臺灣博碩士論文加值系統

肥胖為許多疾病的危險因子，易導致代謝症候群患者往疾病的方向邁進，其中初期的非酒精性脂肪肝疾病，更是疾病治療中的關鍵。本研究利用可以降膽固醇與抗發炎的薑黃，來針對因肥胖所造成的肝臟脂質浸潤與發炎現象，觀察是否會改善代謝與發炎的情形與其調控和變化。
實驗動物模式採用雄性ob/ob小鼠與正常的C57BL/6小鼠，給予22週正常飲食，其中最後兩個禮拜，每天以灌食的方式分別給予實驗小鼠高劑量 (1000 mg/kg)與低劑量 (200 mg/kg)的薑黃一次，每週記錄一次體重，禁食一天後，犧牲取肝臟組織做伊紅-蘇木素染色、Oil-Red O 染色、免疫組織化學染色、聚合酶鏈鎖反應和收集血清作丙氨酸轉氨酶分析。
透過伊紅-蘇木素 (H &; E)和油紅O (Oil-Red O)染色，以及肝臟脂質生合成的相關蛋白SREBP-1c、ACC、FAS和SCD-1 的基因表現，顯示ob/ob小鼠因脂質生合成與脂質堆積而形成的空泡增加，肝細胞也有排列紊亂的情形，在給予薑黃後，有減少脂質的合成、堆積和改善細胞型態的效果。薑黃也可降低肝內發炎因子TNF-α、IL-1β、IL-6、IL-10、MCP-1及IFN-gamma的基因表現與NF-kappaB、F4/80的蛋白質表現，進而證實薑黃可以減輕肥胖所造成的發炎反應。另外，薑黃亦會增加FXR、SHP以及降低CYP7A1 的表現，來調控肝臟膽汁酸的生合成，與改善代謝紊亂所造成的肝損傷。
本實驗證明薑黃可以調控ob/ob小鼠脂質的生合成，降低肝臟中的脂質堆積與發炎情形，具有作為治療非酒精性脂肪肝疾病藥物的潛力。

Obesity is a risk factor for liver diseases, especially for patients with metabolic syndrome. Of which, early nonalcoholic fatty liver disease (NAFLD) is a key to treatment. Curcuma longa (Curcuma) is known to exert potent anti-inflammatory and anti-oxidant effects.
This study investigates the ability of curcuma to ameliorate congenital hepatic steatosis and inflammation from leptin deficient mice (ob/ob mice), and further discusses the implementation of the mechanisms. The mice were randomly divided into 4 groups: negative control (male C57BL/6 mice), positive control (ob/ob mice) groups were fed normal diet for 22 weeks, and two other ob/ob groups were treat with Curcuma (200 and 1000 mg/kg/day) at last two weeks. The Curcuma groups significantly reduced body weight gain, liver weight gain, plasma and liver triglyceride, fatty acid, cholesterol and bile acid compared to the ob/ob control group. H&;E and Oil-Red O stain showed that liver section with lipid droplet accumulation in ob/ob mice were attenuated in Curcuma groups. Additionally, Curcuma down-regulated SREBP-1c, ACC, FAS and SCD-1 mRNA levels, thereby was reducing the hepatic lipogenesis in ob/ob mice. Meanwhile Curcuma also reduced the mRNA expression of inflammatory factors including TNF-α, IL-1β, IL-6, IL-10, MCP-1, IFN-gamma, and reduced the protein expression of NF-kappaB, F4/80 in ob/ob mice. Curcuma also can ameliorate the syntheses of bile acid in liver and reduce liver injury from metabolic disorder, with enhancing FXR and SHP and reducing the CYP7A1 level.
Thus we demonstrated that Curcuma could regulate the lipogenesis to reduce the lipid accumulation and alleviate the inflammation in ob/ob mice. The Curcuma could improve the metabolic disorder and had potential to treat non-alcoholic fatty liver disease.

