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研究生:洪廷芸
研究生(外文):Ting-Yun Hung
論文名稱:母親處理DNA甲基轉移酶抑制劑對ApoE-/-小鼠子代動脈粥狀硬化發展和脂質代謝之研究
論文名稱(外文):The study of maternal DNA methyltransferase inhibitor treatment on the development of atherosclerosis and lipid metabolism in adult Apolipoprotein E deficient mice offspring
指導教授:林甫容
指導教授(外文):Fu-Jung Lin
口試委員:黃青真呂紹俊蘇慧敏蔡幸真
口試委員(外文):Ching-Jang HuangShao-Chun LuHui-Min SuHsing-Chen Tsai
口試日期:2020-07-30
學位類別:碩士
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:2020
畢業學年度:108
語文別:中文
論文頁數:163
中文關鍵詞:發展規劃DNA甲基轉移酶抑制劑動脈粥狀硬化T細胞
外文關鍵詞:Fetal programming5-aza-2′-deoxycytidineatherosclerosisT cell
DOI:10.6342/NTU202003815
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發展規劃 (Developmental programming) 指的是胎兒和新生兒暴露的環境將對成年後的生理功能和疾病風險產生深遠的影響。過去的研究指出,孕婦的營養過剩會造成子代的心血管和代謝方面的問題,其中可能的機制是透過表觀遺傳學。我們實驗室先前研究發現,懷孕前後誘發高膽固醇血症的 ApoE-/- 母鼠所生出的子代在成年後較容易罹患非酒精性脂肪肝和動脈粥狀硬化,且基因表現改變與DNA甲基化程度相關。故本研究的假說為:親代母鼠施打DNA 甲基轉移酶抑制劑 5-aza-2′-deoxycytidine (5Aza-dC) 可以藉由調控DNA甲基化的程度而減緩子代動脈粥狀硬化的發展。
我們使用 ApoE -/- 母鼠餵食控制組飲食 (Control diet, CD),並在懷孕前以及哺乳期間施打 PBS 或 5Aza-dC,親代母鼠共有二組:CD + PBS 以及 CD + 5Aza-dC。所產出的子代在離乳後統一餵食 WD (分別為PBS + CW、5Aza-dC + CW)。結果發現在 16 週齡,5Aza-dC + CW 組子代雄鼠的動脈粥狀硬化程度與 PBS + CW 組相比顯著減緩;5Aza-dC + CW 組子代雌鼠與 PBS + CW 組相比下,動脈粥狀硬化也有減緩的趨勢。且伴隨著雄和雌鼠的脾臟中CD4+ T細胞比例、雄鼠脾臟中CD8+ T 細胞和以及雌鼠淋巴結中促發炎 Th1 細胞的比例與PBS + CW組相比顯著下降。另外, 5Aza-dC + CW 組與 PBS + CW 組雄鼠相比,血清及肝臟三酸甘油酯的累積均較低,但是並沒有改變參與肝臟脂質形成、氧化及運送的轉錄因子及相關基因的 mRNA 表現量。因此,我們推測親代母鼠施打 5Aza-dC 可能使子代的脂質吸收能力下降進而減緩肝臟脂質堆積。為了印證此假說,第二個部分的實驗我們使用ApoE +/- 公鼠餵食 WD,探討直接施打 5Aza-dC 是否會影響小鼠對於脂質的吸收。實驗結果顯示,在攝食量相同的情形下,施打5Aza-dC公鼠糞便排出的三酸甘油酯含量上升。且與施打 PBS 組相比,施打5Aza-dC公鼠在餐後的三酸甘油酯吸收及小腸乳糜微粒的分泌皆顯著下降。探討其可能分子機制,我們發現施打5Aza-dC會顯著下調公鼠空腸中的 Slc27a4 (FATP4) 以及 Mttp 的 mRNA 表現量,並可能因此降低小腸乳糜微粒的分泌。
綜合以上研究可知,親代母鼠施打 5Aza-dC 可能藉由改變脾臟 CD8+ T 細胞、CD4+ T 細胞及淋巴結 Th1 細胞的比例以減緩子代的動脈粥狀硬化;另外,親代母鼠施打 5Aza-dC 可能藉由降低脂質的吸收而減少子代肝臟的三酸甘油酯堆積。此假說也由施打 5Aza-dC的 ApoE +/- 公鼠有降低小腸的乳糜微粒分泌及減少三酸甘油酯吸收得到印證。後續的研究會著重在 5Aza-dC 是否會透過母體效應影響子代脂質的吸收能力以及探討其中的機制。
The environment encountered in fetal and neonatal life exerts a profound influence on physiological function and risk of disease in adult life. A number of epidemiologic and animal studies indicated that maternal over-nutrition during pregnancy leads to the development of cardiovascular and metabolic disease in the adult offspring likely through alterations in DNA methylation. However, the mechanisms underlying the fetal programming of adult disease are still unclear. We aim to investigate whether the maternal treatment of DNA methyltransferase inhibitor (5-aza-2′-deoxycytidine, 5Aza-dC) could ameliorate the development of atherosclerosis in the offspring.
