13(8): 10.
[2] Prescott D L. Rosuvastatin provides superior benefits in lipid therapy [J]. Inpharma, 2001,(1282):6.
[3] Brown W V, Bays H E, Hassman D R, et al.Efficacy and safety of rosuvastatin compared with pravastatin and simvastatin in patients with hypercholesterolemia:a randomized, double-blind,52-week trial [J]. Am Heart J, 2002, 144(6): 1036.
[4] 张印俊．降血脂药物的研究进展[J]．国外医药抗生素分册，2003，24(6)：241．
[5] 黄力．罗伐他汀[J]．国外医学药学分册，2003，30(3)：1561．
[6] 董祝斌，张学农．他汀类药物的研究进展[J]．中国新医药，2003，2(10)：481．
[7] 陈碧珊，苏丽华．他汀类药物的研究进展[J]．中国药房 2005，16(7)：545-546．
[8] Prasad K. Hypocholesterolemic and antiatherosclerotic effect of flax lignan complex isolated from flaxseed [J]. Atherosclerosis.2005, 179(2):269-275.
[9] Raederstorff D, Elste V, Aebischer C, et al. Effect of either gamma-tocotrienol or a tocotrienol mixture on the plasma lipid profile in hamsters [J]. Ann Nutr Metab. 2002; 46(1):17-23.
[10] Baumgart E, Stegmeier K, Schmidt FH,et al.Proliferation of peroxisomes in pericentral hepatocytes of rat liver after administration of a new hypocholesterolemic agent (BM 15766) [J].Lab Invest. 1987,56(5):554-64.
[11] Chen TH, Liu JC, Chang J J, et al. The in vitro inhibitory effect of flavonoid astilbin on 3-hydroxy-3-methylglutaryl coenzyme A reductase on Vero cells [J]. Zhonghua Yi Xue Za Zhi (Taipei). 2001,64(7):382-7.
[12] Roitelman J, Masson D, Avner R,et al. Apomine, a novel hypocholesterolemic agent, accelerates degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and stimulates low density lipoprotein receptor activity [J].J Biol Chem. 2004, 279(8):6465-73.
[13] Homma Y, Kobayashi T, Yamaguchi H,et al.Specific reduction of plasma large, light low-density lipoprotein by a bile acid sequestering resin, cholebine (MCI-196) in type Ⅱ hyperlipoproteinemia [J].Atherosclerosis. 1997, 129(2):241-8.
[14] Meng CQ. Ezetimibe [J].Curr Opin Investig Drugs, 2002, 3(3):427-432.
[15] Dujovne C A,Ettinger M P,McNeer J F,et al. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia [J]. Am Cardiol,2002,90(10): 1092
[16] Calpe-Berdiel L,Escola-Gil JC, Ribas V, et al. Changes in intestinal and liver global gene expression in response to a phytosterol-enriched diet [J].Atherosclerosis. 2005, (1):75-85.
[17] Hui DY, Howles PN. Molecular mechanisms of cholesterol absorption and transport in the intestine [J]. Semin Cell Dev Biol. 2005,16(2): 183-192.
[18] Margarita Garcia-Calvoa, b,c, JeanMarie Lisnocka,c, Herbert G. et al. The target of ezetimibe is Niemann-Pick Cl-Like 1 (NPC1L1) [J].Proc Natl Acad Sci U S A. 2005, 102(23):8132-7.
[19] Sudhop T, Lutjohann D, von Bergmann K. Sterol transporters: targets of natural sterols and new lipid lowering drugs. Pharmacol Ther. 2005 Mar;105(3):333-41.
[20] Vermaak W, Pionto X, Ponsonnet D, et al. Heterozygous familial hypercholesterolemia: coadministration of ezetimibe plus atorvastatin [J]. Atherosclerosis, 2002; 3(suppl 2):230-231
[21] Gagne C, Gaudet D,Bruckert E,et al. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia [J]. Circulation, 2002,105 (21): 2469-2475.
