臺灣博碩士論文加值系統

薏仁，薏苡（Coix lachryma-jobi L. var. mayuen Stapf）的種仁部分，自古以來不僅供作食用，亦為藥膳或食物療法中之重要材料。現今已有研究指出其含有薏仁酯（coixenolide）、薏仁多糖（coixans）等具特殊生理機能之成分。近年來之研究認為：薏仁具有降血脂之功能。因此，為進一步探討薏仁之降血脂機轉，本研究擬由糙薏仁之抽出物著手，以其對人類膽固醇酯轉移蛋白（cholesteryl ester transfer protein, CETP）活性，及對人類肝癌細胞（Hep G2）膽固醇生合成作用之抑制這兩方面進行體外試驗，並藉以設計動物實驗進行探討，以推究薏仁降血脂之作用機制。另一方面，由前人研究亦知山楂（Crataegus pinnatifid fruit）之丙酮抽出物（CP-A1）亦具有抑制CETP活性之作用，因此，本論文中亦取之進行動物實驗，進一步探討山楂降血脂作用機制。
體外試驗結果發現，糙薏仁甲醇抽出物（CL-M1）具有抑制CETP活性之效果，於劑量40 g/ml下對CETP活性之抑制為20∼30 %（IC50≒65∼100 g/ml）。CL-M1經矽膠管柱層析後之最後區分CL-M1-SF16有抑制CETP活性之能力。40 g/ml 的CL-M1對HepG2細胞之HMG-CoA reductase生合成膽固醇作用能抑制約15%。
本研究中選用脂蛋白分佈及血脂代謝表現均十分接近人類的雄性倉鼠為進行動物實驗之對象。於第二次動物實驗中，並採取健菲步脂（gemfibrozil）及山楂丙酮抽出物一齊進入動物實驗。
第一次動物實驗共有三組，分別餵食下列各組飼料：0.15% 高膽固醇組（基礎飼料添加0.15%膽固醇，w/w）（HC-15組，n=7）；0.5% CL-M1組（0.15%高膽固醇飼料添加0.5% CL-M1，w/w）（CL-M50組，n=7）；與1.0% CL-M1組（0.15%高膽固醇飼料添加1.0% CL-M1，w/w）（CL-M100組，n=7）。經過四週飼養期後，CL-M100組與HC-15組相較，顯示出能降低動物血漿中之CETP活性49%（p＜0.05）、三酸甘油酯（triacylglycerol, TG）濃度28%（p＜0.05）、以及肝臟膽固醇含量53%（p＜0.05）。另亦可升高血漿高密度脂蛋白（high density lipoprotein, HDL）含量23%（p＜0.05）。
第二次動物實驗共有五組，分別餵食下列各組飼料：0.25% 高膽固醇組（基礎飼料添加0.25%膽固醇，w/w）（HC-25組，n=8）；0.25% GM組（0.25%高膽固醇飼料添加0.25% gemfibrozil，w/w）（GM-25組，n=8）；0.5% CP-A1組（0.25%高膽固醇飼料添加0.5% CP-A1，w/w）（CP-A50組，n=8）；0.5% CL-M1組（0.25%高膽固醇飼料添加0.5% CL-M1，w/w）（CL-M50組，n=8）；與1.0% CL-M1組（0.25%高膽固醇飼料添加1.0% CL-M1，w/w）（CL-M100組，n=8）。經過四週飼養期後，服用薏仁組CL-M100組與HC-25組相較，顯示出能降低動物血漿中之CETP活性32%（p＜0.05）、TG濃度48%（p＜0.05）、膽固醇濃度26%（p＜0.05）、極低密度脂蛋白（very low density lipoprotein, VLDL）14%（p＜0.05），以及肝臟膽固醇濃度36%（p＜0.05），升高血漿中HDL濃度38%（p＜0.05）。CP-A50組則能顯著降低血漿中TG濃度18%（p＜0.05）。
由本研究推論：人類食用糙薏仁或山楂，應可有助於血脂異常之調節。本研究可得以下結論：糙薏仁甲醇抽出物有降血脂作用。CL-M1之降血脂作用，可能在於抑制CETP活性，因而增加血漿中之HDL和更有效率之reverse cholesterol transport，促進VLDL的代謝，以及肝臟對fatty acid的吸收和降低肝臟膽固醇與TG之製造。山楂丙酮抽出物之降血脂作用推測可能為：促進脂蛋白脂解脢（lipoprotein lipase, LPL）作用，故降低血漿中之TG與FFA值，略升高HDL值。

Coix, (Coix lachryma-jobi L. var. mayuen Stapf), from ancient times, is not only food but also important material of food curative. In present study has showed that it contains coixenolide, coixans etc., which have special functions. Previous studies have indicated that it has the lipid-lowering effect. Thereby, to elucidate the effects, in this study, coix was further extracted by several solvents to obtain the extracts, and then to examine their effects of plasma cholesteryl ester transfer protein (CETP) activity, the effects of cholesterol biosynthesis, and the lipid-lowing effects in vitro and in vivo, trying to understand the mechanism of it’s lipid-lowering effect . On the other hand, fruit of Crataegus pinnatifid, has showed that it’s acetonic extract (CP-A1) could inhibit the CETP activity, so in this study we also take it in animal’s in vivo examination .