In our study, ApoE -/- dams were fed with a control diet (CD), and 5Aza-dC was administrated before pregnancy and during lactation. All offspring were fed with a WD after weaning. Maternal 5Aza-dC treatment ameliorated the development of atherosclerosis in offspring likely through decreasing the CD8+ T cell and CD4+ T cell population of spleen and Th1 cell population in lymph nodes. Furthermore, we showed that upon maternal CD feeding, 5Aza-dC administration decreased hepatic triglyceride accumulation without affecting hepatic de novo lipogenesis, lipid oxidation and lipid transport in male offspring. To examine if 5Aza-dC treatment directly alters lipid metabolism, WD-fed ApoE+/- mice were treated with 5Aza-dC for 6 weeks. Compared to PBS-treated group, 5Aza-dC administration remarkably lowered triglyceride secretion from intestine to circulation in response to an acute dietary fat challenge. In addition, fecal triglyceride levels were significantly higher in 5Aza-dC-treated group compared with those in PBS-treated group. We also found that 5Aza-dC treatment significantly decreased Slc27a4 (FATP4) and Mttp mRNA expression in jejunum of the mice.
Taken together, maternal 5Aza-dC treatment may ameliorate the atherosclerosis through altering lymphocyte population in spleen and lymph nodes of adult offspring. Furthermore, maternal 5Aza-dC treatment may reduce hepatic triglyceride levels through reducing lipid absorption in offspring. Future research will be focused on whether and how triglyceride absorption is affected by maternal 5Aza-dC treatment.
摘要 i
Abstract iii
代號與縮寫對照表 v
總目錄 ix
圖目錄 xv
表目錄 xvii
第一章 緒論 1
第一節 前言 1
第二節 文獻回顧 3
一、代謝症候群 3
二、動脈粥狀硬化 4
三、動脈粥狀硬化病程 5
四、動脈粥狀硬化動物模式 7
1. Apolipoprotein E 基因剔除 (ApoE -/-) 小鼠 8
五、免疫反應與動脈粥狀硬化疾病之關係 9
1. 單核球以及巨噬細胞與動脈粥狀硬化疾病形成之關係 9
2. T細胞與動脈粥狀硬化疾病形成之關係 11
2.1 CD4+ T 細胞亞群 11
2.1.1 Th1輔助細胞 (Helper T type 1 cells) 12
2.1.2 Th2輔助細胞 (Helper T type 2 cells) 12
