臺灣博碩士論文加值系統

大蒜 (Allium sativum L.) 在藥理上之作用包括有抗菌、抗病毒、抗高血壓、降低血糖、抗血栓形成、抗致突變與抗血小板凝集等作用。先前研究指出，大蒜精油及其含硫化合物對於高脂飲食所誘導大鼠體重增加具有抑制作用。肥胖是世界公共衛生與預防醫學上的重要課題，肥胖在已開發與開發中國家是一全球性之流行病，已知其是許多疾病之危害因子，例如糖尿病、癌症、心臟病與高血壓。生物轉換技術可將原料中某些化合物進行化學修飾反應，而轉換成具有特殊用途或功效化合物之技術，例如利用生物轉換技術開發黑蒜產品。但是在台灣開發不易形成體脂肪之黑蒜保健食品仍是缺乏，因此本研究將進行不易形成體脂肪之黑蒜保健食品開發。內容分成二部分：(一) 以體內動物試驗模式探討黑蒜抑制高脂飲食誘導肥胖大鼠之影響；(二) 以體外細胞試驗模式釐清黑蒜抗肥胖作用機轉。(一) 在動物試驗部份，餵食不同飲食之大鼠分別進行生長參數、臟器與脂肪組織重量、血清生化參數與抗氧化防禦系統之測定。結果顯示，高脂飲食給予0.6與1.2%黑蒜之組別在體重、肝臟、腎周與副睪脂肪之增加上較高脂飲食組為低 (p<0.05)。高脂飲食給予0.6與1.2%黑蒜之組別在肝臟三酸甘油酯與膽固醇含量增加上較高脂飲食組為低。在血清三酸甘油酯與肝指數AST含量上，高脂飲食給予0.2-1.2%黑蒜組別可顯著較高脂飲食組為低 (p<0.05)。而在高密度脂蛋白膽固醇含量上，高脂飲食給予0.2-1.2%黑蒜組別可顯著提升其含量。在肝臟和脂肪組織切片中，高脂飲食給予0.2-1.2%黑蒜組別可顯著降低其油滴累積和脂肪組織內較大油滴的產生。此外，高脂飲食誘導肥胖症大鼠之肝臟氧化壓力影響上，高脂飲食給予黑蒜之組別可顯著降低glutathione disulfide (GSSG) (0.6 and 1.2% black garlic in diet) 以及提昇總抗氧化力 (trolox equivalent antioxidant capacity, TEAC) 含量 (0.2-1.2% black garlic in diet)、 glutathione (GSH) 含量 (0.6 and 1.2% black garlic in diet)、glutathione peroxidase (GPx) 活性 (0.2-1.2% black garlic in diet) 、glutathione reductase (GRd) 活性 (1.2% black garlic in diet) 與catalase活性 (0.2-1.2% black garlic in diet) (p<0.05)。此結果證實，攝取黑蒜對抑制高脂飲食所誘導大鼠之血脂質代謝異常與氧化壓力是有幫助。(二) 在細胞試驗部分，本研究將探討黑蒜對3T3-L1脂肪細胞之脂質生合成抑制作用及其分子作用機轉。首先以總多酚含量 (total polyphenolics content) 與總抗氧化力 (TEAC) 評估黑蒜之抗氧化活性，在總多酚含量上，黑蒜水萃取物 (water extract of black garlic, WEBG)、黑蒜甲醇萃取物 (methanol extract of black garlic, MEBG) 和黑蒜乙醇萃取物 (ethanol extract of black garlic, EEBG) 分別為46.44 mg/g、13.38 mg/g和12.16 mg/g。在總抗氧化能力上，WEBG、MEBG和EEBG分別為176.8 μmol/g、36.10 μmol/g和15.14 μmol/g。在三種溶劑萃取物中，黑蒜甲醇萃取物具有最佳的抑制脂肪細胞數目、胞內三酸甘油酯含量與甘油-3-磷酸去氫酶活性。在基因表現上，黑蒜甲醇萃取物亦具有抑制脂肪細胞分化 (PPARγ, SREBP-1c, C/EBPα, and C/EBPβ)、脂質生合成 (FAS, aP2, LPL, ACC, and CD36) 與脂肪細胞激素 (leptin, PAI-1, resistin, CRP, and MCP-1) 之基因表現，以及提升脂質分解 (PGC-1α) 與脂聯素之基因表現。本研究結果顯示黑蒜在動物模式與細胞模式中，具有抑制脂質合成之效應，且此效應是與減低脂肪細胞分化、減低脂質生合成、減少脂肪細胞激素與增加脂質分解作用之調控有關。

Pharmacological actions of garlic (Allium sativum L.) include antibacterial, antiviral, antihypertensive, blood glucose lowering, antithrombotic, antimutagenic and antiplatelet actions. A previously study indicated that the garlic oil and its organosulfur compounds can be beneficial for the suppression of high fat diet-induced body weight gain in rats. Obesity is an important topic in the world of public health and preventive medicine. Obesity has become a global epidemic in both developed and developing countries. It serves as a significant risk factor for various diseases such as diabetes, cancer, heart disease, and hypertension. Moreover, bioconversion technology is a technology which is taken to modify some compounds of organic material by using the specific reaction function and change them to specific compounds for special use. For example, development functional garlic product by bioconversion technique. However, development of black garlic functional food for the prevention of fat accumulation in Taiwan remains scarce. Therefore, the aim of this proposal is to investigate the development of black garlic functional food for the prevention of fat accumulation. There are two topics included in this study: (1) Effect of black garlic on inhibition