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系統識別號 U0026-2107201701384500
論文名稱(中文) CEBPD在極化後巨噬細胞中的功能探討及其對粥狀動脈硬化的進程影響
論文名稱(英文) Investigate the function and consequent effects of CEBPD in polarized macrophages and pathogenesis of atherosclerosis
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 105
學期 2
出版年 106
研究生(中文) 賴弘岳
研究生(英文) Hong-Yue Lai
學號 s58011336
學位類別 博士
語文別 英文
論文頁數 125頁
口試委員 指導教授-王育民
召集委員-劉秉彥
口試委員-蔡曜聲
口試委員-江美治
口試委員-葉宏一
口試委員-李宗玄
中文關鍵字 CEBPD  發炎  巨噬細胞  PTX3  ZNF202  ABCA1  statins 
英文關鍵字 CEBPD  inflammation  macrophages  PTX3  ZNF202  ABCA1  statins 
學科別分類
中文摘要 動脈粥樣硬化是由高血脂症所引起的一種發炎性疾病,也有證據顯示發炎和脂質代謝平衡是密切相關的。巨噬細胞除了調節免疫反應外,也能參與脂質代謝平衡,並在動脈粥樣硬化的進程中扮演關鍵性的角色。然而巨噬細胞是否參與在高血脂所誘導的發炎性疾病,像是動脈粥樣硬化當中,需要進一步的釐清與研究。過去幾年來,我們的研究團隊已成功證實轉錄因子CCAAT/enhancer-binding protein delta (CEBPD)在巨噬細胞發炎及癌症微環境中扮演重要角色。因此,本篇論文主要目的即剖析CEBPD是否參與調控巨噬細胞發炎與脂質代謝平衡,進而影響動脈粥樣硬化的進程。免疫螢光染色結果顯示在人類和小鼠動脈粥樣硬化斑塊中,CEBPD蛋白和巨噬細胞有共位現象,此外,骨髓移植實驗結果顯示接受Cebpd缺陷骨髓細胞的動脈粥樣硬化模式小鼠,在餵食高脂食物後也較不會有動脈粥樣硬化斑塊的形成。細胞實驗結果顯示p38MAPK/CREB這條訊息傳遞路徑能幫助脂質所誘導的CEBPD活化,並促進脂質堆積在M1巨噬細胞而不是在M2巨噬細胞。其調控機制包括PTX3所促進的脂質內吞作用增多及ABCA1所促進的脂質外排作用減少。我們也發現ZNF202能參與調控CEBPD所抑制的ABCA1基因轉錄作用。此外,我們也發現降血脂藥物simvastatin能透過p38MAPK/CREB這條訊息傳遞路徑來抑制CEBPD的活化,進而減少脂質在M1巨噬細胞的堆積。本篇論文強調發炎與脂質代謝平衡交互作用的重要性,並提供靶向巨噬細胞表型來治療心血管疾病的新見解。
英文摘要 Atherosclerosis is an inflammatory disease driven by hyperlipidemia. There are accumulating evidences to support that inflammation and lipid homeostasis are closely linked. Macrophages mediate innate immune responses and lipid homeostasis and act as a key player in atherosclerosis. However, the cross talk among these processes in the development and progression of atherosclerosis are not fully defined. For the past few years, our recent studies successfully demonstrated the important role of the transcription factor CCAAT/enhancer-binding protein delta (CEBPD) in inflammation and cancer microenvironment over macrophages. In this current study, we aimed to dissect whether CEBPD functions at the junction of inflammation and macrophage lipid homeostasis. We found that CEBPD colocalized with macrophages in human and mouse atherosclerotic plaques and that Cebpd deficiency in bone marrow cells suppressed atherosclerotic lesions in hyperlipidemic Apoe-/- mice. In response to modified LDL, the p38MAPK/CREB pathway contributed to CEBPD activation which promoted lipid accumulation in M1 macrophages but not in M2 macrophages. The underlying mechanisms involved in this process included an increase in pentraxin 3 (PTX3)-mediated macropinocytosis of LDL and a reduction in ATP-binding cassette subfamily A member 1 (ABCA1)-mediated cholesterol efflux. Also, we found that ZNF202 mediates CEBPD-repressed ABCA1 gene transcription. In addition, we found that simvastatin (a HMG-CoA reductase inhibitor) can target CEBPD to block lipid accumulation in M1 macrophages. In conclusion, this study underscores the importance of cross talk between inflammation and lipid homeostasis and provides new insight into targeting macrophage phenotypes and functions in cardiovascular diseases.
論文目次 Abstract i
Abstract in Chinese ii
Acknowledgments iii
Contents v
Figure contents ix
Abbreviations xii

