臺灣博碩士論文加值系統

非酒精性脂肪肝疾病(non-alcoholic fatty liver disease; NAFLD)是一種漸進性、非過量酒精導致的複合性肝臟疾病，與肥胖、胰島素拮抗與血脂異常有關。NAFLD始於肝臟內脂肪堆積的單純脂肪變性(steatosis)，當氧化壓力增加時，易進展成脂肪肝炎、肝纖維化、肝硬化甚至是肝癌等。近年來，利用膳食補充劑、營養製劑及功能性食品預防NAFLD及緩解病程的需求遽增。紅麴(Monascus purpureus)及葫蘆巴萃取物(Trigonella foenum-graecum)均被證實具有改善血脂的功效。本研究利用人類肝臟細胞株HepG2以不同濃度油酸和棕櫚酸(oleic acid:palmitic acid=2:1)建立一體外篩選平台，模擬患者的輕度、中度及重度脂肪肝，以探討紅麴及葫蘆巴水萃混合物緩解游離脂肪酸誘導HepG2細胞脂毒性之機制。細胞以0.45、0.9及1.35 mM游離脂肪酸培養24小時後，給予紅麴及葫蘆巴水萃混合物(MFW)的培養基培養24小時。結果顯示，在正常肝細胞模式中，MFW顯著降低脂肪堆積、氧化壓力及腺苷單磷酸活化蛋白激酶(AMPK)的活化，顯著增加晚期細胞凋亡及固醇調節元件結合蛋白(SREBP)、脂肪酸合成酶(FAS)、乙醯輔酶A羧化酶(ACC)、過氧化物酶體增殖物激活受體g (PPAR-g)、過氧化物酶體增殖物激活受體a (PPAR-a)、受體結合蛋白激酶3 (RIP3)與細胞色素c (細胞色素c)的蛋白質表現量。在輕度脂肪肝模式中，MFW顯著降低脂肪堆積、氧化壓力及PPAR- g蛋白表現量。在中度脂肪肝模式中，MFW顯著降低脂肪堆積、氧化壓力及FAS、ACC與PPAR- g蛋白表現量。在重度脂肪肝模式中，MFW顯著降低脂肪堆積及FAS、ACC、cytchrome c與RIP3蛋白表現量，且顯著增加PPAR-a蛋白表現量及細胞存活率。綜上所述，MFW具有降低脂肪合成、增加脂肪氧化及減少脂肪堆積的功效，且具有降低氧化壓力、細胞凋亡及細胞壞死的作用。本研究證實，紅麴合併葫蘆巴水萃物具有開發為預防NAFLD及緩解病程之功能性食品的潛力。

Non-alcoholic fatty liver disease (NAFLD) is a progressive and complicated disease associated with obese, insulin resistance and dyslipidemia, not resulted from excessive alcohol use. NFALD is initiated by fat accumulation of pure steatosis in the liver. Under the condition of excessive oxidative stress, patients with NAFLD may be progessed to nonalcoholic steatohepatitis, fibrosis, cirrhosis and even hepatocellular carcinoma. Recently, the demands of dietary supplements, nutraceuticals, and functional foods to prevent and alleviate the progression of NAFLD are greatly increased. Monascus and Trigonella foenum-graecum extracts have been demonstrated to have beneficial effects on improving hyperlipidemia. To mimic the conditions of mild, moderate, and severe NAFLD, we used human hepatoma HepG2 cells with differnet concentrations of oleic acid and palmitic acid (2:1) to establish an in vitro platform. Using this in vitro platform, we investigated the mechanisms of Monascus and Trigonella foenum-graecum water-extract mixture on attenuating free fatty acid-induced lipotoxicity. After incubated with 0.45, 0.9, and 1.35 mM free fatty acids for 24 hours, HepG2 cells were treated with medium supplemented with combined Monascus and Trigonella foenum-graecum water-extract mixture (MFW) for 24 hours. The results showed that MFW significantly decreased lipid accumulation, oxidative stress and the activation of AMP-activated protein kinase (AMPK) and significantly increased late apoptotic cells and the protein expression of sterol regulatory element-binding protein (SREBP), fatty acid synthase (FAS), acetyl CoA carboxylase (ACC), peroxisome proliferator activated receptor-gama (PPAR-g), peroxisome proliferator activated receptor-alpha (PPAR-a), receptor-interacting protein kinase 3 (RIP3) and cytchrome c in the normal model. In the mild NAFLD model, MFW significantly decreased lipid accumulation, oxidative stress and the protein expression of PPAR-g. In the moderate NAFLD model, MFW significantly decreased lipid accumulation, oxidative stress and the protein expression of FAS, ACC and PPAR-g. In the severe NAFLD model, MFW significantly decreased lipid accumulation and the protein expression of FAS, ACC, cytchrome c and RIP3 and increased the protein expression of PPAR-a and cell viability. Taken together, MFW have the abilities to decrease lipid synthesis, increase fatty acid oxidation and decrease lipid accumulation, as well as have the activities to decrease oxidative stress, cell apoptosis and necrosis. These results suggest that MFW has the potential to be developed as a functional food to prevent and attenuate the progression of NAFLD.

