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研究生:李亭瑤
研究生(外文):Ting-Yau Lee
論文名稱:PEDF抑制3T3L1脂肪細胞生成及保護老鼠免於經高脂飲食誘發的肥胖及代謝性異常
論文名稱(外文):Pigment epithelium-derived factor inhibits adipogenesis in 3T3L1 adipocytes and 3T3L1 adipocytesand metabolic disorders in mice
指導教授:王淑慧王淑慧引用關係
指導教授(外文):Shu-Huei Wang
口試委員:龔秀妮蔡素宜王仰高陳金銓
口試委員(外文):Hsiu-Ni KungSu-Yi TsaiYun-Kao WangChin-Chuan Chen
口試日期:2016-07-26
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:解剖學暨細胞生物學研究所
學門:醫藥衛生學門
學類:醫學學類
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:72
中文關鍵詞:PEDF抑制3T3L1肥胖高脂飲食代謝異常抑制脂肪細胞生成
外文關鍵詞:Pigment epithelium-derived factoradipogenesis3T3L1 adipocytes3T3L1 adipocytesmetabolic disorders
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肥胖是現代人的文明病,帶來許多代謝疾病及心血管疾病,表現出高血糖、高血脂和胰島素耐受性差等代謝異常;而脂肪組織的氧化壓力和發炎是代謝疾病的成因,脂肪細胞分化和脂肪分解的動態平衡調節更是近年來研究的核心。Pigment epithelium-derived factor (PEDF)是由視網膜色素上皮細胞培養液分離出,近年來被廣為研究的蛋白質,含有促進神經生長、抑制血管生成、抑制腫瘤生長、平滑肌細胞增生及發炎等功能。本實驗目的主要探討PEDF對於抑制肥胖及抑制脂肪生成的功能及其調控機制。在動物實驗上,以C57B/6公鼠餵食高脂食物(high fat diet, HF diet)為誘發肥胖(Diet induced obesity, DIO)的動物模式,藉由HF diet合併PEDF服用及以高脂食物誘發肥胖(DIO)的小鼠再服用PEDF,來觀察PEDF對肥胖的抑制及治療效果。在細胞實驗部分,細胞實驗則是以3T3-L1脂肪前細胞分化為脂肪細胞的過程中,在不同時間加入PEDF共同作用,藉由觀察脂肪油滴生成分化的情形,評估PEDF對脂肪細胞分化抑制及脂肪油滴代謝的影響。在動物實驗結果部分發現,PEDF能有效減緩小鼠因HF誘發增加的體重、抑制及減緩脂肪的堆積,同時具有降血糖、血脂、改善胰島素耐受性及降低脂肪組織內巨噬細胞浸潤的發炎反應;另外對於褐色脂肪(Brown adipose tissue; BAT)方面,PEDF能夠增加BAT的表現,藉此提高身體代謝的功能;在肝臟方面,PEDF可以減少肝臟內脂肪堆積、纖維化及氧化性壓力(Reactive oxygen stress; ROS)。在細胞實驗結果部分,PEDF能有效減少脂肪油滴分化及生成。藉由流式細胞及西方墨點法的分析,進一步發現,PEDF可以藉由調控前脂肪細胞的細胞週期,延緩細胞由G0G1進入S時期,經此來達到抑制脂肪細胞分化及生成,同時PEDF也具有促使脂肪分解(Lipolysis),降低脂肪細胞總量。將脂肪組織及細胞蛋白質萃取物,藉由西方墨點法的分析,結果顯示PEDF可能是透過抑制mTOR-S6K的活化,進一步抑制PPAR-γ、CEBP-α、CEBP-β等脂肪生成相關轉錄因子的表現。綜合上述的研究結果顯示,在肥胖代謝相關疾病中,PEDF可以提供未來一個新的治療選擇。

Obesity is the modern disaster of human being, and is the major cause of many metabolic diseases and cardiovascular diseases. It presents with metabolic disorders such as hyperglycemia, hyperlipidemia, and insulin resistance. Previous studies reveal that the oxidative stress and inflammation in the adipose tissues take the responsibility of metabolic diseases, and they also concentrate in the differentiation of adipocytes and the dynamic balance of lipolysis. Pigment epithelium-derived factor (PEDF), a well-known cytokine which isolate from retina pigment epithelial cells, has the multiple function of potential neuronal differentiating activity, anti-neoplasm, smooth muscle growth inhibition, and anti-inflammation. Further studies also demonstrate that the adipose tissue is not only the source of PEDF, but also the target of this unique protein. The aim of this study is to investigate the role of PEDF to inhibit obesity and anti-adipogenesis. In vivo, we feed C57BL/6 mice with high fat (HF) diet as animal model. The animals are divided into HF fed with PEDF group and DIO (diet-induced obesity) with PEDF group, compared with control group, to study the anti-obesity effect of PEDF. In vitro, we use 3T3-L1 preadipocyte as cell model, and treat with PEDF during differentiation and after differentiation. By lipid droplet formation, we inspect the inhibition effect of PEDF to adipocyte differentiation and lipid metabolism such as lipolysis and lipogenesis. In animal study, the data shows that PEDF effectively decreases body weight gain, suppresses and slow down the obesity, decreases white adipose tissue (WAT) formation and inflammation. It also improves insulin resistance, hyperglycemia and decrease serum lipid. In brown adipose tissue (BAT), PEDF decreases the lipid accumulation. In liver, our study proved that PEDF decreases lipid formation and fibrosis. In vitro study, PEDF diminishes lipid droplet formation after 3T3-L1 differentiations. We also found out that PEDF prolongs the cell cycle progress and promotes lipolysis, which may work through mTOR-S6K pathway and subsequent transcription factors such as PPAR-γ, CEBP-α, and CEBP-β. These findings prove the hypothesis that PEDF diminishes white adipocyte formation, promotes lipid metabolism, and subsequent weight loss in mice. In conclusion, PEDF protects against high-fat diet-induced obesity and metabolic disorders in mice, and inhibits adipocyte differentiation in 3T3-L1 cells. It provides a new treatment trend for obesity in the future.