Results showed that CL-M1 (40 g/ml) could reduce the CETP activity 20∼30 %(IC50≒65∼100 g/ml), the other extracts also could reduce the activity, but their solubility were not uniform and easy-controled to know the actually IC50 value. The fractions of CL-M1 by silica gel column chromatography, CL-M1-SF16 has good ability to inhibit the CETP activity, but it was still lower than CL-M1. The other fractions also had the effects of inhibit CETP activity, but were all limited in their solubility. These observations indicated that more than 2 kinds of complounds created the effect of CL-M1 inhibited CETP activity. In addition, CL-M1 also could reduced approximatly 15% cholesterol synthesis of HepG2 cells.
In animal study (I), 3 groups of hamsters were fed with one of the following diets : a 0.15% high cholesterol diet (basal diet plus 0.15% cholesterol, w/w)(HC-15, n=7), a 0.5% CL-M1 diet (0.15% high cholesterol diet plus 0.5% CL-M1, w/w)(CL-M50, n=7), and a 1.0% CL-M1 diet (0.15% high cholesterol diet plus 1.0% CL-M1, w/w)(CL-M100, n=7). After 4 weeks feeding, the CL-M100 animals’ plasma CETP activity , TG content, and liver cholesterol content were significantly lower than from HC-15, the values were 49%, 28% and 53%. And, the high density lipoprotein (HDL) content was higher (23%, p＜0.05).
In animal study (II), 5 groups of hamsters were fed with one of the following diets : a 0.25% high cholesterol diet (basal diet plus 0.25% cholesterol, w/w)(HC-25, n=8), a 0.25% gemfibrozil diet (0.25% high cholesterol diet plus 0.25% gemfibrozil, w/w)(GM-25, n=8), a 0.5% CP-A1 diet (0.25% high cholesterol diet plus 0.5% CP-A1, w/w)(CP-M5, n=8), a 0.5% CL-M1 diet (0.25% high cholesterol diet plus 0.5% CL-M1, w/w)(CL-M50, n=8), and a 1.0% CL-M1 diet (0.25% high cholesterol diet plus 1.0% CL-M1, w/w)(CL-M100, n=8). After 4 weeks feeding, the CL-M100’s plasma CETP activity , TG content, cholesterol content, very low density lipoprotein (VLDL) content and liver cholesterol content were significantly lower than from HC-25, the values were 32%, 48%, 26%, 14% and 36%. And, the HDL content was higher (38%, p＜0.05). CP-A50 diet can lowed plasma TG content significantly (18%, p＜0.05), and had the tendency of lower free fatty acid and VLDL content, higher HDL content.
In conclusion, the lipid-lowering effect of coix was created by more than 2 kinds of different polarity compounds, ane the methanol extract was one of them. The lipid-lowering effect of CL-M1, maybe contanied inhibition of CETP activity, increased plasma HDL and stimulation of reverse cholesterol transport, increased removal of VLDL, induction of hepatic fatty acid uptake and redcution of hepatic triglyceride production. Plus 0.5% CP-A1 couldn’t expressed the effect of lipid-lowering, but according to the results in this study, CP-A1 reduced plasma TG and FFA, its lipid-lowering effect might be stimulated lipoprotein lipase.

中文摘要 ………………………………………………………..I
英文摘要 ………………………………………………………..III
壹、前言 ………………………………………………………..1
貳、文獻整理 …………………………………………………...2
一、高血脂症 ………………………………………………...2
（一）高血脂症之分類 ………………………………….2
（二）動脈硬化與高血脂症 ………………………….…4
（三）高血脂症治療的原則 ………………………...…..5
二、脂質代謝 …………………………………………….…..8
（一）膽固醇 …………………………………………...8
（二）脂蛋白 …………………………………………...11
（三）脂質代謝 ………………………………………...15
（四）膽固醇酯轉移蛋白 ……………………………...22
三、降脂藥物 ………………………….……………………..33
（一）藥物治療的原則 ………………………………...33
（二）降脂藥物選述 ─ gemfibrozil 與 lovastatin…...34
四、薏仁 ……………………………………………………...42
（一）薏仁是營養豐富的食品………………………….42
（二）薏仁具有降血脂之機能性……………………….44
五、山楂 ……………………………………………………...47
（一）山楂中已知之化學成分………………………….47
（二）山楂具有降血脂之機能性……………………….47
參、研究目的 …………………………………………………...50
肆、材料與方法 ………………………………………………...52
一、實驗材料………………………………………………….52
（一）糙薏仁…………………………………………….52
（二）山楂丙酮抽出物………………………………….52
（三）Hep G2細胞……………………………………...52
（四）人類血漿………………………………………….53
（五）實驗動物………………………………………….53
（六）試劑與藥品……………………………………….54
（七）儀器設備………………………………………….56
二、實驗方法………………………………………………….58
（一）體外試驗………………………………………….58
（二）動物實驗………………………………………….61
伍、實驗結果 …………………………………………………...67
一、糙薏仁之抽出率………………………………………….67
二、體外試驗 ………………………………………………...67
（一）實驗樣品對CETP活性之影響………………….67
（二）實驗樣品對HMG-CoA reductase活性之影響…69
二、動物實驗 ………………………………………………...69
（一）第一次動物實驗………………………………….69
（二）第二次動物實驗………………………………….71
陸、討論………………………………………………………….101
一、實驗樣品對CETP活性之影響………………………….101
（一）體外試驗………………………………………….101
（二）動物實驗………………………………………….102
二、實驗樣品對血漿脂質之影響…………………………….104
（一）對TG之影響…………………………………….104
（二）對膽固醇之影響………………………………….104
三、實驗樣品對肝臟膽固醇值之影響……………………….105
柒、結論 ………………………………………………………..106
捌、參考文獻 …………………………………………………..107

丁杏苞、姜岩看、仲英、左春旭。1990。山楂葉化學成分的研究。中國中藥雜誌。15 : 39-41。
王仲志。1998。山楂丙酮抽出物對膽固醇酯轉移蛋白抑制作用之研究。台灣大學食品科技研究所碩士論文。
王富君、陳俊勇。1998。山楂的食療藥膳。中藥材。9 : 483。
江文章、張子文。1993。薏苡的食療與加工利用。第二屆中國飲食文化學術研討會文集。
行政院衛生署。1997。高血脂防治手冊。遠流出版社。
行政院衛生署。1998。87年台灣地區死因統計結果摘要(統計表)。
高德錚、梁純玲。1986。省產薏仁品質之檢定。台中農業改良場研究彙報。13 : 11-18。
陳國群。1996。高血脂症治療藥物。藝軒圖書出版社。
黃士禮。薏苡籽實儲藏條件、抗突變效應、及抗腫瘤效果之研究。台灣大學食品科技研究所博士論文。
楊莉君、陳美櫻、許文晉、白永河、喻小珠、蔡敬民。薏仁對高血脂病患血脂質及血糖之影響。食品科學。25 : 727 — 736。
楊莉君、蔡敬民。1998。薏苡對倉鼠血漿脂質的影響。食品科學。25 : 638 — 650。
楊莉君。1998。薏苡對血與肝脂質之影響。輔仁大學食品營養研究所碩士論文。
Abell, L. L., Levy, B. B. and Kendall, F. E. 1952. A simplified method for the estimation of total cholesterol in serum and demonstration of it’s specificity. J. Biol. Chem. 357-366.
