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研究生:鄭智夫
研究生(外文):Chih-Fu Cheng
論文名稱:Monascus purpureus NTU 568 發酵產物對酒精性肝損傷及肝臟纖維化之保健功效評估
論文名稱(外文):Protective effect of Monascus purpureus NTU 568-fermented products against alcoholic liver disease and hepatic fibrosis
指導教授:潘子明潘子明引用關係
指導教授(外文):Tzu-Ming Pan
口試委員:周正俊廖啟成王志傑李俊霖蔡宗佑何秉穎
口試日期:2017-04-15
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:生化科技學系
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:110
中文關鍵詞:酒精性肝疾病肝臟保護Monascus purpureusankaflavinmonascin
外文關鍵詞:alcoholic liver diseasehepatoprotectiveMonascus purpureusankaflavinmonascin
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Monascus purpureus NTU 568 之發酵代謝產物具有廣泛的生物活性,包括抑制腫瘤、調節高三酸甘油酯、抗氧化及抗發炎等活性。然而,酒精性肝損傷的病理機制並未清楚。因此在本研究中,利用慢性酒精性肝損傷的小鼠作為實驗模式,以評估 M. purpureus NTU 568 發酵紅麴米 (Monascus-fermented red mold rice, RMR) 及紅麴山藥 (Monascus-fermented red mold dioscorea, RMD) 保護肝臟的功效。此實驗模式中,分別餵食酒精誘導肝損傷的小鼠紅麴米及紅麴山藥 307.5 mg/kg (一倍劑量)、615.0 mg/kg (兩倍劑量) 及 1537.5 mg/kg (五倍劑量) 持續餵食五周。餵食紅麴米及紅麴山藥組均顯著降低血清中天門冬胺酸轉胺酶 (aspartate aminotransferase, AST)、丙胺酸轉胺酶 (alanine aminotransferase, ALT)、瘦體素 (lepatin) 及肝臟中三酸甘油酯 (triglyceride, TG)、總膽固醇 (total cholesterol, TC) 及游離脂肪酸 (free fatty acid, FFA) 的累積,並且可提高血清中脂聯素 (adiponectin) 與肝臟中酒精去氫酶 (alcohol dehydrogenase, ADH) 含量。紅麴米及紅麴山藥也可進一步的提升肝臟抗氧化功能、減低肝細胞傷害 (脂肪肝) 並且降低肝臟的促發炎細胞激素含量。重複性的慢性或急性肝臟損傷會造成肝臟一再修復,並且導致肝纖維化疾病產生。而此疾病與活化肝星狀細胞 (hepatic stellate cell, HSCs) 增生及細胞外基質 (extracellular matrixc, ECM) 的累積具有相當大的關連性。以紅麴發酵產物中分離出之 ankaflavin (AK) 及 monascin (MS) 進行體外細胞實驗,不但有效提升 HepG2 細胞中過氧化小體增生劑活化接受體γ (peroxisome proliferator-activated receptor-γ) 含量並降低酒精引起的固醇調節元件結合蛋白 (sterol regulatory element-binding proteins-1) 和 TG 上升,同時也可以抑制肝臟的纖維化。實驗發現利用 AK 及 MS (15 及 30 μM),可有效抑制 HSC-T6 細胞的 Akt/nuclear factor (NF)-κB 及 p38 mitogen-activated protein kinase (MAPK) 分子路徑。同時於 AK (30 μM) 及 MS (30 μM) 濃度下可有效抑制細胞生長並導致細胞凋亡,與控制組相比細胞存活率分別為: 80.2 ± 5.4% 及 62.8 ± 8.2%; P < 0.05。導致細胞週期停滯於 G1 期 (G1 期 AK 與 MS 百分比分別為: 76.1 ± 2.9% 及 79.9 ± 1.8%,控制組為: 65.9 ± 4.9% (P < 0.05)。由以上實驗發現紅麴發酵產物可以有效降低氧化壓力、發炎反應、脂肪肝及抑制肝臟星狀細胞的增生而達到保護酒精性肝疾病的功效。
Monascus purpureus NTU 568 fermented products are reported to exhibit a wide variety of biological effects, including antitumor, antihypertriglyceridemia, antioxidation, and anti-inflammatory activities. However, its role in the pathogenesis of alcoholic liver disease remains obscure. In this study, the hepatoprotective effects of Monascus-fermented red mold rice (RMR) and Monascus-fermented red mold dioscorea (RMD) were evaluated in vivo using chronic alcohol-induced mice as an experimental model. The alcohol-induced mice were orally treated with RMR or RMD at 307.5 mg/kg (1-fold), 615.0 mg/kg (2-fold), and 1537.5 mg/kg (5-fold) for 5 weeks, whereas controls received vehicle only. Treatment with RMR or RMD significantly attenuated the increased level of serum transaminases (AST, aspartate aminotransferase and ALT, alanine aminotransferase), leptin and hepatic triglyceride (TG), total cholesterol (TC), free fatty acid (FFA) accumulation, and increased serum adiponectin, hepatic