臺灣博碩士論文加值系統

Acetyl - CoA carboxylase (ACC) 為脂肪酸生合成關鍵酵素，具兩種重要調節脂肪酸代謝之功能，除了促進脂肪酸合成外，產物malonyl - CoA為脂肪酸氧化之inhibitor。基於抑制脂肪酸合成與促進脂肪酸氧化的觀點，抗ACC藥物及ACC 2基因剔除鼠已證實抑制ACC應可降低代謝症候群之風險(例如，腹部肥胖、高三酸甘油酯血症、胰島素阻抗等)。因此本研究旨在建立脂肪酸代謝關鍵步驟的活性篩選平台，用於評估植物萃製物(台灣常見的中草藥)和多酚類化合物在預防或改善代謝症候群的功效。
自鼠肝分離純化ACC蛋白質，經一連串硫酸銨沉澱、calcium phosphate gel fractionation、DEAE-cellulose chromatography，得ACC酵素。分離出的酵素確認可被已知ACC抑制劑5 - (tetradecyloxy) – 2 - furoyl-coenzyme A (TOFyl - CoA)抑制其活性，亦可被ACC活化物 citrate活化，以Western blot發現確實隨著純化過程而增加ACC蛋白質量。利用此純化ACC測試24種植物乙酸乙酯萃、水萃或酒精萃，篩選出四種乙酸乙酯萃和四種水萃或酒精萃能明顯抑制ACC活性，IC50界於0.04 ~ 0.11 mg / mL。選擇NO.11酸性酒精萃投入動物實驗驗證，給予已誘發代謝症候群的C57BL/6J小鼠飼料中添加1500 mg / kg的NO.11酒精萃，五週後發現確實可降低體重、高三酸甘油酯血症與高胰島素血症之情形，胰島素阻抗亦有明顯改善。
另外，也應用此平台篩選具抗代謝症候群潛能之抗氧化物，綠茶中EGCg為已知具有抑制ACC活性的能力，將EGCg做為正對照，篩出可抑制ACC活性之數種多酚，抑制效果為：Quercetin＞Resveratrol、EGCg＞Curcumin、Genistein＞Naringenin＞Catechin。
因此，此研究成功建立了ACC活性的篩選平台，可運用在未來快速大量進行天然食品中降低代謝症候群功能成分之篩選，有助於日後發展抗代謝症候群健康食品之開發。

Acetyl - CoA carboxylase (ACC), the key enzyme for fatty acid synthesis, plays an important role in fatty acid metabolism. Not only accelerating fatty acid synthesis, its product, malonyl - CoA is also the inhibitor of fatty acid oxidation. According to the theory that inhibition of fatty acid synthesis and / or acceleration of fatty acid oxidation, as shown in the anti-ACC drugs and the ACC2 gene knockout mice, inhibition of ACC might be an effective strategy for lowering the risk of metabolic syndrome (i.e. the clustering of risk factors, including abdominal obesity, hypetriglyceridemia and insulin resistance is seen in an individual.). Therefore, this study tried to establish a screening platform based on the key enzyme which regulates the fatty acid metabolism. The herbal extracts (24 Taiwanese traditional folk – medicine used herbs) and natural antioxidants were tested in this platform to identify their potential in preventing and ameliorating metabolic syndrome.
First, the ACC used in this study was purified from rat livers. After ammonium sulfate precipitation, calcium phosphate gel fractionation and DEAE-cellulose chromatography, the isolated product is confirmed to be ACC by its well-known inhibitor -- 5 - (tetradecyloxy) – 2 - furoyl-coenzyme A (TOFyl - CoA), and activator -- citrate. During the purification process, the quantity of ACC protein enriched as shown in the Western blot. The purified ACC was used to test the ethanol, EA and water extracts of 24 herbs. 4 EA extracts and 4 water extracts had been shown to inhibit the ACC activity apparently. The IC50 is in the range of 0.04 ~ 0.11 mg / mL. Thereafter, the acidic ethanol extract of herbal NO.11 was chosen to test the physical effect in animal study. The acidic ethanol extract of NO.11 was administrated at a dose of 1500 mg / kg to the high fat diet - induced metabolic syndrome C57BL / 6J mice. After 5 weeks, the body weight was significantly reduced in supplemented group. The hypertriglyceridemia and hyperinsulinemia observed in high fat diet group was not happened in supplemented group. In addition, the insulin resistance induced by high fat diet was also ameliorated in supplemented group.
8 antioxidants were also tested in this ACC inhibition platform. The EGCg in green tea had been reported for its inhibition ability on ACC activity. Thus, this compound is chosen as a positive control. The order of polyphenols on inhibiting ACC activity is as follow : Quercetin＞Resveratrol、EGCg＞Curcumin、Genistein＞Naringenin＞Catechin。
This study successfully established a platform for screening compounds with anti–metabolic syndrome potential, based on the inhibition of ACC activity. It can be applied as a high through-put screening for compounds with potential in treating metabolic syndrome. This will be helpful in developing the health foods with anti-metabolic syndrome activity in the future.

