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

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