臺灣博碩士論文加值系統

長期飲酒導致酒精性脂肪肝，進而引起肝發炎、肝硬化。在原住民口耳相傳下，認為牛樟芝(Antrodia camphorate, AC)可以解宿醉，改善肝疾病等病症等等的作用，然而市面上牛樟芝多為人工培養對於保護肝臟的效用眾說紛紜，因此本實驗為探討野生牛樟芝在慢性酒精攝取下是否具保護肝臟作用﹖本研究挑選五週齡雄性Wistar大鼠將其分為四組，飲食皆為chow diet，飲水以20%酒精水溶液取代，先飼養一週適應環境，一週後隨機分組成四組，每組十隻大鼠，分組如下：一) ALC組：給予20%酒精水溶液；二) ALC_Sil組：給予20%酒精水溶液＋0.25g/kg b.w.劑量的silymarin；三) ALC_1X組：給予20%酒精水溶液＋0.025g/kg b.w.劑量的野生牛樟芝子實體粗萃取物；四) ALC_4X組：給予20%酒精水溶液＋0.1g/kg b.w.劑量的野生牛樟芝子實體粗萃取物，持續飼養4週後發現ALC_4X組具有較低的內臟脂肪的重量百分比(p＜0.05)，野生牛樟芝子實體粗萃取物組別(ALC_1X組，ALC_4X組)有較低血清中TC的濃度(p＜0.05)，並且有較少的肝臟中脂肪含量以及TC與TAG (只有ALC_4X組)濃度(p＜0.05)，較高的糞便中TC與膽酸的排泄(p＜0.05)。ALC_1X組與ALC_4X組中肝臟破損指數(AST、ALP)也比ALC組低。另外，野生牛樟芝子實體粗萃取物也可以降低慢性酒精攝取下血清與肝臟中脂質過氧化物(MDA)濃度(p＜0.05)，提高肝臟中總抗氧化能力(TEAC) (p＜0.05)，而肝臟中GSH含量只有ALC_Sil組與ALC_4X組顯著增加(p＜0.05)。酒精代謝方面：ALC_1X組與ALC_4X組中肝臟中ADH、ALDH的基因表現量上升(p＜0.05)，另外，野生牛樟芝子實體粗萃取物也可提升ADH (只有ALC_4X組)、ALDH酵素活性(p＜0.05)，降低血清中酒精濃度(p＜0.05)。在代謝酒精的另一條路徑中，雖然0.1g/kg b.w.野生牛樟芝劑量會向下調控肝臟的CYP2E1的基因表現量(p＜0.05)，但是也減少其代謝過程中所產生的自由基，降低肝臟氧化壓力。同時，野生牛樟芝子實體粗萃取物也幫助提高肝臟中抗氧化酵素SOD、CAT與GSH-Px的活性(p＜0.05)，清除體內因代謝酒精產生的過多自由基，降低肝臟受傷機會，而CAT活性的提高也加速酒精的代謝。在體內膽固醇恆定(Cholesterol homeostatsis)相關基因表現：ALC_1X組與ALC_4X組可降低肝臟中HMG-CoAR基因表現(p＜0.05)減少內生性膽固醇的合成。在體內脂肪酸與三酸甘油酯(Fatty acid and triacylglycerol)生成相關基因表現：野生牛樟芝子實體粗萃取物可降低肝臟中SREBP-1c、ACC (只有ALC_4X組)與FAS基因表現(p＜0.05)。在能量代謝(Energy metabolism)相關基因表現：ALC_4X組中肝臟中PPAR-α的基因表現量相對提高(p＜0.05)。從肝臟切片中觀察慢性飲酒大鼠補充野生牛樟芝子實體粗萃取物可以減少肝臟細胞壞死的病灶與發炎現象產生，同樣在與肝臟發炎相關的基因表現中發現，野生牛樟芝子實體粗萃取物可以降低TNF-α、KLF-6與TGF-β1的基因表現，但是下降的AP-1基因表現只有在0.1g/kg b.w.劑量下發現(p＜0.05)。本實驗結果指出：在慢性酒精攝取下，野生牛樟芝子實體粗萃取物具有降低血清總膽固醇濃度、肝受損指數與肝臟脂肪含量，促進糞便總膽固醇與膽酸的排泄，提高肝臟抗氧化能力，避免酒精氧化造成的傷害；另外，野生牛樟芝子實體粗萃取物則可抑制因慢性酒精攝取下所造成的脂質生成以及發炎相關的基因表現；此外，野生牛樟芝子實體粗萃取物也可相對提升能量代謝相關基因表現，繼而降低肝代謝異常所造成的傷害。

A chronic alcohol comsumption can cause alcoholic fatty liver (AFL), further leading to hepatitis, fibrosis, and cirrhosis. Commercially, Antrodia camphorata (AC) is announced a hepatoprotection. Based on our knowledge, a comprehensive report on the wild AC hepatoprotection against a chronic alcohol comsumption is not available. Hence, this study would like to investigate the wild AC hepatoprotection against a chronic alcohol comsumption via regulations of lipid homeostasis, alcohol metabolism, antioxidant capacity, and profibrosis/inflamation in a rat model.