縮寫對照表…………………………………………………………………..I
組別縮寫意義…………………………………………………………..…III
摘要………………………………………………………………………...IV
Abstract…………………………………………………..………………..VI
第一章 前言………………………………………………………………...1
第二章 文獻回顧…………………………………………………………...2
一、代謝症候群……………………………………………………….........2
(一) 代謝症候群之定義…..……………………………………………………...………2
(二) 代謝症候群之判定方法…………….………………………….…………………...2
(三) 代謝症候群在台灣之判定標準與盛行率………………………………………….3
(四) 代謝症候群之病原論………………………………………………………….…....5
(五) 異常脂肪酸代謝與代謝症候群之相關性………………………………………….6
(六) 治療代謝症候群之方法…………………………………………………………….7
二、乙醯輔酶A羧化酶(Acetyl – Coenzyme A carboxylase)……..……… 7
(一) Acetyl – Coenzyme A carboxylase (ACC)的由來………………..………………7
(二) ACC催化反應………………………..……………………………………………...8
(三) ACC2蛋白質結構與異構物………………….…………………………………......8
(四) ACC的反應產物malonyl – Coenzyme A…………………………………...........10
三、ACC基因表現之調控作用…………….……………………………..10
(一) ACC1…………………………………………………………………………….10
(二) ACC2…………...………………………………………………………………......11
四、ACC酵素活性之調控作用……………………………………………11
(一).ACC活性之異位調控作用 (Allosteric regulation)...……………………………11
(二) ACC活性之共價修飾作用 (Covalent modification regulation)………………12
五、抑制ACC改善代謝症候群之相關研究.............................................13
(一) 基因層次方面……………………………….……………………………………..14
(二) ACC inhibitors.........................................................................................................15
六、天然食材抑制脂肪酸合成之相關研究………………………………18
(一) 多酚成分……………………………….…………………………………………...18
(二).非多酚成分................................................................................................................19
第三章 材料與方法……………………………………………………….21
實驗架構大綱………………………………………..…………………….22
實驗一 建立ACC活性抑制篩選平台並應用於植物萃製物篩選……23
一、建立ACC活性測定方法……………………………….....................23
二、純化ACC(Purification of ACC)………………….…………….....27
三、驗証純化產物…………………………..……………………......38
(一). Citrate活化ACC試驗……………………………………………………………38
(二). 5 - (tetradecyloxy) - 2 - furancarboxylic acid (TOFA)抑制ACC試驗……….38
(三). 西方點墨法(Western blot)分析純化ACC蛋白質………………………………41
四、測試植物萃製物………………..……………………...................42
五、抗代謝症候群之動物實驗……………..…………………….......43
(一) 動物飼養…………………………………………………………………………..43
(二) 試驗飼料之配置…………………………………………………………………...43
(三) 動物犧牲與樣品收集……………………………………………………………...45
(四) 血液生化值分析…………………………………………………………………...45
(五) 肝臟脂質分析……………………………………………………………………...45
(六) 口服葡萄糖耐受測試 Oral Glucose Tolerance Test (OGTT)…………………46
(七) 胰島素耐受測試 Insulin Tolerance Test (ITT)………………………………….46
(八) 肝臟ACC活性分析………………………………………………………………47
實驗二. 篩選抑制ACC活性之天然抗氧化物………………………….48
一、(-)-epigallocatechin gallate (EGCg)…………………………………48
二、天然抗氧化劑……………………………………………………..49
統計分析………………………………………………………...................51
第四章 結果…………………………………………………………….....52
第五章 討論……………………………………………………………...85
第六章 結論……………………………………………………………...96
第七章 參考文獻………………………………………………………...98
附錄……………………………………………………………………….111

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