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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 邱智賢(Chh-Hsien Chiu) | |
| dc.contributor.author | Chien Huang | en |
| dc.contributor.author | 黃謙 | zh_TW |
| dc.date.accessioned | 2022-11-25T03:04:16Z | - |
| dc.date.available | 2023-07-31 | |
| dc.date.copyright | 2021-11-15 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-07-30 | |
| dc.identifier.citation | Becirovic-Agic, M., Chalise, U., Daseke, M. J., 2nd, Konfrst, S., Salomon, J. D., Mishra, P. K., Lindsey, M. L. (2021). Infarct in the Heart: What's MMP-9 Got to Do with It?. Biomolecules, 11(4), 491. Bonnema, D. D., Webb, C. S., Pennington, W. R., Stroud, R. E., Leonardi, A. E., Clark, L. L., McClure, C. D., Finklea, L., Spinale, F. G., Zile, M. R. (2007). Effects of age on plasma matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs). Journal of cardiac failure, 13(7), 530–540. Cai, H., Ma, Y., Jiang, L., Mu, Z., Jiang, Z., Chen, X., Wang, Y., Yang, G. Y., Zhang, Z. (2017). Hypoxia Response Element-Regulated MMP-9 Promotes Neurological Recovery via Glial Scar Degradation and Angiogenesis in Delayed Stroke. Molecular therapy, 25(6), 1448–1459. Calzadilla Bertot, L., Adams, L. A. (2016). The Natural Course of Non-Alcoholic Fatty Liver Disease. International journal of molecular sciences, 17(5), 774. Charzewski, Ł., Krzyśko, K. 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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/81816 | - |
| dc.description.abstract | 非酒精性脂肪肝病（non-alcoholic fatty liver disease，NAFLD）已在過去數十年間逐漸變成最普遍的慢性肝臟疾病。然而，由於慢性肝臟疾病多為多因子複合型，非酒精性脂肪肝病作為單純排除性的病程集合名詞已不適恰，現以代謝功能障礙相關脂肪肝疾病（metabolic dysfunction-associated fatty liver disease，MAFLD）。單純肝臟脂質浸潤在病程中是可逆的，但若缺乏適當的控制，則可能會惡化至不可逆的肝硬化及肝癌階段。雖然肝臟脂質浸潤的詳細致病機制目前仍未詳盡，然先前有臨床報告顯示，血漿中基質金屬蛋白酶第九型（matrix metalloproteinase 9，MMP-9）的濃度在非酒精性脂肪肝炎病患中顯著較高，此現象顯示MMP-9在MAFLD病程進展中可能扮演重要的角色。MMP-9是一具有降解胞外基質能力之蛋白質，能夠調節胞外基質的恆定。在MMP-9眾多標的的截切受質中，Syndecan-1，一種硫酸乙酰肝素蛋白聚醣 (heparan sulfate proteoglycans) ，已在先前研究中被發現能透過調控肝臟中富含三酸甘油酯脂蛋白（TG-rich lipoproteins，TRLs）的清除作用，參與血脂恆定的調節。當Syndecan-1的胞外部分 (ectodomain) 被截切時，會降低肝臟攝入血液中的TRLs，可能因此造成肝臟脂質浸潤的程度下降。 為了更了解MAFLD發展中的生理調節，我們持續餵飼小鼠高脂飼糧8、16及24週並評估其代謝相關表現及肝臟組織的分子活動。結果顯示，隨著餵飼高脂飼糧的時間增加，小鼠體重、肝重比、肝損傷、血中胰島素、血總膽固醇及肝臟中MMP-9活性均顯著增加，而基質金屬蛋白酶組織抑制劑第一型（tissue inhibitor of metalloproteinase 1，TIMP-1）蛋白表現量則顯著下降。高脂飼糧餵飼下，小鼠肝臟中完整的Syndecan-1蛋白表現量下降，而被截切後的Syndecan-1表現量則顯著增加。這部份結果符合我們的假說，即初步證明MMP-9生理活性的增加會截切肝細胞表面Syndecan-1的胞外部分以降低TRLs的持續攝入。而為了進一步釐清MMP-9在MAFLD進程中扮演的角色，我們餵飼野生型及MMP-9基因剔除小鼠高脂飼糧 16週。結果顯示MMP-9 基因剔除小鼠在餵飼高脂飼糧後有顯著增加的三酸甘油脂堆積於肝臟中，組織切片以及油紅染色結果也顯示，餵飼高脂飼糧後，MMP-9基因剔除小鼠的肝臟中堆積較大顆的油滴。在MMP-9缺失小鼠中，除了肝臟中TIMP-1蛋白表現顯著增加，高脂飼糧亦無法激活肝臟中MMP-9活性。此外，血液生化值的結果顯示MMP-9缺失可能對小鼠的肝臟有保護效果。 我們也設計一系列細胞試驗，以釐清MMP-9如何調控肝細胞的脂質堆積。首先我們以脂肪酸誘導肝細胞株FL83B 及Hepa1-6產生脂質堆積。接著利用shRNA及專一性的MMP-9抑制劑以模擬活體中MMP-9缺失的環境。結果顯示MMP-9活性被抑制會增加脂肪酸誘導的肝臟脂質堆積。此外，Syndecan-1被截切的狀況也在脂肪酸誘導的肝細胞中被進一步證明。最後我們添加PMA以刺激肝細胞外的MMP-9活性增加，試圖回復MMP-9活性缺失所造成的肝細胞脂質堆積增加。結果顯示PMA所誘導的MMP-9活性增加可以降低肝細胞中被shMMP-9所增加的脂質堆積。除了脂肪酸誘導的脂質堆積模型，我們也添加TRLs以直接地評估肝細胞與其結合並吸收的能力。結果顯示抑制MMP-9活性可以顯著地回復被PMA所抑制的TRLs結合及吸收能力。 總結來說，此研究中清楚地證明MMP-9會透過截切肝細胞膜上Syndecan-1而達到減緩肝臟脂質堆積的功能，且其活性與TIMP-1表現量之消長可能在MAFLD的早期發展中扮演重要角色。我們認為此研究提供了MAFLD早期發展的分子機轉相當新穎的觀點，並且期待此研究能作為開發MAFLD臨床治療方法的基石。