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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳培哲老師(Pei-Jer Chen) | |
dc.contributor.author | Ya-Wen Cheng | en |
dc.contributor.author | 鄭雅紋 | zh_TW |
dc.date.accessioned | 2021-05-19T17:56:51Z | - |
dc.date.available | 2021-08-26 | |
dc.date.available | 2021-05-19T17:56:51Z | - |
dc.date.copyright | 2016-08-26 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-08-17 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/7874 | - |
dc.description.abstract | 近年來,由於全球肥胖盛行率的增加,與肥胖關係密切的非酒精性脂肪性肝疾病逐漸成為已開發國家中最普遍的肝臟疾病之ㄧ。值得注意的是,肥胖或非酒精性脂肪性肝疾病所引發的肝癌有男性高於女性的趨勢,此現象與B型肝炎病毒引發的肝癌好發在男性病患十分相似。因此我們猜測非酒精性脂肪性肝疾病是否像B型肝炎病毒一樣,可能受男性特定因子影響而導致其性別差異。根據研究指出,受醣類刺激而活化的脂肪生成路徑,在非酒精性脂肪性肝疾病的病患中異常增加,推測為影響非酒精性脂肪性肝疾病脂肪變性的主要途徑。本篇論文因此針對脂肪生成是否藉由調控男性特定致癌的轉錄因子,即雄性激素受體的活性,進而促進了男性患者的肝臟病變之可能性加以探討。
利用果糖餵食公鼠以增進肝臟的脂肪生成後,也發現肝臟的雄性激素受體之轉錄活性顯著上升。若將脂肪酸合成酶抑制劑注射到公鼠體內,不僅會抑制果糖對脂肪生成的影響,同時也抑制了雄性激素受體的轉錄活性。另外在細胞實驗中,不論是使用脂肪生成抑制劑或是抑制脂肪生成重要酵素的基因表現,也驗證了脂肪生成對雄性激素受體之轉錄活性的重要性。我們進一步發現脂肪生成是藉由調控二醯基甘油的生成以增進雄性激素受體的轉錄活性。二醯基甘油是生成多種脂肪分子的重要結構,同時也做為訊息傳導分子以影響許多蛋白的功能,例如活化蛋白激酶C。有趣的是,我們發現脂肪生成所產生的特定二醯基甘油亞型,並非經由蛋白激酶C去調控雄性激素受體的轉錄活性,確切調控機制仍有待研究。 總結本篇論文發現了一個脂肪生成調控雄性激素受體的新穎機制,實驗結果將可能做為解釋非酒精性脂肪性肝疾病引發之肝癌中,男性比例高於女性的分子機制之一。 | zh_TW |
dc.description.abstract | Nonalcoholic fatty liver disease (NAFLD) becomes the most common liver disease in developed countries due to the global epidemic of obesity. Notably, obesity or NAFLD induced hepatocellular carcinoma (HCC) showed male preference, similar to the hepatitis virus induced HCC. It raised a possibility that a male specific factor could be involved in the NAFLD pathogenesis. As the hepatic de novo lipogenesis (DNL) was identified as the major source contributing to the lipid biogenesis in severe metabolic diseases, this study aims to investigate if DNL could via regulating the function of a male specific oncogenic transcriptional factor, the androgen receptor (AR), as a possible mechanism for male prevalence of NAFLD diseases.