Acton, S., rigotti, A., Landschultz, K. T., Xu, S., Hobbs, H. H., and Krieger, M. 1996. Identification of scaverger receptor Sr-Bi as a high density lipoprotein receptor. Scie. 271 : 518-520.
Agellon, L. B, Walsh, A., Hayek, T., Mculin, P., Jiang, X. C., Shelanski, S. A., Breslow, J. L and Tall, A. R. 1991. Reduced high density lipoprotein cholesterol in human cholesteryl ester transfer protein transgenic mice. J. Biol. Chem. 266 : 10796-10801.
Alaupovic, P., Heinonen, T., Shurzinske, L., and Black, D. M. 1997. Effect of a new HMG-CoA reductase inhibitor, atorvastatin, on lipids, apolipoproteins and lipoprotein particles in patients with elevated serum cholesterol and triglyceride levels. Atherissclerosis 133 : 123-33.
Alber, J. J., Tollefson, J. H. Cheng, C. H. and Steinmetz, A. 1984. Isolation and characterization of human plasma transfer proteins, Arteriosclerosis 4 : 49-58.
Alberts, A.W., Chen, J., Kuron, G., Hunt, V., Huff, J., Hoffman, C., Rothrock, J., Lopez, M., Joshua, H., Harris, E., Patchett, A., Monaghan, R., Currie, S., Stapley, E., Albers-Schonberg, G., Hensens, O., Hirshfield, J., Hoogsteen, K., Liesch, J., and Springer, J. 1980. Mevinolin : a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc. Natio. Aca. Sci. USA.. 77 : 3957-61.
Alberts, A. W. 1990. Effect of HMG-CoA reductase inhibitors on cholesterol synthesis. Drug Investigation 2(Suppl.2) : 9-17.
Ambrosch A, Tato F, and Luley C. 1997. Fluorescent determination of CETP activity in plasma. Atherosclerosis 134 (Suppl.) : 100.
Amin, D., Gustafson, S. K., Weinacht, J. M., Cornell, S. A., Neuenschwander, K., Kosmider, B., Scotese, A. C., Regan, J. R. and Perrone, M. H. 1993. RG12561 ( Dalvastatin ) : A novelsynthetic inhibitor of HMG-CoA reductase and cholesterol lowering agent. Pharmacology 46 : 13-22.
Aoki, M. and Tuzihare, N. 1984. Effevts of the hatomngi (Coix lachryma-jobi L. var. ma-yuen) on the blood pressure, cholesterol absorption and serum lipids level. Kaseigaku Zasshi 35 : 89 - 96.
Bakker-Arkema, R. G., Best, J., Fayyad, R., Heinonen, T. M., Marais, A.D., Nawrocki, J. W., and Black, D. M. 1997. A brief review paper of the efficacy and safety of atorvastatin in early clinical trials. Atheroscleosis 131 : 17-23.
Berthou, L., Staels, B., Saldicco, I., Berthelot, K., Casey, J., Fruchart, J. C., Denefle, P., and Branellec, D. 1994. Opposite in vitro and in vivo regulation of hepatic apolipoprotein A-I gene expression by retinoic acid: absence of effects on apolipoprotein A-II gene expression. Arterioscler Thromb. 14 : 1657-1664.
Biardi, L., and Krisans, S. 1996. Compartmentalisation of cholesterol biosynthesis. Conversion of mevalonate to farnesyl diphosphate occurs in the peroxisomes. J. Biol. Chem. 271 : 1784-8.
Breslow, J. L. 1996. High density lipoprotein and heart disease: induced mutant mouse studies. Isra. J. Med. Sci. 32 : 486-9.
Brewer, H. B., Greegg, R. E., Hoeg, J. M and Fojoss. 1988. Apolipoprotein and lipoproteins in human plasma: an overview. Clin. Chem. 34: 4-8.
Brinton, E. A, Eisenberg, S. and Breslow, J. L. 1994. Human HDL cholesterol levels are determined by apo A-I fractional catabolic rate, which correlated inversely with estimates of HDL particle size. Arterioseler. Thromb. 14 : 707-720.