After one week accumulation, 40 male Wistar rats (5-wk age) all drank 20% alcohol solution ad libitum and assigned randomnly into four groups: 1) no treatment (ALC); 2) 0.25g silymarin /kg b.w./day (ALC_Sil); 3) 0.025g wild AC /kg b.w./day (ALC_1X); 4) 0.1g wild AC /kg b.w./day (ALC_4X). The experiment lasted for 4 weeks.
Results indicated that lower (p<0.05) serum TC level, and hepatic TC and TAG levels were observed in the wild AC supplemented groups, especially the ALC_4X group, compaired to those of the ALC group. Meanwhile, wild AC supplemented groups could increase (p<0.05) the TC and bile acid excretion in feces. In regulation of lipid homeostasis in liver of alcohol-fed rats, wild AC downregulated (p<0.05) HMG-CoAR, SREBP-1c, ACC, and FAS gene expressions; while an upregulation (p<0.05) of PPAR-α gene expression was only observered in the ALC_4X group.
Although CYP2E1 gene expression in alcohol-fed rats was downregulated (p<0.05) by supplementing 0.1g wild AC/kg b.w./day, wild AC upregulated (p<0.05) hepatic ADH and ALDH gene expressions, and meanwhile enhanced (p<0.05) the hepatic ADH and ALDH activities, which lower (p<0.05) the serum alcohol concentration. The wild AC also increased (p<0.05) the liver GSH and TEAC levels, as well as, SOD, CAT, and GSH-Px activities, and meanwhile decreased (p<0.05) MDA levels. Besides, the increased CAT activity by supplementing wild AC to alcohol-fed rats could accelerate alcohol metabolism. The wild AC also downregulated (p<0.05) the hepatic TNF-α, KLF-6, AP-1, and TGF-β1 gene expressions of alcohol-fed rats. Following above benefits on the wild AC against a chronic alcohol comsumption, lower (p<0.05) AST and ALP values, as well as mild or no liver necrosis, inflammation and infiltration via a histological examination were observed.

目次
摘要……………………………………………………………………………………… 1
英文摘要………………………………………………………………………………… 3
前言……………………………………………………………………………………… 5
1.文獻回顧……………………………………………………………………………… 7
1-1 酒………………………………………………………………………………… 7
1-1-1 酒的簡介………………………………………………………………… 7
1-1-2 酒精代謝………………………………………………………………… 7
1-1-3 酒與健康………………………………………………………………… 9
1-2 肝臟…………………………………………………………………………… 11
1-3 牛樟芝(Antrodia camphorata)介紹…………………………………………… 15
1-4 水飛薊素(Silymarin)介紹……………………………………………………… 18
1-5 抗氧化物質/酵素系統介紹…………………………………………………… 19
1-5-1 總抗氧化能力(Trolox Equivalent Antioxidant Capacity, TEAC) ……… 20
1-5-2 麩胱甘肽(Glutathione, GSH) …………………………………………… 21
1-5-3 超氧歧化酶(Superoxide Dismutase, SOD) ……………………………… 24
1-5-4過氧化氫酶(Catalase, CAT) ……………………………………………… 24
1-5-5 麩胱甘肽過氧化酶(Glutathione Peroxidase, GSH-Px)………………… 25
