同調拉曼顯微術應用於活體生物系統中脂質代謝之研究

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研究生：	陳威文 Chen, Wei-Wen
論文名稱：	同調拉曼顯微術應用於活體生物系統中脂質代謝之研究 Lipid metabolism in live biological systems studied by coherent anti-Stokes Raman scattering (CARS) microscopy
指導教授：	張大釗 Chang, Ta-Chau 倪其焜 Ni, Chi-Kung
口試委員:	謝佳龍 Hsieh, Chia-Lung 陳壁彰 Chen, Bi-Chang 吳益群 Wu, Yi-Chun 廖仲麒 Liao, Jung-Chi
學位類別：	博士 Doctor
系所名稱：	理學院 - 化學系 Department of Chemistry
論文出版年：	2016
畢業學年度：	105
語文別：	英文
論文頁數：	94
中文關鍵詞：	非線性光學、同調拉曼顯微術、脂質、巨噬細胞、線蟲、同調反史托克拉曼
外文關鍵詞：	nonlinear optics, coherent Raman microscopy, lipid, macrophages, C. elegans, coherent anti-Stokes Raman
相關次數：	點閱：2 下載：0
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脂質分子在生物中具有許多重要功能，例如作為細胞或胞器膜的材料、提供能量的來源、或是成為在不同訊息途徑中的訊息因子。但另一方面，過多的脂質分子的累積卻會造成不同慢性疾病，例如：動脈粥狀硬化、心血管疾病、慢性肝或腎疾病。因此，研究與了解脂質在生物體中的代謝是一個重要議題。
長久以來，脂質分子就被認為是一種"隱形的分子"，因為脂質分子是透明的、不發出螢光、而且不易在活體生物中用螢光染劑染色的分子，因此脂質在活體觀察時不容易被分辨出來。而同調拉曼顯微術，例如：反史托克拉曼顯微術，具有不需任何標定就可經由脂質分子中高密度碳氫鍵的振動模來偵測脂質分子的分布，因此是一種非常合適用來研究活體中脂質代謝的工具。在本篇論文中，我們將會介紹同調拉曼顯微術的架設以及在活體細胞（巨噬細胞）與活體動物（線蟲）中脂質代謝研究上的應用。
當巨噬細胞吞噬過多的低密度脂蛋白及膽固醇後，會形成泡沫細胞，泡沫細胞的形成與動脈粥狀硬化息息相關，死亡的泡沫細胞內的脂質會累積黏在血管壁中，過多的脂質累積則形成動脈硬塊而進一步導致動脈粥狀硬化的病變。在此巨噬細胞系統中，我們利用同調拉曼顯微術去觀測活體細胞中脂肪油滴的累積，我們進一步發展了影像定量分析的方法，因此在無染色標定的活體細胞下，我們可以去量化細胞內脂質含量並與生化方法的分析結果相吻合。我們也證實此分析方法也可以應用在其他種細胞中（例如：CL1-0肺癌細胞）。最後，利用此定量分析方法，我們可以評估脂肪水解抑制劑diethylumbelliferyl phosphate的藥物動力學參數和抑制能力。這個實驗方法將有機會進一步發展成為脂質藥物的篩選平台。
在此篇論文重點在於研究不同脂肪酸的組成成份是否會影響細胞對脂蛋白的攝取（endocytosis）。線蟲中的蛋黃脂蛋白為其主要脂質輸送載體（從腸道輸送到卵細胞），並且在演化上蛋黃脂蛋白與人類的低密度脂蛋白在是屬於同源基因（homologs），因此線蟲十分適合用於脂蛋白代謝的研究。在我們的活體線蟲研究中，我們發現用同調拉曼顯微術不論是用脂質或蛋白質的影像都可以偵測到在線蟲體腔內異常的蛋黃脂蛋白累積，而這些不正常累積可能是因為卵細胞無法正常攝取蛋黃脂蛋白而導致。我們進一步發展了影像分析方法去定量分析不同突變株（fat-1、fat-2、fat-3以及fat-4）內蛋黃脂蛋白運輸情形、其卵細胞內的脂質含量以及卵的發育情形。此外，我們也檢驗了外加不同脂肪酸給fat-2突變株（缺少所有的不飽和脂肪酸）後的影響。最後，我們的研究結果證實omega-6不飽和脂肪酸（而非omega-3不飽和脂肪酸）對於線蟲中蛋黃脂蛋白的運輸以及卵的發育過程扮演不可或缺的角色。
這個論文工作除了展現同調拉曼顯微術是一種對於研究活體生物中脂質代謝非常有用的工具之外，也驗證了omega-6不飽和脂肪酸在脂蛋白的代謝上扮演相當重要的角色。我們相信在活體生物中研究脂質代謝相關課題將能幫助我們去發掘更多潛在基因或代謝途徑，讓我們在未來有可能找到更好的方式去治療脂質代謝相關的疾病。