Brown, M.S. and Goldstein, J.L. 1986. A receptor-mediated pathway for cholesterol homeostasis. Science 232:34-47.
Brown, M.S.Faust, J. R., and Goldstein, J.L. 1978. Induction of 3-hydroxy-3methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterlemic activity, FEBS Lett. 72 : 323-326.
Carriho, A. J. F., Medina, W. L., Nakandakare, E. r., and Quintao, E. C. R. 1997. Plasma cholesteryl ester transfer protein is lowered by treatment of hypercholesterolemia with cholestyramine. Clin. Pharmaco. Therap. 62 : 82-88.
Caslake, M. J., Packard, C. J., Gaw, E., Murray, E., Griffin, B. A., Vallance, B. D., snd Shepherd, J. 1993. Fenofibrate and LDL metabolic heterogeneity in hypercholesterolemia. Arterioscler Thromb. 13 : 702-711.
Chen, J. D., Wu, Y. Z., Tao, Z. L., Chen, Z. M. and Liu, X. P. 1995. Hawthorn （shan zha） drink and its lowering effect on blood lipid levels in humans and rats. Plant in Human Nutrition 77 : 147-154.
Chin, K. L., Luskey, K. L., and Anderson, R. G. W. 1982. Apperarance of crystalloid endoplasmic retiuculum in compactin resistant Chinese hamster cells with a 500-fold increase in 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Proc. Natl. Acad. Sci. U. S. 79 : 1185-1189.
Christensen, N. J. Rubin, C. E. and Cheung, M. C. 1983. Ultrastructural immunolocalization of apolipoprotein B within human jejunal absorptive cells. J. Lipid Res. 24: 1229-1242.
Chung, B. S., Suzuki, H., Hayakawa, S., Kim, J. H., and Nishizawa, Y. 1988. Studies on the plasma cholesterol-lowering component in coix. Nippon Shokuhin Kogyo Gakkaishi. 35(9) : 618 - 623.
Clayton, .P. T. 1998. Disorders of cholesterol biosynthesis. Arch. Dis. Child. 78 : 185-189.
Corsini, A., Maggi, F. M., and Catapano, A. L. 1995. Pharmacology of competitive inhibitors of HMG-CoA reductase. Pharmacol. Res. 31 : 9-27.
Davignon, J., Dallongeville, J., Roederer, G., Roy, M., Fruchart, J. C., Kessling, A. M., Bouthillier, D., and Lussier-Cacan, S. A. 1991. phenocopy of type III dysbetalipoproteinemia occurring in a candidate family for a putative apo E receptor defect. Ann. Med. 23 : 161-7.
Davis, R. A., malone-McNeal, M., and Moses, R. L. 1982. Intrahepatic assembly of very low density lipoprotein ; competition by cholesterol ester for the hydrophobic core. J. Biol. Chem. 257 : 2634-2640.
Desager, J-P. and Horsmans, Y. 1996. Clinical pharmacokinetics of 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. Clin. Pharmacokinet. 31 : 348-371.
Drayna, D., and Lawn, R. 1987. Multiple RFLPs at the human cholesteryl ester transfer protein (CETP) locus. Nuc. Aci. Res. 15 : 4698.
Drayna, D., Jarnagin, A. S., McLean, J., Henzel, W., Kohr, W., Fielding, C., and Lawn, R. 1987. Cloning and sequencing of human cholesteryl ester transfer protein cDNA. Nature 327 : 632-4.
Durrington, P. N., Mackness, M. I., Bhatnagar, D., Julier, K., Prais, H., Arrol, S., Morgan, J., and 1998. Wood, G. N. Effects of two different fibric acid derivatives on lipoproteins, cholesteryl ester transfer, fibrinogen, plasminogen activator inhibitor and paraoxonase activity in type IIb hyperlipoproteinaemia. Atherosclerosis 138 : 217-25.
EAS study group (European Atherosclerosis Siciety). 1988. The regulation an management of Hyperlipidemia in Adults ; A policy statement of the European Atherosclerosis Society. Europ. Heart J. 9 ; 571-600.
Eisenberg, S. 1984. High density lipoprotein metabolism. J. Lipid Res. 25: 1017-1045.
Endo, A. 1992. The discovery and development of HMG-CoA reductase inhibitors. J. Lipid. Res. 33 : 1569-1582.
Erkelens, D. W., Chen, C., Mitchell, C. D., and Glomset, J. A. 1981. Studies of the interaction between apolipoproteins A and C and triacylglycerol-rich particles. Biochimica et Biophysica Acta. 665 : 221-33.
Farmer, A. J., and Gotto Jr, A. M. 1995. Currently available hypolipidaemic drugs and future therapetutic developments. Baillieres. Clin. Enducrinol. Metab. 9 : 825-847.
Farmer, A. J., and Gotto Jr, A. M. 1996. Choosing the right lipid-regulating agent. Drugs 52 : 649-661.
Fielding, C. J. and Fielding, P. E. 1995. Molecular physicology of reverse cholesterol transport. J. Lipid. Res. 36 : 211-328.
Fielding, C. J. and Fielding, P. E. 1996. Dynamics of lipoprotein transport in the human circulatory system. Biochemistry of lipids, lipoproteins and membranes. 495-516.
Folch, J., Less, M. and Sloane-Stanely, G.M. 1957. A simple method for the isolation and purification of total lipids from animal tissue. J. Biol. Chem. 226 : 497-509.