[22] Ouguerram K, Lutton C, Delhon A, et al. Effects ofF2833 on cholesterol metabolism in the genetically hyperlipidemic rat [J]. Eur J Pharmacol. 2001 415(2-3):293-299.
[23] Gallaher DD, Gallaher CM, Mahrt GJ, et al. A glucomannan and chitosan fiber supplement decreases plasma cholesterol and increases cholesterol excretion in overweight normocholesterolemic humans [J]. J Am Coll Nutr. 2002, 21(5):428-433.
[24] Janowski BA. The hypocholesterolemic agent LY295427 up-regulates INSIG-1, identifying the INSIG-1 protein as a mediator of cholesterol homeostasis through SREBP [J]. Proc Natl Acad Sci U S A. 2002,99(20): 12675-80.
[25] Grand-Perret T, Bouillot A, Perrot A, et al. SCAP ligands are potent new lipid -lowering drugs [J]. Nat Med, 2001,7(12): 1332.
[26] Jingwen Liu; Fang Zhang; Cong Li; Synergistic Activation of Human LDL Receptor Expression by SCAP Ligand and Cytokine Oncostatin M [J]. Arteriosclerosis, Thrombosis, and Vascular Biology. 2003; 23:90.
[27] Jessie Zhang, Nicole Dudley-Rucker, Jan R,et al. The steroidal analog GW707 activates the SREBP pathway through disruption of intracellular cholesterol trafficking [J].Journal of Lipid Research, 2004,45:223-231.
[28] 范春雷，沃兴德，罗艳，等．姜黄素对爪蟾卵母细胞表达LDLR的影响[J]．中国中西医结合杂志，2005，25(5)：435．
[29] 窦晓兵，范春雷，洪行球，等．姜黄素对人淋巴细胞LDLR表达影响的研究[J]．中国药学杂志，2005，40(13)：52．
[30] Junquero D, Bruniquel F.Soy isoflavones affect sterol regulatory element binding proteins (SREBPs) and SREBP-regulated genes in HepG2 cells [J]. J Nutr. 2004, 134(11):2942.
[31] Cong Li, Fredric B. Kraemer, et al.Induction of Low Density Lipoprotein Receptor (LDLR) Transcription by Oncostatin M Is Mediated by the Extracellular Signal-regulated Kinase Signaling Pathway and the Repeat 3 Element of the LDLR Promoter [J].The Journal of Biological Chemistry. 1999, 274(10):6747-6753.
[32] Weijia Kong, Parveen Abidi, Fredric B, et al. In vivo activities of cytokine oncostatin M in the regulation of plasma lipid levels [J]. J. Lipid Res., 2005,46: 1163 -1171.
[33] Insull WJ ,Koren M,Davignon J,et al. Efficacy and short - term safety of a new ACAT inhibitor, avasimibe, on lipids, lipoproteins,and apolipoproteins , in patients with combied hyperlipidemia [J]. Atherosclerosis, 2001,157(1): 137.
[34] Junquero D, Bruniquel F, N'Guyen X, et al. F12511, a novel ACAT inhibitor, and atorvastatin regulate endogenous hypercholesterolemia in a synergistic manner in New Zealand rabbits fed a casein-enriched diet [J]. Atherosclerosis. 2001,155(1):131-42.
[35] Miyazaki A, Horiuchi S. ACAT inhibitors [J].Nippon Rinsho.2001, 59(3):675.
[36] Ohishi K, Aiyama R, Hatano H,et al. Structure-activity relationships of N- (3,5 -dimethoxy-4-n-octyloxycinnamoyl)-N'-(3,4-dimethylphenyl) piperazine and analogues as inhibitors of acyl-CoA: cholesterol O-acyltransferase [J]. Chem Pharm Bull (Tokyo). 2001,49(7):830-839.
[37] Matsuyama N, Kosaka T, Fukuhara M, et al. Polyunsaturated fatty acid anilides as inhibitors of acyl-coA: cholesterol acyltransferase (ACAT) [J]. Bioorg Med Chem Lett. 1999, 9(14):2039-42.