1-6 體內脂質平衡…………………………………………………………………… 26
1-7 肝臟發炎相關因子……………………………………………………… 30
2.材料方法……………………………………………………………………………… 34
2-1實驗設計………………………………………………………………………… 34
2-2實驗材料………………………………………………………………………… 35
2-3牛樟芝成分分析………………………………………………………………… 35
2-4動物飼養………………………………………………………………………… 36
2-5樣本採集………………………………………………………………………… 36
2-6實驗分析項目…………………………………………………………………… 37
2-6-1-1大鼠血清總膽固醇（TC）分析………………………………………… 37
2-6-1-2大鼠血清三酸甘油酯(TAG)分析……………………………………… 37
2-6-1-3大鼠肝功能指數(AST、ALT、ALP、γ-GT)分析……………………… 38
2-6-1-4大鼠血清酒精分析……………………………………………………… 39
2-6-1-5大鼠血清脂質過氧化物丙二醛(malondialdehyde, MDA)分析………… 39
2-6-1-6大鼠血清總抗氧化能力分析(Trolox equivalent antioxidant capacity, TEAC)的分析…………………………………………………………
39
2-6-2 大鼠糞便脂質(cholesterol, triacylglycerol)與膽酸分析………………… 40
2-6-3-1大鼠肝臟脂質(cholesterol, triacylglycerol)分析……………………… 41
2-6-3-2大鼠肝臟MDA、GSH、TEAC、ADH、ALDH、SOD、catalase、GPx分析……………………………………………………………………
41
2-6-3-2-1大鼠肝臟脂質過氧化物丙二醛(malondialdehyde, MDA)分析……… 41
2-6-3-2-2大鼠肝臟麩胱甘肽(Glutathione, GSH)分析………………………… 42
2-6-3-2-3大鼠肝臟總抗氧化能力分析(Trolox equivalent antioxidant capacity, TEAC)的分析…………………………………………………………
42
2-6-3-2-4大鼠肝臟酒精去氫酶(alcohol dehydrogenase, ADH)分析…………… 42
2-6-3-2-5大鼠肝臟乙醛去氫酶(acetaldehyde dehydrogenase, ALDH)分析…… 43
2-6-3-2-6 大鼠肝臟超氧歧化酶(superoxide dismutase, SOD)活性…………… 43
2-6-3-2-7 大鼠肝臟過氧化氫酶(Catalase)活性……………………………… 44
2-6-3-2-8 大鼠肝臟麩胱甘肽過氧化酶(Glutathione peroxidase ,GSH-Px)活性 44
2-6-3-3大鼠肝細胞中特定基因之mRNA表現量……………………………… 45
2-7 統計分析………………………………………………………………………… 46
3.實驗結果……………………………………………………………………………… 49
3-1 牛樟芝成分分析………………………………………………………………… 49
3-2 各組大鼠實驗期間體重、飲水、食物攝取量的變化及實驗犧牲後肝臟、心臟、腎臟、脾臟與內臟脂肪組織重量百分比…………………………………
49
3-3 各組大鼠實驗後的血清中總膽固醇與三酸甘油酯含量的差異……………… 50
3-4 各組大鼠肝臟中總脂質、總膽固醇含量與三酸甘油酯含量的差異………… 50
3-5 各組大鼠糞便中總膽固醇、三酸甘油酯與膽酸的含量差異………………… 50
3-6 各組大鼠的肝臟破損指數(AST, ALT, ALP, γ-GT)的差異…………………… 51
3-7 各組大鼠實驗後的血清中脂質過氧化物與總抗氧化物能力含量的差異…… 51
3-8 各組大鼠實驗後肝臟中的脂質過氧化物與抗氧化含量與酵素活性的差異… 51
3-9各組大鼠實驗後肝臟中抗氧化酵素活性的表現……………………………… 52
3-10 各組大鼠血清中酒精含量與肝臟中酒精去氫酶與乙醛去氫酶活性的差異 52
3-11各組大鼠肝臟中脂質代謝相關基因表現量的差異…………………………… 52
3-12各組大鼠肝臟中酒精代謝相關酵素基因表現量的差異……………………… 53
3-13各組大鼠肝臟與發炎相關基因表現量的差異………………………………… 53
3-14各組大鼠肝臟組織結構切片與肝損傷程度的影響…………………………… 54
4.討論…………………………………………………………………………………… 55
4-1野生牛樟芝的化學與生物作用………………………………………………… 55
4-2野生牛樟芝對於大鼠食物攝取、飲水量與生長狀況的影響………………… 56
4-3野生牛樟芝對於大鼠的血清、肝臟與糞便脂肪的影響……………………… 56
4-4野生牛樟芝對大鼠肝功能的影響……………………………………………… 58
4-5野生牛樟芝對於大鼠體內脂質過氧化能力與抗氧化的作用的影響………… 59
4-6野生牛樟芝在基因調控脂質恆定上的表現…………………………………… 60
4-7野生牛樟芝在基因調控酒精代謝上的表現…………………………………… 63
4-8野生牛樟芝在基因調控肝臟發炎上的表現………………………… 65
5.結論…………………………………………………………………………………… 67
實驗圖表………………………………………………………………………………… 70
參考文獻………………………………………………………………………………… 86

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