Fruchart, J. C., Brewer, H. B., and Leitersdorf, E. 1997. Consensus for the Use of Fibrates in the Treatment of Dyslipoproteinemia and Coronary Heart Disease. American. J. Cardiology 81 : 912-917.
Goldberg, A. P., Applebaum-Bowden, D. M., Bierman, E. L., Hazzard, W. R., Haas, L. B., Sherrard, D. J., Brunzell, J. D., Huttunen, J. K., Ehnholm, C., and Nikkila, E. A. 1979. Increase in lipoprotein lipase during clofibrate treatment of hypertriglyceridemia in patients on hemodialysis. N. Engl. J. Med. 301:1073-1076..
Goldberg, A. P., Applebaum-Bowden, D. M., Bierman, EE. L., Harrzard, W. R., Hass, L. B., Sherrard, D. J., Brunzell, J. D., Huttunen, J. K., Ehnholm, C., Nikklia, E. A. 1979. Increase in lipoprotein lipase during clofibrate treatment of hypertriglyceridemia in patients on hemodialysis. N. Engl. J. Med. 301 : 1073-1076.
Goldstein, J. L. and Brown, M. S. 1984. Progress in understanding the LDL receptor and HMG-CoA reductase, two membrane proteins that regulate the plasms cholesterol. J. Lipid Res. 25: 1450-1461.
Goldstein, J. L. and Brown, M. S. 1990. Regulation of the mevalonate pathway. Nature 343 : 425-430.
Gray, J. R. 1972. Fatty acids from certain Andropogoneae. Phytochemistry 11 (3) : 1192-1193.
Grundy, S. M. 1988. HMG-CoA reductase inhibitors for treatment of hypercholesterolemia. N. Engl. J. Med. 319 : 24-33.
Grundy, S. M. 1997. Cholesterol and coronary heart disease. Arch. Intern. Med. 157 : 1177-1184.
Grundy, S. M. and Denke M. A. 1990. Dietary influences on serum lipids and lipoproteins. J. Lipid Res. 31 : 1149-1172.
Hajri, T., Chanussot, F., Ferezou, J., Riottot, M., Lafont, H., Laruelle, C., and Lutton, C. 1997. Reduced cholesterol absorption in hamsters by crilvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Eur. J. Pharmacol 320 : 65-71.
Haubenwallner, I. S., Essenburg, A. D., Barnett, B.C., Pape, M. E., DeMattos, R. B., Krause, B. R., Minton, L. L., Auerbach, B. J., Newton, R. S., and Leff, T. 1995. Hypolipidemic activity of select fibrates correlates to changes in hepatic apolipoprotein CIII expression: a potential physiologic basis for their mode of action. J. Lipid Res. 36:2541-2551.
Havel, R. J. 1992. Role of the liver in hyperlipidemia. Semin. Liver Dis. 12: 356-363.
Havel, R. J. and Hamilton, R. L. 1988. Hepatocytic lipoprotein receptors and intracellular lipoprotein catabolism. Hepatology 8: 1689-1704.
Hayek, T., Oiknine, J., Danker, G., Brook, J. G., and Aviram, M. 1995. HDL apolipoprotein A-1 attenuates oxidative modification of low density lipoprotein : studies in transgenic mice. Eur. J. Clin. Chem. Clin. Biochem. 33 : 721-725.
Heikki, F. M., Eli, O., Harpa, Ｋ. 1987. Helsinki Heart Study: Preliminary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N. Engl. J. Med. 317:1237-1245.
Heller, F. and Harvengt, C. 1983. Effects of clofibrate, bezafibrate, fenofibrate and probucol on plasma lipolytic enzymes in normolipaemic subjects. Eur. J. Clin Pharmacol 25 : 57-63.
Henwood, J. M., and Heel, R. C. 1988. Lovastatin. A preliminary review of its pharmacodynamic properties and therapeutic use in hyperlipidaemia. Drugs 36 : 429-54.
Hertz, J, R., Bishara-Shieban, J, and Bar-Tana, J. 1995. Mode of action of peroxisome proliferators as hypolipidemic drugs. Suppression of apolipoprotein C-III. J. Biol. Chem. 270:13470-13475.
Hesker, C., Swenson, T. and Tall, A. R. 1987. Purification and characterization of human plasma cholesteryl ester transfer protein. J. Biol. Chem. 262: 2275-2282.
Hesler, C. B., Miline, R. W., Swenson, T. L., Weech, P. K., Marcel, Y. L. and Tall, A. R. 1988. Monoclonal antibodies to the Mr. 74,000 cholesteryl ester transfer protein neutralize all of the cholesteryl ester and triglycerid transfer activities in human plasma. J. Biol. Chem. 263: 5020-5023.
Hoeg, J. M. and Brewer, H.B. 1987. 3-Hydroxy-3-methylglutaryl-coenzyme A inhibitors in the treatment of hypercholesterolemia. JAMA, 238: 3532-3536.
Igarashi, M., Takeda, Y., Mori, S., Ishibashi, N., Komatsu, E., Takahashi, K., Fuse, T., Yamamura, M., Kubo, K., Sugiyama, Y., and Saito, Y. 1997. Suppression of neointimal thickening by a newly developed HMG-CoA reductase inhibitor, BAYw6228, and its inhibitory effect on vascular smooth muscle cell growth. Bri. J. Pharmacol 120 : 1172-8.
Ishida, F., Sato, A., Iizuka, Y., and Kamei, T. 1989. Inhibition of acyl coenzyme A: cholesterol acyltransferase by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Chem. Pharm. Bulle. 37 : 1635-6.
