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研究生:王韻涵
研究生(外文):Yun-HanWang
論文名稱:探討ADAR2在代謝疾病中的角色
論文名稱(外文):Exploring the role of ADAR2 in metabolic disorder
指導教授:陳韻雯陳韻雯引用關係
指導教授(外文):Yun-Wen Chen
學位類別:碩士
校院名稱:國立成功大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2020
畢業學年度:108
語文別:英文
論文頁數:69
中文關鍵詞:ADAR2代謝疾病非酒精性脂肪肝
外文關鍵詞:ADAR2metabolic disordernon-alcoholic fatty liver disease
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代謝疾病會破壞正常代謝的現象,包括2型糖尿病(T2DM)和非酒精性脂肪肝(NAFLD)。 NAFLD是由肝臟中脂肪堆積引起的慢性疾病。腺苷到肌苷(A到I)編輯是一種RNA的轉錄後修飾,由作用在RNA上的腺苷脫氨酶 (ADAR)催化。 ADAR種類包含ADAR1、ADAR2和ADAR3。先前研究表明,高葡萄糖會誘導胰臟INS-1β細胞中ADAR2表現量上升。 ADAR2可能在代謝調節中扮演很重要的角色。在這項研究中,我們主要探討ADAR2在代謝疾病進程中的角色。我們在公及母鼠5週齡大時,用野生型(WT)和ADAR2基因剃除(ADAR2-KO)小鼠為動物模型,餵食一般飲食或高脂飲食(HFD)12週。測量每日食物攝取量、飲水量和體重。並且分析代謝相關生化指標。我們也研究了代謝相關途徑(例如:胰島素信號傳遞途徑、脂肪酸合成、糖質新生和肝醣儲存量)。飼食HFD的ADAR2-KO公鼠的體重低於飼餵HFD的WT小鼠。用HFD餵養的ADAR2-KO公鼠改善葡萄糖不耐受性及胰島素阻抗情形,以及糖質新生減少和肝醣儲存增加。飼餵HFD的ADAR2-KO公鼠也被發現血清中的triglycerides (TG)、游離脂肪酸和low-density lipoprotein (LDL)降低。飼餵HFD的ADAR2-KO公鼠肝臟油滴減少、TG含量降低。有趣的是,餵食HFD的ADAR2-KO公鼠肝臟中和脂肪生成相關蛋白,像是sterol regulatory element-binding protein 1 (SREBP-1)、acetyl-coA carboxylase (ACC)、fatty acid synthase (FAS)和stearoyl-CoA desaturase1 (SCD1)的表現量較低。我們還發現餵食HFD的ADAR2-KO公鼠是透過AMP-activated protein kinase (AMPK)信號傳導路徑使肝臟中的脂肪生成和糖質新生減少。此外,與對照組相比,在餵食HFD的ADAR2-KO公鼠肝臟中觀察到insulin-like growth factor binding protein-7 (IGFBP7)蛋白表現量降低。這些結果提供了新的發現,ADAR2-KO改善了HFD誘導的代謝功能障礙,並避免了肝臟TG的堆積。
Metabolic disorders are diseases that disrupt normal metabolism, including type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). NAFLD is a chronic disease caused by a build-up of fat in the liver. Adenosine-to-inosine (A-to-I) editing is a post-transcriptional modification of RNA, catalyzed by adenosine deaminase acting on RNA (ADAR). ADAR family contains ADAR1, ADAR2, and ADAR3. Previous study showed that high glucose induced upregulated ADAR2 expression in pancreatic INS-1 β cells. ADAR2 may thus play an important role in metabolic regulation. In this study, we aimed to investigate the role of ADAR2 in the metabolic disorder progression. We fed male and female mice with standard chow or high-fat-diet (HFD) in wild type (WT) and ADAR2-knockout (ADAR2-KO) mice for 12 weeks starting at the age of 5 weeks. Daily food intake, water intake, and body weight were measured. The analysis of metabolic parameters was determined. Metabolic pathways (e.g. Insulin signaling pathway, fatty acid synthesis, gluconeogenesis, and glycogen storage) were studied. ADAR2-KO male mice fed with HFD had lower body weight compared with WT fed with HFD. ADAR2-KO male mice fed with HFD showed improved glucose tolerance, insulin resistance, as well as decreased gluconeogenesis and increased glycogen storage. ADAR2-KO male mice fed with HFD displayed a lipid profile with decreased plasma triglycerides (TG), free fatty acid and low-density lipoprotein (LDL). ADAR2-KO male mice fed with HFD displayed reduced liver lipid droplets in concert with decrease hepatic TG content. Interestingly, there was lower expression of de novo lipogenesis-related protein, such as sterol regulatory element-binding protein 1 (SREBP-1), acetyl-coA carboxylase (ACC), fatty acid synthase (FAS), and stearoyl-CoA desaturase1 (SCD1) in the liver of ADAR2-KO male mice fed with HFD. We also found that ADAR2-KO male mice fed with HFD had a reduced lipogenesis and gluconeogenesis via AMP-activated protein kinase (AMPK) signaling in the liver. Moreover, decreased insulin-like growth factor binding protein-7 (IGFBP7) expression was observed in the liver of ADAR2-KO male mice fed with HFD compared with that of control. These results provide novel evidence that ADAR2-KO improved HFD-induced metabolic dysfunctions and prevented liver against TG accumulation.
