臺灣博碩士論文加值系統

邁入 21 世紀的我們所面臨很大的危機就是逐年加劇的肥胖問題，肥胖為許多慢性疾病之危險因子，也是全球重要的公共衛生議題。過氧化物酶體增殖物活化受體α (Peroxisome proliferator-activated receptor alpha, PPARα) 為核受器的一員，可受配體 (ligands) 活化進而調控脂質代謝以達到改善肥胖及代謝症候群的效果。故本實驗旨在以 PPARα 轉錄活性分析平台對中草藥及海洋真菌萃取物做功效評估，並進一步篩選活性高之 PPARα 促效劑應用於飲食誘導肥胖之小鼠模式，觀察是否有改善代謝症候群、非酒精性脂肪肝及情緒失調的現象。
本實驗的第一部分以 PPARα 轉錄活性分析細胞實驗篩選自然界純物質及粗萃物成為 PPARα 促效劑潛力。結果顯示牛樟芝內的三萜類化合物 antcin B、C、H、K 均有具有顯著活化 PPARα 之能力，其中以 antcin B、H、K 活化效果最佳，約為正控制組 (1 µM WY14643) 的 120% 左右；此外自然界天然萃物薄姜木、芋葉括樓、台灣鬼督郵及海洋真菌萃取物 (NTOU4295、NTOU4296) 皆具有顯著活化 PPARα 之效果，活化倍率約為正控制組的 40-60%；牛樟芝內麥角固醇 EK100 雖不具有活化 PPARα 之能力，但先前研究發現其有抗發炎、降血糖及降血脂之功能，故在第二部分動物實驗選擇以 antcin K 以及 EK100 輔以正控制組降血脂藥物 fenofibrate 進行後續實驗，旨於探討給予 PPARα 促效劑於高脂飲食誘發小鼠代謝失調及情緒障礙之影響。
第二部份動物實驗採用 4 週齡大 C57BL/6J 公鼠，以 30% 高脂飼料餵食 8 週誘導肥胖，後續小鼠仍餵食高脂飲食但另以管餵方式給予 20 mg/kg/day BW 之 antcin K以及 EK100 持續 4 週，之後增大劑量為 40 mg/kg/day BW 再持續 4 週，另一組給予 PPARα 促效劑 250 mg/kg/day BW 之 fenofibrate 持續 8 週當正控制組，試驗期共 16 週。結果顯示，高脂飲食成功誘導小鼠肥胖，給予 fenofibrate 可顯著降低小鼠體重、脂肪組織及腓腸肌重量、脂肪細胞大小、血清總膽固醇/三酸甘油酯/游離脂肪酸含量、禁食血糖/胰島素以及胰島素阻抗指標 (HOMA-IR index)，並可增加葡萄糖耐受性與胰島素敏感性、並有較高的個體氧氣消耗量及二氧化碳排出量進而增加能量消耗量。可惜的是給予 antcin K 及 EK100 沒有明顯改善小鼠代謝症候群的現象。有趣的是，以尾部懸吊試驗評估小鼠憂鬱狀況，發現給予 fenofibrate 顯著降低小鼠不動之秒數達到降低憂鬱行為之表現；此外，十字迷宮行為試驗評估抗焦慮狀況，發現給予 antcin K 以及 fenofibrate 可顯著提升小鼠進入開放臂之次數達到改善焦慮行為之表現。另外，給予 fenofibrate 雖有抗肥胖的效果，但與其餘組別相比卻有明顯肝腫大及較高 ALT 活性的情形，分析肝臟表現型，發現高脂飲食組有明顯非酒精性脂肪肝的現象，但給予 fenofibrate 能顯著降低肝臟三酸甘油酯含量、減少油滴之堆積，並能活化肝臟 PPARα 下游基因表現，例如參與脂肪酸氧化 (Cpt1a、Acox1)、脂肪酸運送 (Cd36、Fabp1)、脂肪酸合成 (Acaca、Fasn) 及膽固醇運輸 (Abca1) 等基因提升肝臟整體能量代謝達到改善非酒精性脂肪肝的效果。
綜合以上兩部分的實驗，給予 PPARα 促效劑 fenofibrate 具有顯著改善高脂飲食所誘發小鼠肥胖、代謝失調以及情緒障礙之效果，雖然 antcin K 以及 EK100 並無看到預期改善肥胖之效果，但是 antcin K 在行為試驗上有顯著抗焦慮之效果，詳細機制仍有待更進一步的探討。

Prevalence of obesity is rapidly increasing, and has led to increased morbidity and mortality of various chronic diseases. Obesity has become one of most serious public health challenges of the 21st century. Peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily. Activation of PPARα has been shown to ameliorate obesity and metabolic syndrome through regulation of lipid metabolism. The aim of this study is to identify the natural PPARα agonists from Chinese herbs and marine fungus extracts using in vitro PPARα transactivation system. We further investigate the effects of selected PPAR agonists on metabolic abnormalities, non-alcoholic fatty liver disease (NAFLD) and emotional disturbance in diet-induced obesity mouse model.