Jansen, M.D., Haymond, M.W., Gerich, J.E., Cryer, P,E. and Miles, J.M. 1987. Lipolysis during fasting. J. Clin Invest. 79: 207-213.
Javitt, N.B. 1990. HepG2 cells as a resouce for metabolic studies : lipoprotein, cholesterol, and bile acids. FASEB J. 4:161-168.
Jekkel, A., Konya, A., Ilkoy, E., Boros, S., Horvath, G., and Suto, J. 1997. Microbial conversion of mevinolin. J. Antibiotics : 750-754.
Johnson, F. L., St. Clair, F. W., and rudel, L. L. 1983. Studies on the production of low density lipoproteins by perfused liners from nonhuman primates. Effects of dietary cholesterol. J. Clin. Invest. 72 : 221-236.
Kim, Y. K., Son, K. H., Nam, J. Y., Kim, S. U., Jeong, T. S., Lee, w. S., Bok, S. H., Kwom, B. M., Park, y. J., and Kwon, J. M. 1996. Inhibition of cholesteryl ester transfer protein by rosenonolactone derivatives. J. Antibiotics 49 : 815-820.
Kondo, Y., Nakajima, K., Nozoe, S., and Suzuki, S. 1988. Isolation of ovulatory-active substances from crops of Job''s tears (Coix lacryma-jobi L. var. ma-yuen Stapf). Chemical and Pharmaceutical Bulletin 36(8) : 3147-52.
Kothari, H. V., Poirier, K. J., Lee, W. H., and Satoh, Y. 1997. Inhibition of cholesterol ester transfer protein by CGS 25159 and changes in lipoproteins in hamsters. Atherosclerosis 128 : 59-66.
Kuo, M. S., Zielinski, R. J., Cialdella, J. I., Marschke, C. K., Dupuis, M. J., Li, G. P., Kloosterman, D. A., Spilman, C. H. and Marshall, V. P. 1995. Discover, isolation, structure elucidation, and biosynthesis of U-106305, a cholesteryl ester transfer protein inhibitor from UC 11136. J. Am. Chem. Soc. 117: 10629-10634.
Kwiterovich, P. O. 1998. The antiatherogenic role of high-density lipoprotein cholesterol. Am. J. Cardiol. 82 : 13Q-21Q.
La Ville, A. E., Seddon, A. M., Shaikh, M. 1989. Primary prevation of atherosclerosis by lovastatin in a genetically hyperlipidaemic rabbit strain. Atherosclerosis 78 : 205-210.
Lagrost, L. 1994. Cholesteryl ester transfer protein. Biochem. Biophy. Acta. 1215: 209-236.
Lagrost, L. 1994. Regulation of cholesterol ester transfer protein activity: review of in vitro and in vivo studies. Biochem. Biophys. Acta. 1215: 209-236.
Lagrost, L. and Barter, P. J. 1992. Cholesteryl ester transfer protein promotes the association of HDL apolipoproteins A-I and A-II with LDL: Potentiation by oleic acid. Biochem. Biophys. Acta. 1127: 255-262.
Lagrost, L., Gambert, P., Dangremont, V., Athias, A. and Lallemant, C. 1990. Role of cholesteryl ester transfer protein （CETP） in the HDL conversion process as evidenced by using anti-CETP monoclonal antibodies. J. Lipid Res. 31: 1569-1575.
Lamb, R. G., Koch, J. C., snd Bush, S. R. 1993. An enzymatic explanation of the differential effects of oleate and gemfibrozil on cultured hepatocyte tracylglycerol and phosphatidylcholine biosynthesis and secretion. Biochim. Biophys. Acta. 1165:299-305.
Lee, J. C., Coval, S. J. and Clardy, J. 1996. A cholesteryl ester transfer protein inhibitor from an insect-associated fungus. J. Antibiotics 49: 693-696.
Luskey, K. L. 1988. Regulation of cholesterol synthesis : mechanism for control of HMG-CoA reductase. Recent. Prog. Horm. Res. 44 : 35-51.
Mackness, M. I., Arrol, S., And Durrington, P. N. 1991. Paraoxonase prevents accumulation of lipoperoxides in low density lipoprotein. FEBS Lett. 286 : 152-154.
Mann, C. J., Yen, F. T., Grant, A. M., and Bihain, B. E. 1991. Mechanism of plasma cholesteryl ester transfer in hypertriglyceridemia. J Clin Invest. 88 : 2059-2066.
Marais, A. D., Firth, J. C., Bateman, M. E., Byrnes, P., Martens, C., and Mountney, J. 1997. Atorvastatin : an effective lipid-modifying agent in familial hypercholesterolemia. Arteriosclerosis, Thrombosis, and Vascular Biology. 17 : 1527-1531.
Marotti, K. R., Castle, C. K., Boyle, T. P., Lin, A. H., Murray, R. W. and Melchior, G. W. 1993. Several atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein. Nature 364 : 73-75.
Matsunaga, T., Hiasa, Y., Yanagi, Y., Maeda, T., Hattori, N., Yamakawa, K., Yamancuchi, Y., Tanaka, I., Obara, T. and Hamaguchi, H. 1991. Apolipoprotein A-I deficiency due to a codon 84 nonsense mutation of the apolipoprotein A-I gene. Proc. Natl. Acad. Sci. USA. 88 : 2793-2797.
McConathy, W. J., Gesquiere, J. C., Bass, H., Tartar, A., Fruchart, and J-C., Wang, C-S. 1992. Inhibition of lipoprotein lipase activity by synthetic peptides of apolipoprotein C-III. J. Lipid Res. 33 : 995-1003.