of obesity induced by high-fat diet in rats; (2) Study of the molecular mechanism of black garlic on inhibition of adipogenesis in 3T3-L1 adipocytes. (1) In animal model, growth parameters, weights of organ and adipose tissues, serum biochemical parameters, and antioxidant defense systems were measured in rats fed various diets. The results showed that the body weight, liver organ, and adipose tissue weights of the peritoneal and epididymal in the HFD+0.6% black garlic and HFD+1.2% black garlic groups were significantly decreased as compared to the HFD group (p<0.05). Serum triacylglycerol and AST in the HFD+0.2% black garlic, HFD+0.6% black garlic, and HFD+1.2% black garlic groups were significantly decreased as compared to the HFD group (p<0.05). Serum HDL-cholesterol levels in the HFD+0.2% black garlic, HFD+0.6% black garlic and HFD+1.2% black garlic groups were significantly increase as compared to the HFD group (p<0.05). Liver triacylglycerol and cholesterol levels in the HFD+0.6% black garlic and HFD+1.2% black garlic groups were significantly decreased as compared to the HFD group (p<0.05). Moreover, the consumption of black garlic reduced glutathione disulfide (GSSG) (0.6 and 1.2% black garlic in diet), and enhanced the levels of TEAC (trolox equivalent antioxidant capacity) (0.6 and 1.2% black garlic in diet), glutathione (GSH) (0.6 and 1.2% black garlic in diet), glutathione peroxidase (GPx) (0.2-1.2% black garlic in diet), glutathione reductase (GRd) (1.2% black garlic in diet), and catalase (0.6 and 1.2% black garlic in diet) in the hepatic tissue of rats with HFD-induced obesity (p<0.05). These results demonstrated that intake of black garlic could be beneficial for the suppression of high fat diet-induced dyslipidemia and oxidative stress in rats. (2) In cell culture model, we investigated the effect of black garlic on inhibition of adipogenesis in 3T3-L1 adipocytes and its molecular mechanism. The evaluation of antioxidant activity was determined by total phenolics and TEAC assay. The amounts of total phenolics in water extract of black garlic (WEBG), methanol extract of black garlic (MEBG), and ethanol extract of black garlic (EEBG) were 46.44, 13.38, and 12.16 mg/g, respectively. The data indicated that the TEAC values of WEBG, MEBG, and EEBG were 176.8, 36.10, and 15.14 μmol/g, respectively. The results showed that MEBG had the highest inhibition on adipocyte number, intracellular triglyceride, and glycerol-3-phosphate dehydrogenase (GPDH) activity among three solvent extracts tested. In gene expression, MEBG also inhibited the expressions of adipocyte differentiation (PPARγ, SREBP-1c, C/EBPα, and C/EBPβ), lipogenesis (FAS, aP2, LPL, ACC, and CD36), and adipocytokine (leptin, PAI-1, resistin, CRP, and MCP-1), and then up-regulated expressions of lipolysis (PGC-1α) and adiponectin. Our data shows that black garlic has anti-adipogenic effects on animal model and cell culture model, and the anti-adipogenic effect seems to be due to the down-regulation of adipocyte differentiation, lipogenesis, and adipocytokine, and then up-regulated of lipolysis.