[38] Umeda Y, Hirano T, Kako Y, Kamagata K, Okuyama K, Suzuki K A selective inhibitor of intestinal ACAT, EAB309 suppresses both intestinal and hepatic cholesterol output and stimulates chylomicron removal [J]. Life Sci. 1998, 63(13):187-95.
[39] Prasad K. Hypocholesterolemic and antiatherosclerotic effect of flax lignan complex isolated from flaxseed [J]. Atherosclerosis,2005, 179(2):269-75. .
[40] Yokozawa T, Nakagawa T, Kitani K. Antioxidative activity of green tea polyphenol in cholesterol-fed rats [J].J Agric Food Chem. 2002,50(12):3549-52.
[41] Fuhrman B, Volkova N, Kaplan M, et al.Antiatherosclerotic effects of licorice extract supplementation on hypercholesterolemic patients: increased resistance of LDL to atherogenic modifications, reduced plasma lipid levels, and decreased systolic blood pressure [J]. Nutrition, 2002,18(3):268-273.
[42] Chen TH, Liu JC, Chang JJ, et al. The in vitro inhibitory effect of flavonoid astilbin on 3-hydroxy-3-methylglutaryl coenzyme A reductase on Vero cells [J]. Zhonghua Yi Xue Za Zhi (Taipei). 2001, 64(7):382-387.
[43] Ricketts ML, Moore DD, Banz WJ, et al. Molecular mechanisms of action of the soy isoflavones includes activation of promiscuous nuclear receptors [J]. Journal of Nutritional Biochemistry, 2005, (16):321-330.
[44] Lovati MR, Manzoni C, Gianazza E, Arnoldi A, Kurowska E, Carroll KK, Sirtori CR.Soy protein peptides regulate cholesterol homeostasis in Hep G2 cells [J]. J Nutr. 2000, 130(10):2543-2549.
[45] 刘浩然，田育望．中药降脂活性成分药理作用研究概述[J]．湖南中医药导报，2002，8(12)：742-745．
[46] 王宇辉，周超凡．中药降脂研究进展[J]．中国中药杂志，1999，24(3)：184-186．
[47] 楼锦英，中药降脂研究现状[J]．浙江中医学院学报，2002，26(5)：79-80．
[48] 李贵海，孙敬勇，张希林，等．山楂降血脂有效成分的实验研究[J]．中草药，2002，33(1)： 50-52．
[49] 沃兴德，唐利华，李万里，等．姜黄醇提取物对食饵性高脂血症家兔抗氧化和促纤溶作用的研究[J]．浙江中医学院学报，1999，23(2)：25-26．
[50] 沃兴德，洪行球，高承贤，等．姜黄醇提取物、舒降之和血脂康对大鼠食饵性高脂血症脂代谢影响的对比分析[J]．浙江中医学院学报，1998，22(6)：18～20．
[51] 杜军，陈长雄，邵洪．天然降脂红曲的有效成分及毒性成分研究简介[J]．安徽中医临床杂志，2003，15(1)：74-75．
[52] 刘奕琼，张灏，田丰伟．微生物降胆固醇作用研究进展(J]．食品与机械，2003(1)：6-9．
[53] Zhou YF, Mori T, Nagasawa H, et al. Probucol, a hypocholesterolemic agent, prevents the development of uterine adenomyosis induced by pituitary grafting in mice [J]. Anticancer Res. 2004.24(4):2209-2212.
[54] 杜宝俊，涂秀华，李立志．脂可平软胶囊治疗高脂血症临床研究[J]．中国中医药信息杂志．2004，11(9)：757-759．
[55] Rashid S, Curtis DE, Garuti R, et al. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9 [J]. Proc Natl Acad Sci U S A. 2005, 102(15):5374-9.
[56] Weijia Kong, Jing Wei, Parveen Abi,et al. Berberineisa novel cholesterol lowering drug working through a unique mechanism distinct from statins [J]. Nature Medicine 2004 (10):1345-51.
[57] Kuivenhoven JA, Klerkx AH, et al. Role of CETP inhibitors in the treatment of dyslipidemia [J]. Curr Opin Lipidol. 2004, 15(6):631-636.