In the first part of the study, the PPARα transactivation assay was used to identify the potential PPARα agonists from natural pure compounds and crude extracts. We showed that antcin B, C, H, K, triterpenoid compounds from Antrodia cinnamomea, significantly activated PPARα activity (120% vs. 1 μM Wy14643, 100%). In addition, the natural crude extracts from Vitex quinata (Lour.) F. N. Williams, Trichosanthes homophylla, Ainsliaea reflexa Merr, as well as few marine fungus extracts (NTOU4295, NTOU4296) increased PPARα activity (40-60% vs. 1 μM Wy14643, 100%). In contrast to antcins, EK100, an ergosterol from Antrodia cinnamomea, has limited effects on PPARα activation. Given that EK100 has been shown to exhibit anti-inflammatory, anti-diabetic and anti-hyperlipidemic effects, antcin K, EK100 and fenofibrate (hypolipidemic drugs as positive control) were tested in high-fat diet induced obese mouse model.
4-week-old C57BL/6J mice were fed with 30% high-fat diet to induce obesity for 8 weeks. The mice were treated with antcin K (20 mg/kg/day BW) for 4 weeks and then (40 mg/kg/day BW) for another 4 weeks, EK100 (20 mg/kg/day BW) for 4 weeks and then (40 mg/kg/day BW) for another 4 weeks, fenofibrate (250 mg/kg/day BW) for 8 weeks, or vehicle for 8 weeks afterward. We showed that high-fat diet has successfully induced mice obesity. Treatment of fenofibrate significantly reduced body weight, fat mass, gastrocnemius weight, adipocytes size, serum cholesterol / triglyceride / NEFA and fasting glucose / insulin / HOMR-IR index. In addition, treatment of fenofibrate in mice significantly improved glucose tolerance, insulin sensitivity, increased oxygen consumption and carbon dioxide production. Unexpectedly, antcin K and EK100 have limited effects on prevention of obesity. Interestingly, to further investigate antidepressant activity of PPARα agonists, tail suspension test was performed. We found that treatment of fenofibrate significantly reduced the immobility time compared to high-fat group, indicating less depression-like behavior. Furthermore, we also investigate antianxiety-like activity of PPARα agonists using elevated plus maze. We found that mice treatment with antcin K and fenofibrate significantly increased the time spent in open arms, suggesting less anxiety-like behavior. Although treatment of fenofibrate prevented obesity, the mice exhibited hepatomegaly and increased ALT activity. Besides, hepatic lipid accumulation was significantly decreased in fenofibrate-treated group, suggesting a significant effect on treatment of NAFLD. Exploring the mechanism, the expression of hepatic PPARα target genes, such as fatty acid oxidation (Cpt1a, Acox1), fatty acid transport (Cd36, Fabp1), fatty acid synthesis (Acaca, Fasn) and cholesterol transport (Abca1) was markedly elevated to increased energy metabolism rates in the liver and ameliorated the non-alcoholic fatty liver disease.