McGowan, M. W., Artiss, J. D., Strandbergh, D. R. and Zak, B. 1983. Aperoxidse-coupled method for the colorimetric determination of serum triglyceride. Clin. Chem. 29 : 538-542.
Muck, W., Ritter, W., Ochmann, K., Unger, S., Ahr, G., wingender, W., and Kuhlmann, J. 1997. Absolute and relative bioavailability of the MHG-CoA reductase inhibitor cerivastatin. International J. Clinical Pharmacology and Therapeutics 35 : 255-260.
Nagao, T., Otsuka, H., Kohda, H., Sato, T., and Yamasaki, K. 1985. Benzoxazinones from Coix lachryma-jobi var. ma-yuen. Phytochemistry 24 (12) 2959-2962.
Nakeya, N. 1996. Experience in clinical use of new cholesterol lowering drugs. Drugs afecting lipid metabolism 483-488.
National Cholesterol Education Program. 1988. Report if the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel). Arch Intern. Med. 148 : 36-69.
National Cholesterol Education Program. 1994. Second report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation 89 : 1329-1445.
Ness, G.C., Zhao, Z. and Lopez, D. 1996. Inhibitors of cholesterol biosynthesis increase hepatic low-density lipoprotein receptor protein degradation. Arch. Biochem. Biophys. 325 : 242-248
Newnham, H. H. and Barter, P. J. 1992. Changes in particle size of high density lipoproteins during incubation with very low density lipoproteins, cholesteryl ester transfer protein and lipoprotein lipase. Biochem. Biophys. Acta. 1125 : 294-304.
Nielsen, L. B.m Stender, S., and Kjeldsen, K. 1993. Effect of lovastatin on cholesterol absorption in cholesterol-fed rabbits. Pharmacol Toxicol. 72 : 148-151.
Nigon, F., Lesnik, P., Rouis, M., and Chapman, M. J. 1991. Discrete subspecies of human low density lipoproteins are heterogeneous in their interaction with the cellular LDL receptor. J. Lipid. Res. 32 : 1741-1753.
Ohtani, H., Hayashi, K., Hirata, Y., Dojo, S., Nakashima, K., Nishio, E., Kurushima, H., Saeki, m. and Kajiyama, G. 1990. Effects of dietary cholesterol and fatty acids on plasma cholesterol level and hepatic lipoprotein metabolism. J. Lipid Res. 31 : 1413-1422.
Otsuka, H., Takeuchi, M., Inoshiri, S., Sato, T., and Yamasaki, K. 1989. Phenolic compounds from Coix lachryma-jobi var. ma-yuen. Phytochemistry 28 (3) 883-886.
Park, Y., Suzuki, H., Lee, y. S., Hayakawa, S., and Wada, S. 1987. Effect of Coix on plasma, liver, and fecal lipid components in the rat fed on lard- or soybean oil-cholesterol diet. Biochemical and metabolic biology 39 : 11-17.
Quinet, E., Agellon, L., Marcel, Y., Miline, R. K. and Tall, A. R. 1990. Atherogenic diet increases cholesteryl ester transfer protein mRNA in rabbit liver. J. Clin. Invest. 85 : 357-363.
Rajendran, S., Parasakthy, K., Devaraj, H. and Niranjali, S. 1996. Effect of tinture of Crataegus on the LDL-receptor activity of hepatic plasma membrane of rats fed an atherogenic diet. Atherosclerosis 123 : 253-241.
Reed, D.R., Tordoff, M.G. and Friedman, M. I. 1991. Enhanced acceptance and metabolism of rats fed a high -fat diet. Am. J. Physiol. 261 : 1084-1088.
Rudney, H., and Sexton, R. C. Regulation of cholesterol biosynthesis. Ann. Rev. Nut. 6 : 245-72.
Russell, D.W. and Setchell, K. D. R. 1992. Bile acid biosynthesis. Biochemistry 31 : 4737-4749.
Sammett, D. and Tall, A. R. 1985. Mechanisms of enhancement of cholesteryl ester transfer protein activity by lipolysis. J. Biol. Chem. 260 : 6687-6697.
Schaffer, J. E., and Lodish, H. F. 1994. Expression cloning and characterization of a novel adipocyte long chain fatty acid transport protein. Cell 79 : 427-36.
Schneider, W. J. 1996. Removal of lipoproteins from plasma. Biochemistry of lipids, lipoproteins and membranes pp.517-541.
Schoonjans, K., Staels, B., Grimaldi, P., and Auwerx, J. 1993. Acyl-CoA synthetase mRNA expression is controlled by fibric-acid derivatives, feeding and liver proliferation. Eur. J. Biochem. 216 : 615-622.
Schoonjans, K., Watanabe, M., Suzuki, H., Mahfoudi, A., Krey, G., Wahli, W., Grimaldi P., Staels, B., Yamamoto, T, and Auwerx J. 1995. Induction of the acyl-coenzyme A synthetase gene by fibrates and fatty acids is mediated by a peroxisome proliferator response element in the C promotor. J. Biol. Chem. 70 : 19269-19276.
Sirtori and Franceschini. 1988. Effects of fibrates on serum lipids and atherosclerosis. Pharmacol. Ther. 37 : 167-191.
Smith, J. D, Brinton, E. A. and Breslow, J. L. 1992. Polymorphisms in human apolipoprotein A-I gene promoter region, J. Clin. Znvest. 89 : 1796-1800.
Spady, D. K. and Dietschy, J. M. 1985. Dietary saturated triglyceride suppress hepatic low density lipoprotein receptor in the hamster. Pro. Ntal. Acad. Sci. U.S.A. 53: 4526-4530.