[1] Soutar AK.Intracellular transport of the low-density lipoprotein receptor [J]. Bioch Soci Tran,1996,34(8):547-552.
[2] 陈碧珊，苏丽华．他汀类药物的研究进展[J]．中国药房，2005，16(7)：545-546．
[3] Garcia-Calvo M,Lisnock J,Bull HG,et al.The target of ezetimibe is Niemann - Pick C1- Like 1 (NPC1L1) [J]. Proc Natl Acad Sci U S A. 2005,102(23):8132-8137.
[4] Grand-Perret T, Bouillot A, Perrot A, et al. SCAP ligands are potent new lipid-lowering drugs [J]. Nat Med,2001,7(12): 1332.
[5] Jessie Zhang, Nicole Dudley-Rucker, Jan R. Crowley, et al. The steroidal analog GW707 activates the SREBP pathway through disruption of intracellular cholesterol trafficking[J]. Journal of Lipid Research, 2004,45:223-231.
[6] Janowski BA. The hypocholesterolemic agent LY295427 up-regulates INSIG-1, identifying the INSIG-1 protein as a mediator of cholesterol homeostasis through SREBP [J]. Proc Natl Acad Sci U S A. 2002 99(20):12675-80.
[7] Eimear Mullen, Rachel M. Brown, Timothy F, et al. Soy isoflavones affect sterol regulatory element binding proteins (SREBPs) and SREBP- regulated genes in HepG2 cells [J]. J Nutr. 2004,134(11):2942-7.
[8] Weijia Kong, Parveen Abidi, Fredric B.,et al. In vivo activities of cytokine oncostatin M in the regulation of plasma lipid levels [J]. J. Lipid Res., 2005; 46:1163-1171.
[9] 沃兴德，唐利华，李万里等．姜黄醇提取物对食饵性高脂血症家兔抗氧化和促纤溶作用的研究[J]．浙江中医学院学报，1999，23(2)：25-26．
[10] 窦晓兵，范春雷，洪行球，等．姜黄素对人淋巴细胞低密度脂蛋白受体表达影响的研究[J]，中国药学杂志 2005；40(13)：980-982．
[11] Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis [J]. Science, 1986:232-234.
[12] Soutar AK & Knight BL. Structure and regulation of the LDL-receptor and its gene [J]. British Medical Bulletin, 1990,46(4): 891-916.
[13] Brown M.S. & Goldstein J.L.The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor [J]. Cell, 1997,89:331-340.
[14] Wang X, Sato R, Brown MS, et al.SREBP-1, a membrane-bound transcription factor released by sterol regulated proteolysis [J]. Cell, 1994, 77(1): 53-62.
[14] Adams CM, Goldstein JL&Brown MS. Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles [J]. Proc Natl Acad Sci, 2003, 100(19): 10647-10652.
[15] Brown MS& Goldstein JL. A proteolytic pathway that controls the cholesterol content of membranes,cells, and blood [J]. Proc Natl Acad Sci, 1999, 96(10): 11041-11048.
[16] Arun Radhakrishnan,Yukio Ikeda,Hyock Joo Kwon,et al. Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi:Oxysterols block transport by binding to Insig [J]. Proc Natl Acad Sci,2007, 104(16):6511-6518.
[17] 严瑾，沃兴德，范春雷，等．山楂叶总黄酮对PPAR γ-PPRE信号调控系统的影响[J]．中国药学杂志，2005，40(8)：625-628．
[18] 唐建华，高小平，张义正．低密度脂蛋白受体／报告基因系统建立及中药降脂药物的筛选[J]．天然产物研究与开发[J]．2005，17(3)：316-319．
[19] Dou Xiaobing, Fan Chunlei, Hong Xingqiu, et al. Effect of curcumin on expression of LDL-R in human lymphocytes [J]. Chin Pharmaceu J. 2005, 40(13): 980-982
[20] Qian Ying, Fan Chunlei, Dou Xiaobing,et al. Effect of curcumin on sterol regulatory report system in HEK-293 [J]. Chin Pharmacol Bull. 2006,22(7):257-260.