Taken together, treatment of PPARα agonist fenofibrate prevented obesity, metabolic disorders, emotional disturbance in high-fat diet fed C57BL/6J male mice. Although antcin K and EK100 treatment has limited effects in this study, the potential anti-anxiety function of antcin K remains to be further investigated.

中文摘要 I
ABSTRACT III
縮寫對照表 VI
總目錄 IX
圖目錄 XV
表目錄 XVIII
第一章 緒論 1
第一節 前言 1
第二節 文獻回顧 3
一、 肥胖 (Obesity) 3
1. 肥胖定義 3
2. 肥胖與代謝症候群 (Obesity and metabolic syndrome) 4
3. 肥胖與非酒精性脂肪肝 (Obesity and Non-alcoholic fatty liver disease, NAFLD) 5
4. 肥胖與行為失調 8
二、 脂肪組織 (Adipose tissue) 9
1. 白色脂肪細胞 (White adipocytes) 10
2. 棕色脂肪細胞 (Brown adipocytes) 11
3. 米色脂肪細胞 (Beige/Brite adipocytes) 12
三、 過氧化物酶體增殖物活化受體 (Peroxisome Proliferator-Activated Receptors, PPARs) 15
1. PPARs 簡介 15
2. PPARs 異形體 (Isoforms) 16
四、 PPARα 與脂肪組織 17
五、 PPARα與非酒精性脂肪肝 19
六、 PPARα 與行為失調 21
七、 PPARα 促效劑 fenofibrate 22
八、 牛樟芝 (Antrodia cinnamomea) 24
1. 牛樟芝簡介 24
2. 牛樟芝成分及生物活性 25
3. 牛樟芝三萜類化合物樟芝酸 K (antcin K) 26
4. 牛樟芝麥角固醇 Ergostatrien-3β-ol (EK100) 27
第三節 研究假說及實驗架構 28
一、 研究假說 28
二、 實驗架構 29
1. 第一部份實驗試驗對象 29
2. 第一部份實驗實驗樣品 29
3. 第一部份實驗分析項目 29
4. 第二部份實驗試驗對象 30
5. 第二部份實驗實驗飼料 30
6. 第二部份實驗試驗期 30
7. 第二部份實驗分析項目 30
第二章 自然界純物質及粗萃物作為 PPARΑ 促效劑潛力之篩選 31
第一節 前言 31
第二節 實驗材料與方法 32
一、 樣品來源 32
1. 純物質 32
2. 粗萃物 32
二、 CHO-K1細胞株PPARα轉錄活性分析試驗 32
1. 細胞株使用 32
2. 培養基與分析試劑 33
3. 短暫轉染使用試劑、分析試劑 33
4. CHO-K1 細胞培養方法 35
5. 短暫轉染 35
三、 數據分析 37
第三節 實驗結果 38
一、 樟芝酸 antcin 類對 PPARα 以及 PPARγ 轉錄活性影響 38
二、 其餘純物質對 PPARα 轉錄活性影響 38
三、 其餘粗萃物對 PPARα 轉錄活性影響 38
四、 其餘粗萃物對 PPARγ 轉錄活性影響 39
五、 antcin K、EK100、fenofibrate、fenofibric acid物對 PPARα 轉錄活性影響 39
第四節 討論 46
一、 樟芝酸 (antins) 顯著活化 PPARα 46
二、 自然界其餘 PPARα 促效劑 48
三、 麥角固醇 EK100 於 PPARα 轉錄活性分析之探討 50
四、 fenofibrate於 PPARα 轉錄活性分析之探討 50
五、 -COOH基團於PPARα 轉錄活性試驗之影響 51
第五節 結論 52
第三章 探討給予 PPARΑ 促效劑於高脂飲食誘發小鼠代謝失調及情緒障礙之影響 53
第一節 前言 53
第二節 實驗架構 55
一、 分析項目 56
