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研究生:李玉麟
研究生(外文):Yu-Lin Lee
論文名稱:探討橄欖萃取物在in vitro 及in vivo對高脂所引起的肝臟病變與胰島素阻抗之影響
論文名稱(外文):The effects of olive extract on high fat-induced liver damage and insulin resistance in vitro and in vivo
指導教授:姜安娜姜安娜引用關係
指導教授(外文):An-Na Chiang
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生化暨分子生物研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:中文
論文頁數:105
中文關鍵詞:高脂肝臟病變胰島素阻抗橄欖萃取物
外文關鍵詞:high fathepatic steatosisinsulin resistanceOlive extract
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肥胖致使體內易形成慢性發炎反應,胰島素阻抗和肝臟病變皆是肥胖引起慢性發炎反應相關之代謝疾病。橄欖萃取物(Olive extract)中富含具有抗發炎和抗氧化功能的多酚類。然而目前橄欖萃取物對於肥胖誘導之胰島素阻抗和肝臟病變的相關研究甚少,本研究目的是欲探討橄欖萃取物(Olive extract, OE)是否具有改善肥胖造成之胰島素阻抗和肝臟病變的能力。吾等利用餵食C57BL/6J小鼠60%高脂飲食短期(14週)、中期(21週)和長期(28週),並且在最後六週每日分別給予小鼠50 mg/kg、100 mg/kg與150 mg/kg不同劑量的橄欖萃取物。實驗結果發現,長期(28週)餵食60%高脂飲食的小鼠會產生較嚴重的胰島素阻抗和肝臟病變現象相比於短期(14週)和中期(21週)在體重、副睪脂肪量、肝臟中脂肪浸潤情形、發炎相關蛋白Nuclear Factor Kappa B (NF-κB) subunit p65/p50、c-Jun N-terminal Kinase (JNK)、tumor necrosis factor α (TNF-α)與interleukin 6(IL-6)表現量、血糖、胰島素濃度、游離脂肪酸含量、血清總膽固醇和肝臟三酸甘油脂含量的影響亦較顯著,給予150 mg/kg OE的小鼠,對長期餵食高脂飲食的小鼠可減緩因高脂飲食所造成的體重上升、脂肪堆積、胰島素濃度和胰島素阻抗指標(HOMA-IR)的現象,亦降低血清游離脂肪酸、血清和肝臟中總膽固醇和三酸甘油脂含量,進而改善肝臟脂肪浸潤的情形,許多發炎相關蛋白NF-κB subunit p65/p50、JNK、TNF-α與IL-6表現量在肝臟中均下降,而與肝臟病變和胰島素阻抗高度相關蛋白Hypoxia-inducible factor (HIF)-1 alpha (HIF-1α)表現量亦下降。吾等亦探討橄欖萃取物(OE)對3T3-L1脂肪細胞在750 µM 棕櫚酸處理下進行葡萄糖攝取以及HepG2肝癌細胞在500 µM 棕櫚酸處理下脂質堆積情形與HIF-1α的表現影響,橄欖萃取物明顯可增加棕櫚酸所抑制3T3-L1脂肪細胞進行的葡萄糖攝取,但並未調控葡萄糖轉運蛋白(Glucose transporter 4, GLUT4)的表現;在HepG2肝癌細胞中橄欖萃取物可減少肝臟脂質堆積情形,50 mg/ml、100 mg/ml 和150 mg/ml OE可降低HIF-1α表現並呈現劑量依賴性的行為。總結本研究結果,認為OE具有減緩高脂飲食誘導的體重上升、胰島素阻抗和肝臟脂質堆積的功能,並似乎可透過減少HIF-1α的表現以改善肝臟病變與胰島素阻抗之潛力。



Insulin resistance and hepatic steatosis are the most common complications of obesity, which results in chronic inflammation in vivo. Olive extract (OE) contains polyphenolic compounds, which is able to exert the biological functions of anti-inflammation and anti-oxidation. However, the effects of OE on insulin resistance and hepatic steatosis are still unknown. The objectives of this study were to determine whether OE can improve high fat diet (HFD)-induced obesity as well as insulin resistance and steatosis. C57BL/6J mice were fed with 60% HFD for short term (14 weeks)、medium term (21 weeks) and long term (28 weeks) and supplemented with OE ( 50 mg/kg, 100 mg/kg, 150 mg/kg body weight daily) for 6 weeks before sacrifice. We found that mice treated with 60% HFD significantly increased body weight, epididymal adipose tissue weight, hepatic lipid infiltration, expressions of Nuclear Factor Kappa B (NF-κB) subunit p65/p50, c-Jun N-terminal Kinase (JNK), tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), levels of blood glucose, insulin, free fatty acid, serum total cholesterol and hepatic triglyceride levels. Moreover, insulin resistance and steatosis were formed in C57BL/6J mice fed HFD for 28 weeks. 150 mg/kg of OE treatment ameliorated HFD-induced body weight gain, lipid accumulation, and serum levels of insulin and HOMA-IR. Besides, 150 mg/kg OE supplementation significantly reduced serum free fatty acid, serum and hepatic total cholesterol and triglycerides levels, resulting in steatosis improvement. The expression of several inflammatory proteins such as NF-κB subunit p65/p50, JNK, TNF-α, and IL-6 were all down-regulated in the liver of mice treated with 60% HFD. The expression of hepatic steatosis and insulin resistance-related protein Hypoxia-inducible factor (HIF)-1 alpha (HIF-1α) was down-regulated in the liver. I also determined the effects of OE on glucose uptake in 3T3-L1 adipocytes treated with 750 µM of palmitate. Furthermore, lipid accumulation and the expression of HIF-1α was also examined in HepG2 cells treated with 500 µM of palmitate. OE significantly increase glucose uptake in palmitate-treated 3T3-L1 adipocytes, but not affect the level of glucose transporter 4 (GLUT4). Lipid accumulation and expression of HIF-1α were decreased in HepG2 cells by 50 mg/ml, 100 mg/ml and 150 mg/ml OE in a dose dependent manner. Taken together, OE not only ameliorates HFD induced body weight gain and insulin resistance and prevents hepatic lipid accumulation in vivo, but also decreases HIF-1α protein expression in vitro, suggesting a promising potential for improvement of steatosis or insulin resistance.