目錄
指導教授推薦書 ii
口試委員會審定書 iii
國家圖書館博碩士論文電子檔案上網授權書 iv
長庚大學博碩士論文著作授權書 v
致謝 vi
中文摘要 vii
Abstract ix
縮寫對照表 xi
圖表目錄 xviii
第一章 緒論 1
1-1肥胖與非酒精性脂肪肝疾病 1
1-1-1肥胖 1
1-1-2非酒精性脂肪肝疾病 2
1-1-3脂質生合成與發炎反應 5
1-1-4膽汁酸與肝內脂肪代謝 7
1-2 肥胖的中醫觀點 9
1-3薑黃 14
第二章 研究目的 20
第三章 材料與方法 22
3-1實驗流程設計 22
3-2薑黃粉末製備 24
3-3組織學檢查 24
3-3-1蘇木紫-伊紅 (Hematoxyli-eosin, H&;E Stain)染色 24
3-3-2油紅組織染色 (Oil Red O Stain) 25
3-3-3免疫組織化學染色 25
3-4肝臟組織與血清值之測定 26
3-4-1丙胺酸轉胺酶 (ALT) 26
3-4-2肝臟與血清中的三酸甘油脂 (triglyceride, TG)、脂肪酸 (fatty acid, FA)、膽固醇 (cholesterol, Chol) ，以及膽汁酸 (bile acid, BA)表現 27
3-5反轉錄多鏈聚合酶反應 (Reverse transcription polymerase chain reaction, RT-PCR ) 27
3-5-1 RNA純化 28
3-5-2製備互補DNA (cDNA) 29
3-5-3聚合酶鏈反應引子 (PCR primers) 29
3-5-4半定量RT-PCR 29
3-6西方墨點法 (Western blotting) 30
3-6-1組織蛋白質的萃取 32
3-6-2蛋白質定量 33
3-6-3蛋白質電泳分析 (SDS-polyacrylamide gel electrophoresis 33
analysis) 33
3-6-4西方墨點轉漬法 34
3-7統計方式 35
第四章 研究結果 36
4-1薑黃對肥胖小鼠體重、肝臟組織重量以及脂肪組織重量之影響 36
4-2血液生化值檢驗 36
4-2-1血清中Alanine transaminase (ALT)之變化 36
4-2-2血清與肝臟中triglyceride (TG)之變化 37
4-2-3血清與肝臟中fatty Acid (FA)之變化 37
4-2-4血清與肝臟中cholesterol (Chol)之變化 38
4-2-5血清與肝臟中bile Acid (BA)之變化 39
4-3病理組織切片 39
4-3-1薑黃對肝臟組織切片 (H &;E Stain)之影響 39
4-3-2薑黃對脂質堆積 (Oil-Red O Stain)之影響 40
4-4薑黃對肥胖小鼠肝內SREBP-1c、FAS 、ACC、SCD-1 mRNA的表達變化 40
4-5薑黃對TNF-α、IL-1β、IL-10、IL-6、MCP-1、IFN-、NF-B之影響 41
4-6薑黃對NF-B之影響 41
4-7薑黃對F4/80之影響 42
4-8薑黃對FXR之影響 42
4-9薑黃對肥胖小鼠肝內FXR、SHP、CYP7A1 mRNA的表達變化 43
第五章 討論 45
第六章 結論 50
參考文獻 63

圖表目錄
附圖1薑黃對肥胖小鼠體重、肝臟、脂肪組織重量及血清ALT檢測值 51
附圖2薑黃對肥胖小鼠肝臟與血清中的三酸甘油脂 (triglyceride)和脂肪酸 (fatty acid)檢測值 52
附圖3薑黃對肥胖小鼠肝臟與血清中的膽固醇 (cholesterol)和膽汁酸 (bile acid)檢測值 53
附圖4薑黃對肝臟組織切片 (H &;E Stain)及肝臟脂質堆積 (Oil-Red O Stain)之影響 54
附圖5薑黃對肥胖小鼠肝內SREBP-1c、FAS、ACC、SCD-1的mRNA變化 55
圖6薑黃對肥胖小鼠肝內TNF-α、IL-1β、IL-10、IL-6、MCP-1、IFN-、NF-B之影響 56
附圖7薑黃對肥胖小鼠肝臟的NF-B、F4/80免疫組織化學染色 (IHC)之影響 57
附圖8薑黃對肥胖小鼠肝臟內FXR之影響 58
附圖9薑黃對肥胖小鼠肝內FXR、SHP、CYP7A1的mRNA變化 59
附表一RT-PCR引子 60
附表二Q-PCR引子 62

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