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研究生:莊佳穎
研究生(外文):Chia-Ying Chuang
論文名稱:山苦瓜活化過氧化體增殖劑活化受器PPARs之成分分離與鑑定
論文名稱(外文):Isolation and identification of the activators of nuclear receptor PPARs in Momordica charantia L. var. abbreviate Seringe
指導教授:黃青真黃青真引用關係
指導教授(外文):Ching-Jang Huang
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:微生物與生化學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
論文頁數:106
中文關鍵詞:山苦瓜過氧化體增殖劑活化受器
外文關鍵詞:PPARMomordica charantia L. var. abbreviate Serin
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本實驗室之前的研究結果顯示山苦瓜 (Momordica charantia L. var. abbreviate Seringe) 乙酸乙酯萃物含有可活化 PPAR�� 與 PPAR�蛂A誘發其下游基因表現的物質。 PPARs (Peroxisome proliferators activated receptors) 屬於核受器家族之一員,為經由 ligand 活化之轉錄因子,其弁鄏b調節葡萄糖及脂質代謝、運輸與貯存,亦參與調控發炎反應;目前已知 fibrate 類降血脂藥為 PPAR�� 的活化劑,而治療糖尿病藥 thiazolidinediones (TZDs) 為 PPAR�� 的 ligand。本研究之目的在純化並鑑定山苦瓜中可活化 PPAR�� 與 PPAR�� 之化合物。將山苦瓜全果凍乾之乙酸乙酯萃取物,經正己烷及90%甲醇/10%水對萃,得到之正己烷萃取物以正相矽膠管柱依極性分離後,利用 transactivation assay 追蹤具有活化 PPAR�� 之區分物,再以 HPLC進一步單離純化有效成分,並藉由質譜儀與 NMR 鑑定活化物之結構。結果發現,山苦瓜中之成分9cis, 11trans, 13trans-18:3 conjugated linolenic acid (CLN),主要以酯化態存在於三酸甘油酯中,可活化 PPAR�恁A其最大活化倍數與正對照組 Wy-14643相當 (p<0.05),且具劑量反應。比較純化之9c, 11t, 13t- CLN 與一般常見脂肪酸於相同濃度 (180 �嵱) 之活化效果,發現除了 palmitic acid 外, oleic acid 、 linoleic acid 、 linolenic acid 、9c, 11t- CLA 與 9c, 11t, 13t- CLN 均可顯著活化 PPAR�恁A尤以9c, 11t- CLA 與9c, 11t, 13t- CLN 之活化效果較佳。進一步以45 �嵱、90 �嵱 與180 �嵱 之 9c, 11t, 13t- CLN 處理可表現 PPAR�� 且對 PP (peroxisome proliferators) 有反應之大鼠肝癌細胞株 H4ⅡEC3 共72小時,發現45 �嵱 與90 �嵱 之9c, 11t, 13t- CLN 能促進 H4ⅡEC3 中 PPAR�� 標的基因 acyl-CoA oxidase (ACO) 之酵素活性,而180 �嵱 9c, 11t, 13t- CLN 處理後,此 ACO 活性更顯著高於以50 �嵱 Wy-14643 所處理之細胞 (p<0.05)。接著探討活化成分於山苦瓜中含量與分布,經光譜推算而得,1公斤山苦瓜凍乾物約含7.1公克9c, 11t, 13t- CLN,而一公斤之新鮮山苦瓜中約有0.42 公克之9c, 11t, 13t-CLN。分別萃取山苦瓜種籽與果肉,發現9c, 11t, 13t- CLN 主要分布於種籽,而種籽之乙酸乙酯萃取物可顯著活化 PPAR�恁C比較各種山苦瓜品系活化�nPPAR���n程度與9c, 11t, 13t- CLN 含量之相關度,結果並無相關,顯示山苦瓜中或釧|含有其他可活化 PPAR�� 之成分。在探討山苦瓜中 PPAR�� 活化成分方面,採用前述尋找 PPAR�� 活化物時所萃取與分離之樣品,結果藉 transactivation assay 發現山苦瓜中某種植物固醇混合物可顯著活化 PPAR�蛂C由上述結果可知,山苦瓜活化 PPAR�� 之成分可能包括 9c, 11t, 13t- CLN,而活化 PPAR�� 之成分可能包含特殊植物固醇,因此其開發為調節血脂與血糖保健食品之潛能,值得深究。