致謝....................................................i
摘要...................................................ii
Abstract...............................................iv
目錄...................................................vi
緒論....................................................1
一、橄欖萃取物(Olive extract)的基本介紹....................1
二、肥胖(obesity)與發炎反應...............................2
三、肥胖(obesity)與胰島素阻抗(insulin resistance).........3
四、肥胖與肝臟病變(steatosis).............................4
五、研究目標.............................................6
實驗材料.................................................7 一、細胞培養.............................................7
二、實驗藥品.............................................7
三、實驗套組.............................................9
四、抗體.................................................9
五、實驗材料............................................10
六、儀器設備............................................10
實驗方法................................................12
一、細胞培養 (cell culture).............................12
二、處理細胞藥品製備.....................................15
三、細胞蛋白萃取 (cell lysate extraction)................16
四、十二烷基硫酸鈉-聚丙烯醯胺凝膠電泳分析 (sodium dodecyl
sulfate polyacrylamide gel electrophoresis, SDS-PAGE)..................................................17
五、西方墨點法 (western blot analysis)..................20
六、細胞存活率測定(MTT assay)............................21
七、葡萄糖攝取 (Glucose uptake assay)...................22
八、細胞-酵素連接免疫吸附分析 (Cell-enzyme-link Immunosorbent assay, cell-based ELISA).................23
九、油紅染色法 (Oil-Red O assay)........................24
十、高脂誘導肥胖小鼠模式之建構............................25
十一、小鼠血糖測定.......................................27
十二、動物實驗..........................................28
十三、小鼠組織切片染色...................................29
十四、小鼠組織與血清中總膽固醇及三酸甘油脂測定..............29
十五、小鼠肝臟組織脂質過氧化測定( Malondialdehyde assay, MDA
assay).................................................30
十六、小鼠血清胰島素(serum insulin)測定...................32
十七、小鼠血清總游離脂肪酸(serum free fatty acid)測定.....................................................32
十八、實驗數據統計分析...................................33
實驗結果................................................34
一、探討橄欖萃取物對於短期(14週)高脂飲食(60% high fat diet, HFD誘導體內脂肪囤積與醣類、脂質代謝之影響..................34
二、探討橄欖萃取物對於短期(14週)高脂飲食(60% HFD)誘導肝臟脂質
累積及肝臟與發炎反應相關蛋白質表現之影響...................36
三、探討橄欖萃取物對於中期(21週)高脂飲食(60% high fat diet, HFD)誘導體內脂肪囤積與醣類、脂質代謝之影響.................38
四、探討橄欖萃取物對於中期(21週)高脂飲食(60% high fat diet, HFD)誘導肝臟脂質累積及肝臟與發炎反應相關蛋白質表現之影響.....................................................41
五、探討橄欖萃取物對於長期(28週)高脂飲食(60% high fat diet, HFD)誘導體內脂肪囤積與醣類、脂質代謝之影響.................42
六、探討橄欖萃取物對於長期(28週)高脂飲食(60% high fat diet, HFD)誘導肝臟脂質累積及肝臟與發炎反應相關蛋白質表現之影響.....................................................47
七、探討棕櫚酸與橄欖萃取物對於成熟老鼠前脂肪細胞株細胞生長之影
響.....................................................48
八、探討橄欖萃取物在棕櫚酸處理情況下,對於3T3-L1脂肪細胞進行
葡萄糖攝取(glucose uptake)之調控影響.....................49
九、探討橄欖萃取物在棕櫚酸處理情況下,對於胰島素刺激3T3-L1脂肪
細胞Glucose transporter 4 (GLUT4)轉移至細胞膜之調控影響.....................................................50
十、探討橄欖萃取物在棕櫚酸處理情況下,對人類肝癌細胞中脂肪堆積
之影響.................................................51
十一、探討橄欖萃取物在棕櫚酸處理情況下,對人類肝癌細胞中缺氧誘
導因子(Hypoxia-inducible factor 1α, HIF-1α)表現之影響.....................................................51
實驗討論................................................53
圖表...................................................60
Fig 1. The effect of olive extract on body weight and blood glucose in C57BL/6J mice fed a 60% high fat diet for 14 weeks...........................................60
Fig 2. The effect of olive extract on epididymal white adipose tissue weight in C57BL/6J mice fed a 60% high fat diet for 14 weeks......................................62