目錄
口試委員審定書………………………………………………………………………I
致謝……………………………………………………………………………..…….II
目錄 III
圖目錄 VI
中文摘要 VIII
英文摘要 IX
壹、 前言 1
一、 簡介肥胖及衍生的相關疾病 1
二、 肥胖與代謝症候群(METABOLIC SYNDROME) 2
三、 高脂食物、肥胖與脂肪組織(ADIPOSE TISSUE) 2
四、 脂肪分化過程的調控 3
五、 脂質分解是減少肥胖,促進代謝的重要因素 3
六、 肝臟(LIVER)與肥胖 4
七、 骨骼肌(SKELETAL MUSCLE)與肥胖 4
八、 肥胖與MTOR(MAMMALIAN TARGET OF RAPAMYCIN)/S6K PATHWAY相關性 4
九、 PEDF(PIGMENT EPITHELIUM-DERIVED FACTOR)介紹 5
十、 研究動機及實驗設計 6
貳、 實驗材料設計與方法 8
實驗材料及儀器設備 8
一、 儀器設備 8
二、 實驗材料與試劑 8
1. 肥胖模式 8
2. 小鼠血液生化值及甘油(GLYCEROL)檢測 8
3. 細胞株………….. 9
4. 3T3-L1脂肪前軀細胞分化試劑 9
5. 石蠟切片包埋 9
6. 冷凍切片包埋 10
7. 蘇木紫-伊紅染色(HEMATOXYLIN& EOSIN STAIN) 10
8. 免疫組織化學染色(IMMUNOHISTOCHEMISTRY) 10
9. 蛋白質萃取(PROTEIN EXTRACTION) 1X LYSIS BUFFER PROTEINASE INHIBITOR .COCKTAIL BCA PROTEIN ASSAY (SIGMA)………………………..10
10. 馬森三色染劑(MASSON TRICHROME STAIN) 10
11. 天狼星紅苦味酸染色(PICROSIRIUS RED STAIN) 11
12. 西方墨點法(WESTERN BLOT) 11
13. 流式細胞儀分析(FLOW CYTOMETRY ANALYSIS) 13
14. 結晶紫(CRYSTAL VIOLET)染色 13
15. 油紅組織(OIL RED O)染色 蘇丹紅粉末(SIGMA) 2-PROPANOL 13
16. ROS活性氧類偵測 DHE (SIGMA) DCFDA (SIGMA) 13
三、實驗設計 13
1. 肥胖小鼠模式: 13
2. 細胞培養 14
3. 石蠟切片包埋 15
4. 冷凍切片包埋 15
5. 蘇木紫-伊紅染色(HEMATOXYLIN& EOSIN STAIN) 15
6. 免疫組織化學染色(IMMUNOHISTOCHEMISTRY) 16
7. OIL RED O STAIN (ORO染色): 16
8. 天狼星紅苦味酸染色(PICROSIRIUS RED STAIN) 17
9. 西方墨點法(WESTERN BLOT) 17
10. 流式細胞儀分析(FLOW CYTOMETRY ANALYSIS) 18
11. 結晶紫(CRYSTAL VIOLET)染色 18
12. 油紅組織(OIL RED O; ORO)染色 18
13. 馬森三色染劑(MASSON TRICHROME STAIN) 19
14. 小鼠代謝實驗(METABOLIC TEST) 19
15. 胰島素耐受性測試(IPITT) 19
16. 葡萄糖耐受性測試(IPGTT) 19
17. ELISA 20
18. 統計分析…………………………………………………………………….20
參、 結果RESULT: 21
一、 PEDF具有減緩因高脂餵食誘發體重增加的作用 21
二、 PEDF減少體組成的脂肪含量 21
三、 PEDF改善血液生化值 22
四、 PEDF會增加能量消耗(ENERGY EXPENDITURE)及恢復小鼠活動力(REARING ACTIVITY) 22
五、 PEDF有助維持血糖代謝的恆定性 22
六、 PEDF對胰島素及肥胖相關賀爾蒙的影響 23