中文摘要 Abstract in Chinese…………………………………………………………………….I
Abstract in English…………………………….……......................................................................III
Abbreviations…………………………….....................................................................................VII
List of tables……………………………………….......................................................................X
List of figures…………………………………………...................................................................XII
Introduction
1. Metabolic disorders……………………………………………………………………………….2
1.1 Obesity…………………………………………………………………………………...2
1.1.1 Epidemiology………………………………………………………………………...2
1.1.2 Pathophysiology……………………………………………………………………...2
1.2 Diabetes mellitus…………………………………………………………………………3
1.2.1 Epidemiology………………………………………………………………………...4
1.2.2 Pathophysiology……………………………………………………………………...4
1.3 Non-alcoholic fatty liver disease (NAFLD)
1.3.1 Epidemiology………………………………………………………………………...5
1.3.2 Risk factors…………………………………………………………………………...5
1.3.3 Progression of NAFLD……………………………………………………………….6
1.4 Insulin resistance and NAFLD…………………………………………………………...6
1.4.1 Epidemiology………………………………………………………………………...6
1.4.2 Mechanisms…………………………………………………………………………..7
2. RNA editing………………………………………………………………………………………7
2.1 Adenosine-to-inosine (A-to-I) editing……………………………………………………8
2.2 Adenosine deaminase acting on RNA (ADAR)………………………………………….8
2.3 RNA editing and human disease………………………………………………………….8
3. Hepatic metabolism………………………………………………………………………………9
3.1 Glucose metabolism……………………………………………………………………...9
3.1.1 Insulin signaling……………………………………………………………………...9
3.1.2 Gluconeogenesis…………………………………………………………………….10
3.2 Lipid metabolism………………………………………………………………………..10
3.2.1 Lipogenesis……………………………………………………………………………..10
4. IGFBP7………………………………………………………………………………………….11
5. Aim of this study………………………………………………………………………………..11
Materials and Methods
1. Materials………………………………………………………………………………………..13
2. Recipes…………………………………………………………………………………………16
3. Methods
3.1 Animals and the obesity animal models………………………………………………...19
3.2 Genotyping……………………………………………………………………………...19
3.3 Glucose metabolism tests……………………………………………………………….19
3.4 Fasting blood glucose, insulin levels, and HOMA-IR in plasma……………………….20
3.5 Lipid metabolism biochemical indicators in plasma……………………………………21
3.6 Organs weight measurements…………………………………………………………...22
3.7 Body composition and energy expenditure……………………………………………..22
3.8 Organs lipid droplets……………………………………………………………………22
3.9 Liver glycogen content………………………………………………………………….23
3.10 Protein of liver tissue preparations……………………………………………………...23
3.11 Western blots……………………………………………………………………………23
3.12 Statistics………………………………………………………………………………...24
Results…………………………………………………………….………………………………25
Conclusion and Discussion…………………………….................................................................31
References……………………………………………………….…..............................................37
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