The C57BL/6 male mice fed with high carbohydrate diet (HCD) were used to examine the effect of DNL for the transcriptional activity of AR. The results showed HCD-increased DNL could stimulate the transcriptional activity of AR, which could be abolished by the inhibitor for fatty acid synthase (FASN). This has been validated in the cell culture based assay system, showing a decrease of AR activity by suppressing the lipogenesis either by inhibitors for lipogenic enzymes or by knocking down of ACC | en |
dc.description.provenance | Made available in DSpace on 2021-05-19T17:56:51Z (GMT). No. of bitstreams: 1 ntu-105-D98448006-1.pdf: 3868148 bytes, checksum: 5242d62d3ae8df71f8a28c564636d890 (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | 口試委員會審定書 I
序言與誌謝 II Abstract III 中文摘要 V Abbreviation List VI Index VIII Introduction 1 1. Obesity and hepatocellular carcinoma (HCC) 1 1.1Epidemiology and risk factors for HCC 1 1.2 Obesity, NAFLD and HC 2 2. Nonalcoholic fatty liver disease (NAFLD) 3 2.1 NAFLD pathogenesis 3 2.2 Risk factors for NAFLD 4 2.3 Lipogenesis in association with NAFLD progression 5 3. De novo lipogenesis 6 3.1 De novo lipogenesis (DNL) process 6 3.2 Transcriptional factors involved in regulating lipogenesis 6 3.3 Contribution of lipogenesis in liver tumor 9 4. 1,2-diacylglycerol (DAG) 11 4.1 The synthesis and biologic functions of DAG 11 4.2 DAG binding to activate the DAG effector kinases 13 4.3 Dysregulation of DAG biogenesis and insulin resistance 14 5. Androgen receptor (AR) 16 5.1 AR functions as a transcriptional factor 16 5.2 AR functions in metabolism 18 5.3 AR functions in hepatitis virus induced hepatocarcinogenesis 20 Hypothesis and Purpose 21 Materials and Methods 22 1. Plasmid Constructs 22 2. Chemicals 23 3. Animals and diets 24 4. Hydrodynamic injection of ARE reporter plasmid 24 5. Lipogenic inhibitor treatment 25 6. Hepatic Triglyceride extraction and determination 25 7. Hepatic Diacylglycerol extraction 26 8. LC/MS/MS for DAGs analysis 26 9. RT-PCR and Quantitative reverse transcription-PCR 27 10. Cell culture and Dual-Luciferase reporter assay 28 11. Western blotting 29 12. Lentivirus production 29 13. GST protein Purification 30 14. [3H]PDBu Binding assay 30 15. Liposome preparation 31 16. Flotation experiments 31 17. Immunoprecipitation 32 18. Chromatin immunoprecipitation 33 Result 34 1. Active lipogenesis increases the transcriptional activity of hepatic AR in vivo34 2. Inhibition of lipogenesis represses AR transcriptional activity in vitro 36 3. Diacylglycerols (DAGs) as the molecules in DNL process to mediate increased transcriptional activity of AR 36 4. DAG activates the transcriptional activity of AR independent of the protein kinase C (PKC) activity 39 5. DAG increased AR transcriptional activity through activating of c-Src and Akt pathway in hepatocytes 39 6. -catenin involved in the regulation of DAG to AR transcriptional activity 40 7. AR-DBD region is important for DAG regulation to AR transcriptional activity 41 8. DAG didn’t affect the DNA binding ability of AR 42 9. Specific DAG isoforms enriched in HCD might increase the transcriptional activity of AR 43 Discussion 45 Figures and Tables 54 Figure 1: Kinetics of lipogenic genes in high carbohydrates diet and high fat diet fed mice 54 Figure 2: Active lipogenesis increases the transcriptional activity of hepatic AR in vivo 56 Figure 3: AR transcriptional activity in mice liver decreased by C75 treatment 58 Figure 4: Blockage of lipogenesis repressed the transcriptional activity of hepatic AR in vitro 59 Figure 5: Schematic representation of the enzymatic steps involved in lipogenesis and TG synthesize pathway and inhibitors for target proteins 60 Figure6: Lipogenesis may upregulate AR transcriptional activity through increasing diacylglycerol (DAG) level 61 Figure 7: 1,2-diacylglycerol (DAG) as the molecules in DNL process to mediate increased transcriptional activity of AR 63 Figure 8: DAG activates the transcriptional activity of AR independent of the protein kinase C (PKC) activity 65 Figure 9: DAG increased AR transcriptional activity through activation of c-Src and Akt pathway in hepatocytes 66 Figure 10: -catenin involved in the regulation of DAG to AR transcriptional Activity 68 Figure 11: AR-DBD region is important for DAG regulation to AR transcriptional activity 70 Figure 12: DAG didn’t affect the DNA binding ability of AR 71 Figure 13: Specific DAG isoforms enriched in HCD increased AR transcriptional activity 72 Figure 14: Investigation of the interaction between DAG and AR 73 Figure 15: A proposed model of the upregulation of AR transcriptional activity by carbohydrates-enriched DAG isoforms 75 Table 1: Primer list 76 Tables 2: Measure of [3H]PDBu binding 77 References 78 Appendixes 90 Antibodies used condition for the western blot 90 | |
dc.language.iso | en | |
dc.title | 男性肝細胞中脂肪新生路徑對雄性激素受體活性之調控研究 | zh_TW |
dc.title | De novo lipogenesis in regulating the transcriptional activity of androgen receptor in male hepatocytes | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-2 | |
dc.description.degree | 博士 | |
dc.contributor.coadvisor | 葉秀慧老師(Shiou-Hwei Yeh) | |
dc.contributor.oralexamcommittee | 郭錦樺老師,吳君泰老師,丁詩同老師 | |
dc.subject.keyword | 雄性激素受體,脂肪新生路徑,性別, | zh_TW |
dc.subject.keyword | De novo lipogenesis,androgen receptor,gender,hepatocytes, | en |
dc.relation.page | 90 | |
dc.identifier.doi | 10.6342/NTU201602728 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2016-08-17 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
顯示於系所單位: | 分子醫學研究所 |
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