七、 PEDF降低HF DIET誘發的脂肪細胞面積 23
八、 PEDF增加BAT(BROWN ADIPOSE TISSUE)的數量和活性 23
九、 PEDF降低發炎反應 24
十、 PEDF抑制3T3-L1脂肪細胞分化 24
十一、PEDF延緩3T3L1脂肪前驅細胞週期進行 25
十二、PEDF抑制脂肪細胞生成(ADIPOGENESIS)轉錄因子表現 26
十三、PEDF抑制MTOR-S6K 路徑 26
十四、PEDF促進脂肪油滴分解 26
十五、PEDF減少3T3-L1脂肪前驅細胞的ROS的表現 27
十六、PEDF減緩高脂食物引起的肝臟傷害及減少脂肪肝 27
十七、PEDF降低肝臟纖維化程度 27
十八、PEDF減少PA對HEPG2肝細胞的毒性及脂肪油滴生成情形 28
十九、PEDF回復HEPG2的ROS表現 28
二十、PEDF回復HEPG2因PA處理後誘發葡萄萄吸收功能受損的情形 28
二十一、PEDF減少PA對C2C12骨骼肌細胞的毒性 29
二十二、PEDF回復C2C12因PA處理後誘發葡萄萄吸收功能受損的情形 29
肆、 討論DISCUSSION: 30
伍、 結論: 33
陸、 附圖: 34
柒、 文獻REFERENCES: 68
圖表目錄
圖表 1本研究的目標 34
圖表 2 實驗小鼠的分組實驗。 35
圖表 3細胞實驗模式 36
圖表 4 PEDF有效減緩體重增加的幅度 37
圖表 5 PEDF減少體組成的脂肪含量。 38
圖表 6 PEDF增加能量消耗(ENERGY EXPENDITURE)。 39
圖表 7 PEDF會恢復小鼠活動力(REARING ACTIVITY)。 40
圖表 8 PEDF有助維持血糖代謝的恆定性。 41
圖表 9 PEDF對胰島素及肥胖相關賀爾蒙的影響。 42
圖表 10 PEDF降低HF誘發的脂肪細胞面積 43
圖表 11 PEDF回復HF造成BAT(BROWN ADIPOSE TISSUE)中細胞數量的減少、油滴的堆積及COXIV的表現 44
圖表 12 PEDF降低HF造成脂肪組織中的發炎反應。 45
圖表 13 WAT組織發炎相關蛋白表現量受 PEDF影響。 46
圖表 14 PEDF抑制脂肪細胞分化 47
圖表 15 PEDF對MDI分化後油滴生成的影響,PEDF濃度越高,脂肪分化及油滴生成抑制的效果越顯著。 48
圖表 16 PEDF延緩3T3L1脂肪前驅細胞週期進行。 49
圖表 17 PEDF對細胞分化週期的影響。 50
圖表 18 PEDF影響了細胞週期轉調控因子表現 51
圖表 19 PEDF抑制IWAT組織中脂肪細胞生成(ADIPOGENESIS)轉錄因子表現 52
圖表 20 PEDF抑制3T3-L1 PREADIPOCYTE脂肪細胞生成(ADIPOGENESIS)轉錄因子表現。 53
圖表 21 PEDF抑制MTOR-S6K 路徑。 54
圖表 22 PEDF促進脂肪油滴分解 55
圖表 23 PEDF減少3T3-L1脂肪前驅細胞的ROS的表現 56
圖表 24 PEDF有保護肝臟的作用 57
圖表 25 PEDF降低肝臟纖維化程度 58
圖表 26 PEDF減少PA對HEPG2肝細胞的毒性。 59
圖表 27 PEDF減少PA促進HEPG2肝細胞油滴的生成。 60
圖表 28 PEDF有助經PA處理HEPG2細胞進行LIPOLYSIS 61
圖表 29 PEDF會減少HEPG2的ROS表現量 62
圖表 30 PEDF回復HEPG2因PA處理後誘發葡萄糖吸收功能受損的情形 63
圖表 31 PEDF減少PA對C2C12細胞(MYOBLAST)的毒性。 64
圖表 32 PEDF回復C2C12因PA處理後誘發葡萄糖吸收功能受損的情形….…..65
表格 1 (TABLE 1)小鼠高脂食物的配方………………………………….…………...66
表格 2 (TABLE 2)各項生值…………………...…………………………….…………67





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