Lipids have various crucial functions in biological systems, such as being the building blocks of membranes, providing as fuel molecules, and acting as signaling molecules(such as steroid hormones). However, the excess intake of lipids can be one major reason that causes several chronic diseases, such as atherosclerosis, cardiovascular disease, chronic liver or kidney diseases. Therefore, it is important to study and understand the lipid metabolism in the biological systems.
For a long time, lipids have been regarded as “the invisible molecules” for in vivo observation because they are transparent, intrinsically non-fluorescent, and difficult to be tagged with fluorophores. Coherent Raman technique, such as coherent anti-Stokes Raman scattering (CARS) microscopy, provides a label-free way to specifically visualize biomolecules, particularly for detecting lipids, in living organisms at subcellular resolution, which makes it a powerful tool for the study of lipid metabolism and lipid biology. In this thesis, we will present the construction of CARS microscopy and the studies of lipid metabolism in the live cell system (macrophages) and in live animal model (C. elegans).
The accumulation of lipid in macrophages is a key factor that promotes the formation of atherosclerotic lesion. In the study of live cell system (macrophages), we developed an automated quantitative analysis method for the real-time assessment of lipid content in living macrophages. This method can monitor the lipid accumulation and hydrolysis in the living cells in real time at single-cell level without any labeling. We showed that this method can also be applied to other type of cells such as lung cancer cells (CL1-0), which broadens the possible applications of this method. Finally, we demonstrated its potential for kinetic study of drugs and for high-throughput screening of lipid therapeutic agents.
To verify the question – whether the composition of fatty acids affects the uptake of lipoprotein, we chose C. elegans as a model animal for the study because the yolk lipoprotein in C. elegans is homologous human low-density lipoprotein (LDL) and both of them (yolk lipoprotein and LDL) act the same function, as the major lipid carrier delivering lipid into cells. In the study of live animal model (C. elegans), we first demonstrated that the abnormal accumulation of secreted yolk lipoprotein in the pseudocoelom of live C. elegans can be detected by CARS microscopy at both protein (~1665 cm−1) and lipid (~2845 cm−1) Raman bands. In addition, we developed image analysis protocols to quantitatively measure the abnormal accumulation of secreted yolk lipoprotein and the oocyte lipid content in PUFA-deficient fat mutants (fat-1, fat-2, fat-3, fat-4) and PUFA-supplemented fat-2 worms (the PUFA add-back experiments). Our results reveal that the omega-6 PUFAs, not omega-3 PUFAs, play a critical role in modulating lipid/yolk level in the oocytes and regulating reproductive efficiency of C. elegans.
This thesis work not only demonstrates that CARS microscopy is a useful technique for the label-free examination of lipid metabolism in live biological systems but also elucidates that omega-6 PUFA is a key factor that strongly influences the uptake of lipoprotein in the biological systems. We believe that the extensive and intensive researches based on live cell/animal model will help us to understand the genetics as well as metabolic pathways in lipid biology, and will possibly find a way to tackle human lipid metabolic diseases in the future.

摘要    I
Abstract    III
Chapter 1    Coherent anti-Stokes Raman scattering (CARS) microscopy    1
1.1    Introduction to CARS microscopy    1
1.2    Setup of our CARS microscope    4
1.3    Calibration data of our CARS microscope    5
Chapter 2    Live cell system – macrophages    8
2.1    Macrophages and atherosclerosis    8
2.2    Optimization of CARS imaging wavelengths    9
2.3    Characterization of CARS intensity    10
2.4    Automated quantitative analysis of cellular lipid content    12
2.5    Kinetic analysis of lipid dynamics in live macrophages    14
2.6    Discussion    16
2.7    Summary    18
Chapter 3    Live animal model – Caenorhabditis elegans    19
3.1    An emerging animal model for lipid biology: C. elegans    19
3.2    Lipid transportation and the development of oocytes in C. elegans    20
3.3    Our hypothesis and designed experiments    22
3.4    Characterization of lipid storage in C. elegans    23
3.5    Detection of abnormal yolk lipoprotein accumulation by CARS    23
3.6    Quantitative analysis of abnormal yolk lipoprotein accumulation    25
3.7    Time-dependent increase of yolk lipoprotein accumulation    26
3.8    Examination of yolk lipoprotein accumulation in mutants    27
3.9    Quantitative analysis of lipid delivery into oocytes    28
3.10    Examination of oocyte lipid content in mutants    29
3.11    Examination of the development of oocytes    30
3.12    Discussion    33
3.13    Summary    36
Chapter 4    Conclusion    38
Figures    40
Figure 1.1    40
Figure 1.2    41
Figure 1.3    43
Figure 1.4    44
Figure 1.5    45
Figure 1.6    46
Figure 2.1    47
Figure 2.2    48
Figure 2.3    49
Figure 2.4    50
Figure 2.5    51
Figure 2.6    52
Figure 2.7    53
Figure 2.8    54
Figure 2.9    55
Figure 2.10    56
Figure 3.1    57
Figure 3.2    58
Figure 3.3    59
Figure 3.4    60
Figure 3.5    61
Figure 3.6    62
Figure 3.7    63
Figure 3.8    65
Figure 3.9    66
Figure 3.10    67
Figure 3.11    68
Figure 3.12    69
Figure 3.13    70
Figure 3.14    71
Figure 3.15    72
Figure 3.16    73
Figure 3.17    74
Figure 3.18    75
Movie    76
Movie 1    76
Reference    77
Appendix I    85
Appendix II: Materials and chemicals used in this thesis work    92
Publication list    94


                                

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