第三節 材料與方法 56
一、 樣品來源 56
二、 管餵溶液配置 56
三、 C57BL/6J 公鼠飼養 57
四、 飼料使用與配置 58
五、 禁食血清樣本收集 58
六、 禁食血清三酸甘油酯分析 61
七、 禁食血清膽固醇分析 61
八、 禁食血糖分析 62
九、 禁食血清游離脂肪酸分析 62
十、 血清脂蛋白分布情形分析 63
十一、 血清胰島素分析 63
十二、 胰島素抗性指標 HOMA-IR index 計算 64
十三、 葡萄糖耐受性測試 (Intraperitoneal glucose tolerance test) 64
十四、 氧氣消耗量、二氧化碳生成量以及呼吸商分析 (Indirect calorimetry study) 65
十五、 寒冷暴露試驗 (Cold tolerance test) 65
十六、 尾部懸吊試驗 (Tail suspension test,TST) 66
十七、 高架十字迷宮 (Elevated plus maze, EPM) 66
十八、 動物犧牲及取樣 67
十九、 肝脂 (肝臟三酸甘油酯、肝臟膽固醇) 分析 68
1. 肝脂萃取方法 68
2. 肝臟三酸甘油酯分析 68
3. 肝臟膽固醇分析 68
二十、 血清天門冬胺酸轉胺酶 (AST)、血清丙胺酸轉胺酶 (ALT) 分析 69
二十一、 肝臟與脂肪組織切片 H & E 染色 69
二十二、 肝臟組織Oil red O染色 69
1. 冷凍切片 69
2. Oil red O配置 70
3. Oil red O 染色 70
二十三、 糞便膽酸分析 71
二十四、 肝臟基因表現分析 71
1. Total RNA 抽取 71
2. Total RNA 反轉錄為cDNA 72
3. Quantitative Real-time PCR 73
二十五、 數據分析 73
第四節 實驗結果 76
一、 肥胖指標 76
1. 體重變化量 76
2. 攝食量、攝食利用率、能量攝取、能量利用率 76
3. 組織絕對重量、相對重量 77
4. 白色脂肪組織數位攝影、肥胖指數、白色脂肪重量-體重相關性 78
5. 鼠蹊部白色脂肪組織 H&E 染色 78
二、 血清生化指標 79
1. 禁食血清三酸甘油酯 79
2. 禁食血清游離脂肪酸 79
3. 禁食血清膽固醇 79
4. 禁食血糖 79
5. 血清脂蛋白分布情形 80
6. 葡萄糖耐受性測試 80
7. 禁食血清胰島素與 HOMR-IR index 80
三、 新陳代謝分析 81
1. 氧氣消耗量 81
2. 二氧化碳生成量 81
3. 呼吸商 82
4. 每日能量消耗 82
5. 寒冷暴露試驗 83
6. 棕色脂肪組織 H&E 染色 83
四、 行為試驗分析 83
1. 尾部懸吊試驗 83
2. 高架十字迷宮 84
五、 肝臟表現型與基因表現分析 84
1. 肝臟數位攝影、肝臟 AST/ALT 分析 84
2. 肝臟脂肪分析 85
3. 肝臟組織切片 H&E 及 Oil red O 染色 85
4. 肝臟基因表現分析 86
5. 糞便膽酸分析 87
第五節 討論 115
一、 給予 fenofibrate 降低小鼠肥胖情形 115
二、 給予 fenofibrate 降低小鼠攝食量 117
三、 給予 fenofibrate 減少白色脂肪組織 118
四、 給予 fenofibrate 改善血清生化指標 119
五、 給予 fenofibrate 對脂蛋白分佈之影響 120
六、 給予 fenofibrate 提升葡萄萄耐受性並減緩胰島素阻抗 121
七、 給予 PPARα 促效劑 fenofibrate 提升能量消耗 122
八、 給予試驗飼料無顯著提升產熱效力之效果 123
九、 給予 fenofibrate 改善高脂飲食誘發之憂鬱行為 123
十、 給予 antcinK 以及 fenofibrate 改善高脂飲食誘發之焦慮行為 124
十一、 給予 fenofibrate 改善高脂飲食所造成之非酒精性脂肪肝 127
十二、 給予 fenofibrate 提升肝臟整體能量代謝 128
第六節 結論 134
第四章 總結論與未來展望 135
第五章 參考文獻 137

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