alcohol dehydrogenase (ADH) levels. Furthermore, RMR and RMD elevates hepatic antioxidant ability that reduced hepatic cell damage (steatosis) and decreased tissue inflammatory cytokine levels. Hepatic fibrosis represents a wound-healing process in the liver and a response to acute or chronic hepatic injuries observed in diseases. The increased proliferation of activated hepatic stellate cells (HSCs) is associated with hepatic fibrosis and excessive extracellular matrix (ECM)-protein production. In this study, we isolated the compounds, ankaflavin (AK) and monascin (MS) from M. purpureus-fermented metabolites that were not only significantly induced peroxisome proliferator-activated receptor-γ expression and concomitant suppression of ethanol-induced elevation of sterol regulatory element-binding proteins-1 and TG in HepG2 cells but also inhibited hepatic fibrosis in vitro. We examined the inhibitory effects of the AK and MS (15 and 30 μM), on the Akt/nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK) signaling pathways in HSC-T6 (activated hepatic stellate cell line). AK and MS (30 μM, 30 μM) induced apoptosis and significantly inhibited cell growth (cell viabilities: 80.2 ± 5.4% and 62.8 ± 8.2%, respectively, versus control cells; P < 0.05). Apoptosis and G1 phase arrest (G1 phase percentages: 76.1 ± 2.9% and 79.9 ± 1.8% respectively, versus control cells 65.9 ± 4.9%; P < 0.05) correlated with increased p53 and p21 levels and caspase 3 activity, and decreased cyclin D1 and Bcl-2-family protein levels (P < 0.05, all cases). These findings suggest that Monascus-fermented products may represent a novel, protective strategy against alcoholic liver disease by attenuating oxidative stress, inflammatory response, steatosis and inhibit heaptic stellate cell proliferation.
縮寫表…………………………………………………………………………………… II
中文摘要………………………………………………………………………………… IV
英文摘要………………………………………………………………………………… VI
目錄……………………………………………………………………………………… VIII
圖目錄…………………………………………………………………………………… XI
表目錄…………………………………………………………………………………… XIII
第壹章 文獻回顧…………………………………………………………………….…. 1
一、紅麴介紹及備製…..……………………………………………………………….. 1
二、紅麴於食品上的應用……………….....……………………………………………. 3
三、紅麴之保健功效研究…………..…………………………………………………… 3
(一) 紅麴菌發酵產物之降膽固醇功效…..……………………………………………. 3
(二) 紅麴菌發酵產物之降血壓功效…..………………………………………………. 5
(三) 紅麴菌發酵產物之降血糖功效……….………………………………………….. 6
(四) 紅麴菌發酵產物之抗疲勞功效………………….....…………………………….. 6
(五) 紅麴發酵產物抑制阿茲海默症之類澱粉樣蛋白沉積與改善記憶學習功效…... 7
(六) 紅麴萃取物降低體脂肪功效……………………………………………………... 8
(七) 紅麴代謝產物抑制腫瘤生長及轉移功效…………….………………………….. 8
(八) 紅麴代謝產物改善糖尿病功效…………………………………………………... 8
(九) 紅麴預防骨質疏鬆症功效……………………..…………………………………. 9
(十) 紅麴代謝產物改善酒精性脂肪肝功效...…………………………….…………... 9
(十一) 紅麴發酵產物之抗氧化功效…………………………………………………. 10
四、紅麴發酵產物………………………………...……………………………...……… 10
(一) 膽固醇合成抑制劑−monacolins….………..…………………………….………... 10
(二) 紅麴色素及azaphilone …………………………………………………..………... 12
(三) 抗氧化物-dimerumic acid (DMA)、deferricoprogen (DFC)….…………………… 12
(四) 胺基酸類化合物…………...……………………………………………………… 12
(五) 黴菌毒素- citrinin…..………………………...…………………………………… 14
(六) 紅麴二次代謝產物 monascin 與 ankaflavin 之生理功效……………….…….