The peroxisome proliferators-activated receptors (PPARs) are dietary lipid sensors that regulate fatty acids and carbohydrate metabolism, and which are ligand-activated transcription factors belonging to the nuclear receptor superfamily. The hypolipidemic effects of the fibrate drugs and the antidiabetic effects of the glitazone drugs in humen are mediated by the PPAR�� and PPAR�� signalling, respectively. In a previous study, Chao (2003) found that the ethyl acetate (EA) extract of wild bitter melon (Momordica charantia L. var. abbreviate Seringe) could activate PPAR�� and PPAR��. The aim of the study is to isolate and identify the activators of nuclear receptor PPAR�� and PPAR�� in wild bitter melon.
The EA extract of wild bitter melon was partitioned with n-hexane and 90% methanol / 10% H2O, and the n-hexane extract was futher separated by silica gel column chromatography and preparative HPLC. A transactivation assay employing a clone of CHOK1 cells stably transfected with a (UAS)4-tk-alkaline phosphatase reporter and a chimeric receptor of GAL4-rPPAR�� LBD was used to track the active component. Mass spectroscopy and NMR were used to elucidate the chemical structure of the active compounds. The isolated 9cis, 11trans, 13trans-18:3 conjugated linolenic acid (9c, 11t, 13t- CLN) was found to activate PPAR�� to an extent that was equivalent to the positive control, 5 �嵱 Wy-14643 (p<0.05). Compared to common fatty acids, including oleic acid, linoleic acid and linolenic acid, 9c, 11t- CLA and 9c, 11t, 13t- CLN activated PPAR���nto�na higher extent. The isolated 9c, 11t, 13t- CLN was then incorporated into the medium to treat a peroxisome proliferators-responsive murine hepatoma cell line, H4ⅡEC3, for 72 hours. Treated cells showed significantly higher activity of acyl-CoA oxidase compared to Wy-14643, indicating that 9c, 11t, 13t- CLN was able to act on a natural PPAR�� signaling pathway in this cell line. The content of 9c, 11t, 13t- CLN in wild bitter melon was estimated to be about 7.1 g / kg dried wild bitter melon and about 0.42 g / kg fresh wild bitter melon. By monitored the UV spectroscopy of 9c, 11t, 13t- CLN in EA extracts prepared from seeds and flesh of wild bitter melon, respectively. The 9c, 11t, 13t- CLN was found to be mainly distributed in the seeds. However, the EA extract of seeds and flesh both showed significantly PPAR�� activation. Among 7 strains of wild bitter melon, the fold of PPAR�� activation was not correlated to the content of 9c, 11t, 13t- CLN estimation by UV absorption at 268.8 nm implying the possible existence of other active compounds in wild bitter melon.
To identify the compounds that activate PPAR�� in wild bitter melon, a transactivation assay employing a clone mixture of reporter gene transient and a chimeric receptor of GAL4-rPPAR�� LBD was cotransfected into CHOK1 cells and used to track the fractionation procedure used to isolate PPAR�� activator described above. The active fraction in wild bitter melon was found to be a mixture of phytolsterols.
In conclusion, we isolated and characterized, from wild bitter melon, 9c, 11t, 13t- CLN and a phytolsterol mixture that can function as activators of PPAR�� and PPAR��, respectively. The results suggest that wild bitter melon has a potential to develop as a healthy food for hyperglycemia and hyperlipidemia.



目錄

縮寫對照表…………………………………………………………………………2
中文摘要……………………………………………………………………………3
英文摘要……………………………………………………………………………4
第一章 緒論
第一節 前言……………………………………………………………………10
第二節 文獻回顧
一、過氧化體…………………………………………………………11
二、過氧化體增殖劑…………………………………………………11
三、過氧化體增殖劑活化受器 (PPAR)……………………………. 12
(一) PPAR 緣起………………………………………………….13
(二) PPAR 分布………………………………………………….13
(三) PPAR 基因結構…………………………………………….14
(四) PPAR 結構與弁遄K……………………………………….14
(五) PPAR 活化劑與 ligand…………………………………….15
(六) PPAR 作用模式…………………………………………….17
(七) PPAR 生理效應…………………………………………….18
四、苦瓜之介紹
(一) 名稱………………………………………………………...22
(二) 植物性狀…………………………………………………...22
(三) 生育過程…………………………………………………...22
(四) 栽培環境…………………………………………………...23
(五) 生產及分布………………………………………………...23
(六) 品種………………………………………………………...23
(七) 苦瓜特性…………………………………………………...24
(八) 生理效用…………………………………………………...25
(九) 山苦瓜之介紹……………………………………………...29
第三節 動機、目的與研究架構………………..……………………………..30

第二章 山苦瓜活化 PPAR�� 成分之探討
第一節 實驗設計……………………………………………………………....32
第二節 材料與方法…………………………………………………………....32
實驗一、山苦瓜活化 PPAR�� 之成分分離與鑑定………………….32
一、利用 transactivation assay 測定樣品活化 PPAR���n能力....32
二、山苦瓜中活化 PPAR�� 之成份分離與鑑定………………..36
實驗二、比較各式脂肪酸與山苦瓜純化物活化 PPAR�� 之情形…..40
實驗三、山苦瓜純化物對 H4ⅡEC3 細胞株 ACO 活性之影響….41
實驗四、探討活化 PPAR�� 之成分於山苦瓜中含量與分布……….46
一、9c, 11t, 13t- CLN於山苦瓜中含量…………………….46
二、分離山苦瓜種籽與果肉觀察9c, 11t, 13t- CLN之分布
實驗五、比較各品系山苦瓜乙酸乙酯萃取物於三酸甘油酯水解後之活化效果與活化成分含量之相關………………………..47
第三節 結果……………………………………………………………………48
第四節 討論……………………………………………………………………71
第三章 山苦瓜活化 PPAR�� 成分之探討
第一節 前言……………………………………………………………………77
第二節 材料與方法……………………………………………………………78
一、利用 transactivation assay測定樣品活化 PPAR���n能力…………78
二、山苦瓜活化 PPAR�� 之成份研究……………………………….81
第三節 結果……………………………………………………………………83
第四節 討論……………………………………………………………………93
第四章 總結……………………………………………………………96
第五章 參考文獻………………………………………………………98


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