Spady, D. K. and Dietschy, J.M. 1988. Interaction of dietary cholesterol and triglycerides in the regulation of hepatic low density lipoprotein transport in the hamster. J. Clin. Invest. 81 : 300-309.
Spady, D. K., Medding, J. B. and Dietschy, J. M. 1986. Kinetic constants for receptor-dependent and receptor-independent low density lipoprotein traneport in the tissue of the rat and hamster. J. Clin. Invest. 77 : 1474-1481.
Speijer, H. , Groener, J. E. M., van ramshorst, E., and van Tol, A. 1991. Different locations of cholesteryl ester transfer protein and phospholipid transfer protein activaties in plasma. Atherosclertsis 90 : 159-168.
Stalenhoef, A. F. H., Malloy, M. J. and Kane, J. P. 1984. Metabolism of apolipoprotein B-48 and B-100 of triglyceride-rich lipoproteins in normal and lipoprotein lipase-deficient humans. Proc. Natl. Acad. Sci. USA 81 : 1939-1843.
Stamler J., Wentworth, D. and Neaton, J. 1986. Is the relationship between serum cholesterol and risk of death from CHD continuous and graded? 1986. JAMA. 256 : 2823-2328.
Stein, Y., Stein, O., Olivecrona, T. and Halperin, G. 1985. Putative role of cholesteryl ester transfer protein in removal of cholesteryl ester from vascular interstitium studied in a model system in cell culture. Biochem. Biophys. Acta. 834 : 336-345.
Steinberg, D. 1997. Oxidative modification of LDL and atherogenesis. Circulation 95 : 1062-1071.
Swenson, T., Hesler, C. B., Brown, M. L., Quinet, E., Trotta, P. P., Haslanger, M. F., Gaeta, F. C., Marcel, Y. L., Milne, R. W. and Tall, A. R. 1989. Mechanism of cholesteryl ester transfer protein inhibition by a neutralizing monoclonal antibody and mapping of the monoclonal epitope. J. Biol. Chem. 264: 14318-14326.
Swift, L. L., manowitz, N. R., Dun, G. D., and Le Quire, V. S. 1979. Cholesterol and saturated fat diet induces hepatic synthesis of cholesterol-rich lipoproteins. Clin. Res. 27 : 378A.
Tall, A. R, Abreu, E. and Shuman, J. S. 1983 Separation of plasma phospholipid transfer protein from cholesterol ester / phospholipid exchange protein. J. Biol. Chem. 258: 2174-2186.
Tall, A. R. 1990. Plasma high density lipoprotein-metabolism and relationship to atherogenesis. J. Clin. Invest. 86: 379-384.
Tall, A. R. 1993. Plasma cholesterol ester transfer protein. J. Lipid Res. 34: 1255-1274.
Tall, A. R. 1995. Plasma lipid transfer proteins. Annu. Rev. Biochem. 64:235-257.
Tall, A. R., Abreu, E. and Shuman, J. S. 1983. Separation of plasma phospholipid transfer protein from cholesterol ester / phospholipid exchange protein. J. Biol. Chem. 258: 2174-2186.
Thompson, G. R. 1989. A handbook of hyperlipidemia. Current Science. Printed in the London.
Thurnhofer, H., Schabel, J. and Botz, M. 1991. Cholesterol transfer protein located in the intestinal brush border membrane. Partial purification and characterization. Biochem. Biophys. Acta. 1064 : 275-286.
Tomoda, H., Matsushima, C, Tabata, N., Namatame, I., Tanaka, H., Bamberger, M. J., Arai, H., Fukazawa, M., inoue, K., and Omura, S. 1999. Saturate-sepecific inhibition of cholesteryl ester transfer protein by azaphilones. J. Anti. 52 : 160-170.
Van Tol, A., Kahri, J., Eislel, B., Sane, T., and Taskiene, M. J. 1996. Gemfibrozil increases plasma levels of cholesterylester transfer protein (CETP), but lowers cholesterylester transfer in hypertriglyceridemic subjects. Kluwer Academic Publisher and Fondazione Giovanni. Printed in the Netherlansds.
Vu-Dac N, Schoonjans K, Kosykh V, Dallongeville J, Fruchart JC, Staels B, and Auwerx J. 1995. Fibrates increase haman apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor. J. Clin. Invest. 96:741-750.
Wang, S., Deng, L., Brown, M. L., Agellon, L. B. and Tall, A. R. 1991. Structure-function studies of human cholesteryl ester transfer protein by linker insertion scanning mutagenesis. Biochemistry 30: 3484-3490.
Wang, S., Deng, L., Milne, R. W. and Tall, A. R. 1992. Identification of a sequence within the C-terminal 26 amino acids of cholesteryl ester transfer protein responsible for binding a neutralizing monoclonal antibody and necessary for neutral lipid transfer activity. J. Biol. Chem. 267: 17487-17490.
Wang, S., Wang, X., Deng, L., Rassart, E., Milne, R. W. and Tall, A. R. 1993. Identification of a sequence within the C-terminal 26 amino acids of cholesteryl ester transfer protein responsible for binding a neutralizing monoclonal antibody and necessary for neutral lipid transfer activity. J. Biol. Chem. 268: 1955-1959.
Yen, F. Y., Deckelbanm, R. J., Mann, C. J., Marcel, Y. L., Milne, R. W., and Tall, A. R. 1989. Inhibition of cholesteryl ester transfer protein activity by monoclonal antibody : Effect on cholesteryl ester formation and neutral lipid mass transfer in human plasma. J. Clin. Invest. 83: 2018-2024.