[21] Fan Chunlei, Qian Ying, Lu Dezhao, et al. Establishing Sterol Regulatory Report System in Xenopus Oocytes and its Application for Screening of Lipid-lowering Drugs.Chin Pharmaceu J [J]. 2006(41)9:664-668.
[22] Fan CL,Wo XD, Qian Y, et al. Effect of curcumin on the expression of LDL receptor in mouse macrophages [J]. J Ethnopharmacol. 2006,105(1-2):251-254.
[23] Fan CL,Wo XD,Luo Y, et al. Effect of Curcumin on Expression of Human Low Density Lipoprotein Receptors in Xenopus Laevis Oocytes [J]. Chin J Inte Trad West Med, 2005,25(5):432-435.
[24] Grundy SM. Pathogenesis of hyperlipoproteinemia [J]. J Lip Res,1994,35(5):1611-1618.
[25] Salleh MN, et al, Inhibition of low-density lipoprotein oxidation and up-regulation of low-density lipoprotein receptor in HepG2 cells by tropical plant extracts [J]. J Agric Food Chem 2002, 50(13): 3693-3697.
[26] Lian Xin,Lin Jie, Wang Lvya,et al. One Sample of Familial Hypemholesterolemia [J]. Chinese Journal of Laboratory Medicine,2005,28(5):548.
[27] Knight BL, Patel DD, Soutar AK. Regulation of synthesis and cell content of the low- density-lipoprotein receptor protein in cultured fibroblasts from normal and familial hypercholesterolaemic subjects [J]. Eur J Biochem. 1987,163(1):189-196.
[28] Brown MS, Goldstein JL. Regulation of the activity of the low density lipoprotein receptor in human fibroblasts [J]. Cell. 1975,6(3):307-316.
[29] Golstein,J.L., Brown M.S., Anderson,R.G.W.,et al. Receptor-mediated endocytosis: Concepts emerging from the LDL receptor system [J]. Ann. Rev. Cell Biol. 1985,1:1-39.
[30] Briggers, M.R, Yokoyama C, Brown, M S, et al. Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter [J]. J Biol Chem. 1993. 268(19): 14490-14496.
[31] Brown M S, Goldstein J L. A receptor-mediated pathway for cholesterol homeostasis [J]. Science. 1986,232:234.
[32] Mcpherson R,Gauthier A.Molecular regulation of SREBP function:the Insig-SCAP connection and isoform specific modulation of lipid sythesis [J].Biochem Cell Biol,2004,82:201-211.
[33] Weijia Kong, Jing Wei, Parveen Abidi, et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins [J]. Nature Medicine, 2004 (10):1345-1351.
[34] 宋剑南．从生物化学角度看痰及痰癖相关．中国中医基础医学杂志[J]，2000，6(3)：40-43．
[35] 王东生，袁肇凯，余亚明．痰疲与动脉粥样硬化相关性探讨[J]．山东中医药大学学报，2003．27 C3)：162-164．
[36] 王鸣瑞，韩明向．高脂血证脏腑病机的研究进展[J]．中国中医基础医学杂志，2005，11(4)：316-319．
[37] 孙丽英，焦亚斌，康广盛．高脂血症的病因病机研究进展[J]．中医药学报，2004，32(2)：70-71．
[38] 刘红跃．高脂血症的中医药治疗研究进展[J]．吉林中医药，2004，24(8)：56-57．
[39] 陈伯钧，潘宗奇，苏学旭．高血脂症的中西医结合治疗进展[J]．现代中西医结合杂志．2005，14(21)：2882-2884．
[40] 杨永宗．动脉粥样硬化性心血管病基础与临床[M]．科学出版社．2004，62-90．
[41] 叶平．血脂的基础与临床．人民军医出版社[M]，2002年，117-171．
[42] Grand-Perret T, Bouillot A,Perrot A,et al.SCAP ligands are potent new lipid-lowering drugs.Nat Med,2001,7:1332-1338.