2.1.3 Th17輔助細胞 (Helper T type 17 cells) 13
2.1.4 調節型T細胞 (Regulatory T cell) 13
六、肝臟脂質代謝之調控 15
1. 循環脂質的攝取 16
2. de novo lipogenesis 17
3. 脂肪酸氧化 17
4. VLDL 的排出 18
七、腸道脂質吸收之調控 18
八、發展規劃學說 21
九、表觀遺傳學 21
1. 甲基化 22
1.1 DNA甲基轉移酶抑制劑 5-Aza-2′-deoxycytidine (5Aza-dC) 22
2. 組蛋白修飾 24
3. MicroRNA干擾 25
第三節 研究假說與實驗架構 27
一、研究假說 27
二、實驗架構 27
第二章 母鼠施打5Aza-dC對子代心血管疾病及代謝之影響 29
第一節 前言與實驗設計 29
一、前言 29
二、實驗設計 30
第二節 材料與方法 31
一、實驗動物 31
二、飼料配製 31
1. 控制組飲食 (Control diet, CD) 31
2. 西方飲食 (Western diet, WD) 31
三、親代實驗排程 33
四、子代實驗排程 33
五、禁食血清樣本收集 33
六、腹腔注射葡萄糖耐受性測試 (Intraperitoneal glucose tolerance test, IPGTT) 33
1. 藥品配製 33
2. 實驗流程 34
七、5Aza-dC的配置 34
八、動物犧牲及樣品收集 34
1. 器具與溶液配置 34
2. 犧牲流程 35
九、血清生化分析 35
1. 三酸甘油酯 (triglyceride, TG) 測定 35
十、粥狀硬化斑塊分析 (Atherosclerotic lesion analysis) 36
1. ORO 染劑配製 36
2. En face染色步驟 36
3. 主動脈竇 (aortic sinus) 橫斷面分析 37
4. 主動脈竇染色步驟 37
十一、脾臟細胞分析之取得與分離 38
1. 實驗材料 38
2. 實驗方法 38
十二、骨髓衍生巨噬細胞 (Bone marrow-derived macrophages, BMDMs) 之取得與分離 38
1. 實驗材料 38
2. 實驗方法 39
十三、血液單核細胞 (Peripheral blood mononuclear cells, PBMCs) 分析 39
1. 血液單核細胞之分離 39
1.1 實驗材料 39
1.2 實驗方法 40
2. 血液單核細胞計數與比例分析 40
2.1實驗抗體及溶液 40
2.2實驗方法 41
十四、細胞凋亡分析 41
1. 實驗套組 41
2. 實驗方法 41
十五、淋巴結 (Lymph nodes) 細胞分析 42
1. 淋巴結細胞之取得與分離 42
1.1實驗材料 42
1.2實驗方法 42
2. 淋巴結細胞計數與比例測定 42
十六、CD4+ T細胞的負選擇前之細胞比例測定 43
1. 實驗抗體及溶液 43
2. 實驗方法 43
十七、CD4+ T細胞的負選擇 (Negative selection of CD4+ T cells) 43
1. 實驗抗體及溶液 43
2. 實驗方法 44
十八、T細胞再刺激 (Re-stimulation) 44
1. 實驗溶液 44
2. 實驗方法 45
十九、淋巴結細胞之細胞介素 (Cytokine) 及轉錄因子比例測定 45
1. 實驗抗體及溶液 45
2. 實驗方法 45
二十、肝臟組織切片染色 46
二十一、肝臟脂質含量分析 46
1. 肝臟脂質萃取 46
2. 肝臟三酸甘油酯測定 47
二十二、基因 mRNA 表現分析 47
1. 肝臟總 RNA 抽取 47
2. 去除DNA 48
3. Total RNA 反轉錄為cDNA 48
4. Quantitative Real-time PCR 49
二十三 、統計分析 49
第三節 實驗結果 52
一、親代母鼠的體重及血液生化指標 52
二、施打 5Aza-dC 對母鼠的肝毒性及骨隨衍生巨噬細胞 (Bone marrow-derived macrophages, BMDMs) 和脾臟細胞凋亡之影響 52
三、子代離乳後至犧牲期間的體重變化 52
四、子代離乳後至犧牲期間的血脂變化 53
五、腹腔注射葡萄糖耐受性試驗 53
六、腹腔注射胰島素耐受性試驗 53
七、子代 16 週齡犧牲組織重量 54
八、子代動脈粥狀硬化分析 54
九、子代的血液周邊單核細胞 (Peripheral blood mononuclear cells, PBMCs) 組成分析 54