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-25T03:04:16Z (GMT). No. of bitstreams: 1 U0001-3007202112225600.pdf: 43184364 bytes, checksum: 05e384952cb9a43c56e85e2f8dddcb24 (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | 口試委員會審定書……………………………………………………………………... i 致謝 ………………………………………………………………………………...…. ii 中文摘要 …………………………………………………………………………....... iii Abstract ………………………………………………………………………...…….… v Contents ………………………………………..………………………….................. viii Figure Index ……………………………………………………..………………..…..... x Table Index ……………………………………………………………………..…...... xiii Chapter 1. Introduction 1.1 Non-alcoholic fatty liver disease (NAFLD) …………………………………..… 1 1.2 Metabolic dysfunction-associated fatty liver disease (MAFLD)………………… 3 1.3 The potential roles of MMP-9 in NAFLD ………………………………...……... 5 1.4 Matrix metalloproteinase-9 (MMP-9) ………………………………….……..…. 6 1.5 Hepatic Syndecan-1 mediates lipoprotein metabolism …………………………. 10 1.6 Specific aims of this study…………………………………………………......... 12 Chapter 2. Materials and Methods ……………………………………………..…... 13 Chapter 3. The physiological regulation of MMP-9 in MAFLD in mice 3.1 The time-course effects of high-fat diet on MAFLD development in mice....…... 29 3.2 MMP-9 knockout changed HFD-induced MAFLD in mice ……………...…….. 40 Chapter 4. The molecular mechanisms of MMP-9 regulated lipid accumulation… 59 Chapter 5. Discussion………………………………………………………………… 78 Reference …………………………………………………………….………….......... 88 Curriculum Vitae of author ………………………………………….……………. 100 Full-length article of published papers …………………………………………… 103 | |
| dc.language.iso | en | |
| dc.subject | Syndecan-1 | zh_TW |
| dc.subject | 基質金屬蛋白酶組織抑制劑第一型 | zh_TW |
| dc.subject | 基質金屬蛋白酶第九型 | zh_TW |
| dc.subject | 代謝功能障礙相關脂肪肝疾病 | zh_TW |
| dc.subject | 非酒精性脂肪肝病 | zh_TW |
| dc.subject | 富含三酸甘油酯脂蛋白 | zh_TW |
| dc.subject | 肝臟脂質堆積 | zh_TW |
| dc.subject | Lipid accumulation | en |
| dc.subject | TG-rich lipoprotein | en |
| dc.subject | Non-alcoholic fatty liver disease | en |
| dc.subject | Syndecan-1 | en |
| dc.subject | Tissue inhibitor of metalloproteinase-1 | en |
| dc.subject | Matrix metalloproteinase-9 | en |
| dc.subject | Metabolic dysfunction-associated fatty liver disease | en |
| dc.title | 基質金屬蛋白酶第九型在代謝功能障礙相關脂肪肝疾病之生理調控與分子機制 | zh_TW |
| dc.title | The Physiological Regulation and Molecular Mechanisms of Matrix Metalloproteinase-9 in Metabolic Dysfunction-Associated Fatty Liver Disease | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.coadvisor | 江逸凡(Yi-Fan Jiang) | |
| dc.contributor.oralexamcommittee | 鍾德憲(Hsin-Tsai Liu),吳兩新(Chih-Yang Tseng),陳億乘,黃啟彰,黃惠君,徐慶琳 | |
| dc.subject.keyword | 非酒精性脂肪肝病,代謝功能障礙相關脂肪肝疾病,基質金屬蛋白酶第九型,基質金屬蛋白酶組織抑制劑第一型,Syndecan-1,富含三酸甘油酯脂蛋白,肝臟脂質堆積, | zh_TW |
| dc.subject.keyword | Non-alcoholic fatty liver disease,Metabolic dysfunction-associated fatty liver disease,Matrix metalloproteinase-9,Tissue inhibitor of metalloproteinase-1,Syndecan-1,TG-rich lipoprotein,Lipid accumulation, | en |
| dc.relation.page | 149 | |
| dc.identifier.doi | 10.6342/NTU202101926 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2021-08-02 | |
| dc.contributor.author-college | 生物資源暨農學院 | zh_TW |
| dc.contributor.author-dept | 動物科學技術學研究所 | zh_TW |
| dc.date.embargo-lift | 2023-07-31 | - |
| 顯示於系所單位： | 動物科學技術學系 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| U0001-3007202112225600.pdf | 42.17 MB | Adobe PDF | 檢視/開啟 |
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