Fig 3. The effect of olive extract on liver appearance and hepatic histology in C57BL/6J mice fed a 60% high fat diet for 14 weeks......................................63
Fig 4. The effect of olive extract on expression of p65 and p50 in liver of C57BL/6J mice fed a 60% high fat diet for 14 weeks...........................................64
Fig 5. The effect of olive extract on expression of JNK, TNF-α, and IL-6 in the liver of C57BL/6J mice fed a 60% high fat diet for 14 weeks.............................65
Fig 6. The effect of olive extract on body weight and blood glucose in C57BL/6J mice fed a 60% high fat diet for 21 weeks...........................................67
Fig 7. The effect of olive extract on epididymal white adipose tissue weight in C57BL/6J mice fed a 60% high fat diet for 21 weeks......................................69
Fig 8. The effect of olive extract on liver appearance and histology in C57BL/6J mice fed a 60% high fat diet for 21 weeks...........................................70
Fig 9. The effect of olive extract on expression of p65 and p50 in liver of C57BL/6J mice fed a 60% high fat diet for 21 weeks...........................................71
Fig 10. The effect of olive extract on expression of JNK, TNF-α, and IL-6 in liver of C57BL/6J mice fed a 60% high fat diet for 21 weeks..................................72
Fig 11. The effect of olive extract on body weight and blood glucose in C57BL/6J mice fed a 60% high fat diet (HFD) for 28 weeks.....................................74
Fig 12. The effect of olive extract on epididymal white adipose tissue weight in C57BL/6J mice fed a 60% high fat diet for 28 weeks......................................76
Fig 13. The effect of olive extract on liver appearance and histology in C57BL/6J mice fed a 60% high fat diet for 28 weeks...........................................77
Fig 14. The effect of olive extract on expression of p65 and p50 in liver of C57BL/6J mice fed a 60% high fat diet for 28 weeks...........................................78
Fig 15. The effect of olive extract on expression of JNK, TNF-α, and IL-6 in liver of C57BL/6J mice fed a 60% high fat diet for 28 weeks..................................79
Fig 16. The effect of olive extract on expression of HIF-1α in liver of C57BL/6J mice fed a 60% high fat diet for 28 weeks...............................................81
Fig 17. The effect of olive extract on cell viability in 3T3-L1 cells treated with palmitate....................82
Fig 18. The effect of olive extract on glucose uptake in palmitate induced 3T3-L1 cells.........................83
Fig 19. The effect of olive extract on GLUT4 translocation in palmitate treated 3T3-L1 cells..................................................84
Fig 20. The effect of olive extract on intracellular lipid accumulation in HepG2 cells treated with palmitate..............................................85
Fig 21. The effect of olive extract on protein expression of Hypoxia-inducible factor 1α (HIF-1α) in HepG2 cells treated with palmitate.................................86
Table 1. Biometric parameters of the control and the experimental groups in C57BL/6J mice fed a 60% high fat diet (HFD) for 14 weeks................................87
Table 2. Biometric parameters of the control and the experimental groups in C57BL/6J mice fed a 60% high fat diet (HFD) for 21 weeks................................88
Table 3. Biometric parameters of the control and the experimental groups in C57BL/6J mice fed a 60% high fat diet (HFD) for 28 weeks................................89
Supplementary Fig. S1. DIO rodent adjusted calories diet (w/10% energy from fat) formulas and nutritional profiles...............................................90
Supplementary Fig. S2. DIO rodent adjusted calories diet (w/60% energy from fat) formulas and nutritional profiles...............................................91
參考文獻................................................92







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