十、子代脾臟中免疫細胞之組成分析 55
十一、子代淋巴結中免疫細胞之組成分析 56
十二、子代肝臟脂質含量分析 56
十三、子代肝臟組織切片 57
十四、子代肝臟mRNA表現量分析 57
1. 三酸甘油酯代謝相關基因表現量 57
1.1 肝臟接收 FFA 的相關基因 57
1.2肝臟脂質合成 (DNL) 的相關基因 57
1.3 肝臟脂質氧化的相關基因 58
1.4肝臟 VLDL 排出的相關基因 58
第四節 討論 84
一、親代母鼠施打5Aza-dC不會造成 BMDMs 和脾臟細胞凋亡 84
二、親代母鼠施打5Aza-dC對子代生理指標之影響 84
1. 親代母鼠施打5Aza-dC對子代體重、血液脂質含量及組織重量之影響 84
2. 親代母鼠施打5Aza-dC對子代血糖調控之影響 85
三、親代母鼠施打 5Aza-dC對子代動脈粥狀硬化之影響 86
1. 親代母鼠施打 5Aza-dC 顯著降低 CW 組子代動脈粥狀硬化斑塊面積 86
2. 親代母鼠施打 5Aza-dC 對於子代免疫細胞之調節 87
2.1 親代母鼠施打 5Aza-dC 對於子代 CD4 + T 細胞及 Th1 之影響 88
2.2 親代母鼠施打 5Aza-dC 對於子代 Th17 細胞之影響 89
2.3 親代母鼠施打 5Aza-dC 對於子代 Treg 之影響 90
2.4 親代母鼠施打 5Aza-dC 對於子代 CD8 + T 細胞之影響 91
2.5 親代母鼠施打 5Aza-dC 對於子代 B 細胞之影響 92
2.6 親代母鼠施打 5Aza-dC 對於子代單核球及巨噬細胞之影響 93
四、親代母鼠施打 5Aza-dC對子代代謝之影響 95
1. 親代母鼠施打5Aza-dC顯著降低CW組子代雄鼠肝臟三酸甘油酯堆積 95
第五節 結論 98
第三章 公鼠施打5Aza-dC對脂質吸收之影響 99
第一節 前言與實驗設計 99
一、前言 99
二、實驗設計 99
第二節 材料與方法 100
一、實驗動物 100
二、飼料配製 100
三、動物飼養 100
四、5Aza-dC的配置 100
五、血清生化分析 101
1. 三酸甘油酯 (triglyceride, TG) 測定 101
2. 膽固醇 (TC) 測定 101
六、糞便脂質含量分析 101
1. 糞便脂質萃取 101
2. 糞便三酸甘油酯測定 101
3. 糞便膽固醇測定 102
七、餐後三酸肝油酯之吸收分析 102
八、餐後小腸三酸甘油酯之分泌測定 102
九、動物犧牲及樣品收集 103
1. 器具與溶液配置 103
2. 犧牲流程 103
十、肝臟脂質含量分析 104
1. 肝臟脂質萃取 104
2. 肝臟三酸甘油酯測定 104
3. 肝臟膽固醇測定 104
十一、小腸、肝臟及性腺脂肪組織切片染色 104
十二、基因mRNA表現量分析 105
1. 空腸總 RNA 抽取 105
2. 去除DNA 105
3. Total RNA反轉錄為cDNA 105
4. Quantitative real time PCR 105
十三、統計分析 105
第三節 實驗結果 106
一、ApoE +/- 公鼠的體重及攝食量變化 106
二、ApoE +/- 公鼠的血清及糞便脂質含量變化 106
三、餐後三酸甘油酯吸收之分析 106
四、餐後小腸三酸甘油酯分泌之分析 106
五、ApoE +/- 公鼠 15 週齡犧牲組織重量 107
六、ApoE +/- 公鼠 15 週齡血液、肝臟及糞便脂質含量分析 107
七、ApoE +/- 公鼠 15 週齡肝臟、性腺脂肪及十二指腸 H & E 染色分析 107
八、ApoE +/- 公鼠空腸基因mRNA表現量分析 107
第四節 討論 122
一、ApoE +/- 公鼠直接施打 5Aza-dC 對於餐後三酸甘油酯吸收之影響 122
二、ApoE +/- 公鼠直接施打 5Aza-dC 在 15 週齡犧牲的各項指標分析 123
1. 肝臟脂質含量分析 123
2. 血液脂質含量分析 124
3. 小腸切片分析 125
三、ApoE +/- 公鼠施打 5Aza-dC 使空腸的 Slc27a4 (FATP4) 及 Mttp 的mRNA表現量下降 126
四、腸道中 MTTP 表現量調控之討論 128
第五節 結論 130
第四章 總結 131
附錄 133
第五章 參考文獻 148
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