中文摘要 I
Abstract III
誌謝 V
目錄 VI
圖目錄 XI
縮寫 XIV
第一章 緒言 1
第二章 文獻回顧 2
第一節 非酒精性脂肪肝臟疾病 2
一、 定義 2
二、 盛行率 3
三、 危險因子 4
四、 病理生理學 4
第二節 非酒精性肝臟疾病致病機轉 9
一、 脂肪酸攝入 9
二、 內生性脂肪合成 10
三、 脂肪酸氧化 13
四、 極低密度脂蛋白運輸 16
五、 能量代謝 19
第三節 脂毒性 20
一、 粒腺體功能異常 20
二、 細胞凋亡 21
三、 細胞壞死 25
第四節 非酒精性脂肪肝臟疾病治療方式 27
一、 生活型態調整 27
二、 藥物治療 28
第五節 紅麴 29
一、 來源及有效成分 29
二、 生活物質之功效 30
第六節 葫蘆巴 31
一、 來源及有效成分 31
二、 生活物質之功效 31
第三章 目的與假說 33
第四章 材料與方法 35
第一節 細胞培養與繼代 35
第二節 NAFLD模式之建立 35
一、 正常模式(NC) 36
二、 輕度脂肪肝模式(LX) 37
三、 中度脂肪肝模式(MX) 37
四、 重度脂肪肝模式(HX) 37
第三節 實驗分組及流程 37
第四節 分析項目 39
一、 細胞存活分析 39
二、 脂肪堆積：油紅染色 39
三、 氧化壓力分析 40
四、 細胞凋亡/壞死定性分析：Hoechst 33342/PI染色 41
五、 細胞凋亡/壞死定量分析：Annexin V-FITC/PI staining 41
六、 蛋白質萃取 44
七、 西方墨點法 45
第五節 統計分析 46
第五章 實驗結果 47
第一節 游離脂肪酸濃度測試 47
一、 細胞存活分析(cell viability) 47
二、 脂肪堆積：油紅染色 47
三、 每單位HepG2細胞脂肪堆積指標(oil red/cell viability) 47
四、 氧化壓力分析(Oxidative stress) 48
第二節 游離脂肪酸誘導HEPG2細胞脂毒性模式 54
第三節 MFW對正常肝細胞模式的影響 58
一、 細胞存活分析(cell viability) 58
二、 每單位HepG2細胞脂肪堆積指標(oil red/cell viability) 58
三、 氧化壓力分析(Oxidative stress) 58
四、 細胞凋亡壞死分析 58
第四節 MFW對輕度脂肪肝細胞模式的影響 64
一、 細胞存活分析(cell viability) 64
二、 每單位HepG2細胞脂肪堆積指標(oil red/cell viability) 64
三、 氧化壓力分析(Oxidative stress) 64
四、 細胞凋亡壞死分析 64
第五節 MFW對中度脂肪肝細胞模式的影響 70
一、 細胞存活分析(cell viability) 70
二、 每單位HepG2細胞脂肪堆積指標(oil red/cell viability) 70
三、 氧化壓力分析(Oxidative stress) 70
四、 細胞凋亡壞死分析 70
第六節 MFW對重度脂肪肝細胞模式的影響 76
一、 細胞存活分析(cell viability) 76
二、 每單位HepG2細胞脂肪堆積指標(oil red/cell viability) 76
三、 氧化壓力分析(Oxidative stress) 76
四、 細胞凋亡壞死分析 76
第七節 MFW對脂肪合成與氧化相關酵素之影響 82
第八節 MFW對肝臟細胞能量恆定的影響 86
第九節 MFW對細胞凋亡與壞死訊號路徑的影響 88
第六章 討論 90
第一節 游離脂肪酸誘導HEPG2細胞脂毒性模式 90
第二節 游離脂肪酸誘導HEPG2細胞脂毒性之機制 92
第三節 MFW對正常肝細胞模式的影響 95
第四節 MFW對脂肪肝細胞模式的影響 97
一、 輕度及中度脂肪肝細胞模式 97
二、 重度脂肪肝細胞模式 99
第七章 結論 102
第八章 參考文獻 103
附錄 115

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