五、山藥之功效研究..………………………………………………………...…….….. 14
16
(一) 山藥簡介、成分與營養價值….…………………………………………….…….. 16
(二) 山藥生理機能……………………………………………..………………………. 18
六、酒精性肝損傷….……………………………………………………….…..……… 18
(一) 酒精性肝損傷的臨床病徵………………………………………….…………….. 18
(二) 酒精性肝損傷的診斷.…………………………………………………………….. 19
(三) 酒精性肝損傷的相關分子機制………………………………………...………… 19
(四) 酒精性肝損傷的治療方法………………………………………………………... 21
七、肝臟纖維化………………………………………………………………………... 22
(一) 肝星狀細胞..………………………………………………………….…………… 22
(二) 活化之肝星狀細胞…………………………………………………………….….. 23
第貳章 研究動機與目的…..…………………………………………………………… 25
第參章 材料與方法….……………………………………………………………..…... 28
一、儀器及藥品……..………………………………………………………………….. 28
二、實驗方法……………………………………………………………………………. 31
(一) 紅麴發酵產物改善 Lieber-DeCarli liquid diet 誘導酒精性肝損傷小鼠模式….. 31
(二) 紅麴發酵產物改善肝臟纖維化之分子路徑探討……...…………………….…... 45
第肆章 結果與討論……...……………………………………………………………... 48
一、紅麴發酵產物改善 Lieber-DeCarli liquid diet誘導酒精性肝損傷小鼠模式…... 48
(一) 紅麴米及紅麴山藥對於體重及肝臟的改善功能................……………………... 48
(二) 紅麴米及紅麴山藥對於肝臟及腎臟組織影響………........................................... 48
(三) 紅麴米及紅麴山藥改善酒精性肝損傷之功效……………………………........... 55
(四) 紅麴米及紅麴山藥增強肝臟中抗氧化酵素的能力…........................................... 60
(五) 紅麴米及紅麴山藥肝臟脂質及血清生化數值評估…........................................... 63
(六) 紅麴米及紅麴山藥肝臟細胞激素影響…............................................................... 67
(七) 利用 HPLC 測定紅麴米及紅麴山藥的二次代謝物含量…................................. 67
(八) 紅麴發酵產物 AK 及 MS 對慢性酒精性肝損傷之影響………...…….............70
(九) 紅麴發酵產物 AK 及 MS 提升轉錄因子 PPAR-γ並降低 SREBP-1 及
三酸甘油酯含量…………………………………………………………………74
二、紅麴發酵產物 AK 及 MS 誘導肝臟星狀細胞凋亡分子路徑探討…………….. 78
(一) AK 和 MS 對於 HSC-T6 細胞及肝臟初代細胞的影響…................................. 78
(二) AK 和 MS 對於HSC-T6細胞週期的影響…………………….………………... 78
(三) AK 和 MS 誘導 HSC-T6 細胞凋亡………………….….................................... 84
(四) AK 和 MS 影響 HSC-T6 細胞 PI3K/Akt 分子路徑及 NF-κB 活性…..…… 87
(五) AK 和 MS 影響 HSC-T6 細胞 p38 MAPK 分子路徑…................................... 90
(六) AK 和 MS 經由 PI3K/Akt 與 p38 MAPK 分子路徑促使 HSC-T6 細胞凋亡 90
第伍章 結論…………………………………………………………………………….. 94
第陸章 參考文獻……………………………………………………………………….. 95
第柒章 附錄…………………………………………………………………………….. 110
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