Chapter 1. Introduction 1
1.1 Overview of atherosclerosis 1
1.1.1 Inflammation and atherosclerosis 1
1.1.2 The role of macrophages in atherosclerosis 2
1.1.3 Mechanisms controlling macrophage lipoprotein uptake and efflux 2
1.1.4 The role of pinocytosis in macrophage lipoprotein uptake 3
1.1.5 Macrophage polarization and functional phenotypes 5
1.2 The CCAAT/enhancer-binding protein family of transcription factors 6
1.2.1 Biological roles of the CCAAT/enhancer-binding proteins 6
1.2.2 Inflammation and CCAAT/enhancer binding protein delta (CEBPD) 6
1.3 The role of Pentraxin 3 (PTX3) in atherosclerosis 7
1.4 The role of ATP-binding cassette subfamily A member 1 (ABCA1) in atherosclerosis 8
1.5 HMG-CoA reductase inhibitors (statins) 9
1.6 Rationale and significance 10

Chapter 2. Materials and methods 12
2.1 Materials 12
2.2 Reagents and inhibitors 12
2.3 Cell preparations 12
2.4 Immunofluorescence (IF) staining 13
2.5 Animal studies 14
2.6 Immunohistochemistry (IHC) staining 15
2.7 Oil Red O staining 16
2.8 LDL modification 16
2.9 Pinocytosis assay 16
2.10 BODIPY-cholesterol efflux assay 17
2.11 Next generation sequencing (NGS) analysis 17
2.12 Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) 18
2.13 Construction of plasmids 18
2.14 Plasmid transfection and reporter assay 19
2.15 Chromatin immunoprecipitation (ChIP) assay 19
2.16 Western blot analysis 20
2.17 Lentiviral knockdown assay 20
2.18 Production of recombinant proteins 21
2.19 Generation of D360-Luc transgenic mice and genotyping 21
2.20 Statistical analysis 22

Chapter 3. Results 23
3.1 CEBPD is expressed in macrophages in human atherosclerotic plaques 23
3.2 Cebpd deficiency in bone marrow cells suppresses atherosclerotic lesions in hyperlipidemic Apoe-/- mice 23
3.3 CEBPD is responsive to modified LDL via the p38MAPK/CREB pathway 24
3.4 Activation of CEBPD contributes to lipid accumulation in M1 macrophages 25
3.5 CEBPD-mediated increased uptake of LDL and impaired cholesterol efflux lead to lipid accumulation in M1 macrophages 25
3.6 The loss of CEBPD reduces PTX3 transcripts and increases ABCA1 transcripts in mouse and THP-1 M1 macrophages 26
3.7 Ptx3 and Abca1 are involved in Cebpd deficiency-attenuated lipid accumulation in M1 macrophages 27
3.8 CEBPD activates PTX3 gene transcription in M1 macrophages 27
3.9 PTX3 promotes lipid accumulation through macropinocytosis in mouse M1 macrophages 28
3.10 CEBPD represses ABCA1 gene transcription in M1 macrophages 28
3.11 CEBPD cooperates with GATA1 to activate ZNF202 gene transcription in M1 macrophages 29
3.12 ZNF202 represses ABCA1 gene transcription in M1 macrophages 30
3.13 ZNF202 mediates CEBPD-repressed ABCA1 gene transcription in M1 macrophages 30
3.14 Simvastatin suppresses CEBPD expression by inhibiting the p38MAPK/CREB pathway 31
3.15 Simvastatin attenuates lipid accumulation in mouse M1 macrophages 31

Chapter 4. Discussion 33
4.1 CEBPD plays a functional role in lipid accumulation in M1 macrophages 33
4.2 The loss of Cebpd reduces the lipid burden in M1 macrophages 33
4.3 PTX3 promotes lipid accumulation via macropinocytosis of LDL in M1 macrophages 34
4.4 Abca1 is involved in increased plasma HDL levels in Cebpd-/- mice 35
4.5 The repression of ABCA1 gene transcription might be mediated through a miR33-independent pathway 36
4.6 Relevant statin concentrations claim pleiotropic effects 36
4.7 CEBPD-mediated lipid accumulation could represent a new therapeutic target for cardiovascular diseases 37
4.8 Conclusion 38
References 39
Figures and legends 47
Appendixes 91
Curriculum vitae 95
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