目次
中文摘要………………………………………………………………… I
英文摘要……………………………………………………………… III
前言……………………………………………………………………… 1
壹、文獻回顧…………………………………………………………… 4
一、肥胖………………………………………………………………… 4
二、大蒜………………………………………………………………… 7
三、脂質相關訊息分子 ……………………………………………… 11
(一)脂肪細胞分化的調控分子 ……………………………………… 11
(二)脂質合成與代謝的調控分子 …………………………………… 20
(三)脂肪細胞激素的調控分子 ……………………………………… 32
貳、材料方法………………………………………………………… 37
一、實驗設計………………………………………………………… 37
(一)以體內動物試驗模式探討黑蒜抑制高脂飲食誘導肥胖大鼠之潛力評估 …………………………………………………………………… 37
(二)以體外細胞試驗模式釐清黑蒜抗肥胖之作用機轉 …………… 38
二、材料 ……………………………………………………………… 39
(一)儀器 ……………………………………………………………… 39
(二)藥品 ……………………………………………………………… 39
三、方法 ……………………………………………………………… 41
第一部分 以體內動物試驗模式探討黑蒜抑制高脂飲食誘導肥胖大鼠之潛力評估 …………………………………………………………… 41
ㄧ、樣品 ……………………………………………………………… 41
二、動物、飲食與實驗設計 ………………………………………… 42
三、血清生化參數測定 ……………………………………………… 42
四、肝臟總脂質分析 ………………………………………………… 43
(一)總脂肪萃取 ……………………………………………………… 43
(二)三酸甘油酯測定 ………………………………………………… 43
(三)總膽固醇測定 …………………………………………………… 43
五、肝臟與脂肪組織結構切片與油滴累積之影響 ………………… 44
六、抗氧化酵素分析 ………………………………………………… 44
(一)組織均質液製備 ………………………………………………… 44
(二)蛋白質含量測定 ………………………………………………… 44
(三)總抗氧化能力測定 ……………………………………………… 44
(四)超氧歧化酶 (Superoxide dismutase, SOD) 活性測定……… 44
(五)麩胱甘肽 (Glutathione, GSH) 和氧化態麩胱甘肽 (Glutathione disulfide, GSSG) 分析 …………………………… 45
(六)麩胱甘肽還原酶 (Glutathione reductase, GRd) 活性測定 ………………………………………………………………………… 45
(七)麩胱甘肽過氧化酶 (Glutathione peroxidase, GPx) 活性測定……………………………………………………………………… 45
(八)Catalase酵素活性測定 ………………………………………… 46
七、統計分析 ………………………………………………………… 46
第二部分 以體外細胞試驗模式釐清黑蒜抗肥胖作用機轉………… 46
ㄧ、不同極性溶劑之黑蒜萃取物製備 ……………………………… 46
(一)總多酚化合物分析 ……………………………………………… 46
(二)總抗氧化能力測定 ……………………………………………… 47
二、3T3-L1前脂肪細胞 ……………………………………………… 47
三、3T3-L1前脂肪細胞培養 ………………………………………… 47
四、脂肪細胞之分化培養 …………………………………………… 47
五、脂肪細胞數目分析 (油紅染色分析)…………………………… 48
六、三酸甘油酯 (Triglyceride) 含量測定 ……………………… 48
七、蛋白質含量測定 (Protein assay) …………………………… 48
八、Glycerol-3-phosphate dehydrogenase (GPDH) 活性分析 … 48
九、蛋白質表現分析 ………………………………………………… 49
(一)聚丙烯醯胺膠體電泳法 (SDS-PAGE electrophoresis assay) ………………………………………………………………………… 49
(二)SDS-PAGE膠片配製 ……………………………………………… 49
(三)西方轉漬法 (Western blot assay) ………………………… 50
十、基因表現分析…………………………………………………… 50
(一)細胞RNA萃取 …………………………………………………… 50
(二)RNA濃度測定法…………………………………………………… 51
(三)反轉錄反應 (Reverse transcription) ……………………… 51
(四)即時定量反轉錄聚合酶連鎖反應 (Real time RT-PCR) ………………………………………………………………………… 51
十ㄧ、統計分析 ……………………………………………………… 51
参、結果 ……………………………………………………………… 54
第一部分 以體內動物試驗模式探討黑蒜抑制高脂飲食誘導肥胖大鼠之潛力評估 …………………………………………………………… 54
一、黑蒜對高脂飲食誘導肥胖大鼠之體重、食物攝取量與能量攝取之影響 …………………………………………………………………… 54
二、黑蒜對高脂飲食誘導肥胖大鼠之臟器重量之影響 …………… 54
三、黑蒜對高脂飲食誘導肥胖大鼠之血清生化參數之影響 ……… 54
四、黑蒜對高脂飲食誘導肥胖大鼠之肝臟總脂質、三酸甘油酯與膽固醇含量之影響 ………………………………………………………… 55
五、黑蒜對高脂飲食誘導肥胖大鼠之肝臟與脂肪組織切片之影響…55
六、黑蒜對高脂飲食誘導肥胖大鼠之肝臟抗氧化酵素之影響………55
第二部分 以體外細胞試驗模式釐清黑蒜抗肥胖作用機轉………… 56
一、不同溶劑之黑蒜萃取物之總多酚化合物與總抗氧化能力之分析56
二、不同溶劑黑蒜萃取物對3T3-L1脂肪細胞數目 (油紅染色) 之影響…………………………………………………………………………56
三、不同溶劑黑蒜萃取物對3T3-L1脂肪細胞胞內三酸甘油酯之影響57
四、黑蒜甲醇萃取物對調控脂肪細胞GPDH酵素活性之影響…………57
五、黑蒜甲醇萃取物對調控脂肪細胞分化之蛋白質表現影響………57
六、黑蒜甲醇萃取物對調控脂肪細胞相關基因表現影響……………57
肆、討論 ……………………………………………………………… 59
第一部分 以體內動物試驗模式探討黑蒜抑制高脂飲食誘導肥胖大鼠之潛力評估 …………………………………………………………… 59
第二部分 以體外細胞試驗模式釐清黑蒜抗肥胖作用機轉………… 62
伍、總結論 …………………………………………………………… 65
陸、實驗圖表 ………………………………………………………… 66
柒、參考文獻 ………………………………………………………… 84
捌、附錄……………………………………………………………… 101

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