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系統識別號 U0026-0206201116292600
論文名稱(中文) 極低/低密度脂蛋白之蛋白質體與調控C型肝炎病毒感染之功能性分析
論文名稱(英文) The functional study on VLDL/LDL proteome in the regulation of hepatitis C virus infection
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 99
學期 2
出版年 100
研究生(中文) 孫宏羽
研究生(英文) Hung-Yu Sun
學號 S5893149
學位類別 博士
語文別 英文
論文頁數 105頁
口試委員 口試委員-陳士隆
口試委員-鄭如茜
召集委員-張定宗
口試委員-廖寶琦
指導教授-楊孔嘉
中文關鍵字 低密度脂蛋白  C型肝炎病毒  病毒脂質顆粒  載脂蛋白  蛋白質體  脂蛋白酶 
英文關鍵字 low-density lipoprotein  lipoprotein liapse  LVP  HCV  apoCs  lipoproteomes 
學科別分類
中文摘要 極低密度脂蛋白(very-low-density lipoprotein, VLDL)及低密度脂蛋白(low-density lipoprotein, LDL)均是由載脂蛋白B所構成的脂蛋白且富含三酸甘油脂,主要功能是將脂肪從肝臟運送到周邊組織中。在循環過程中,極低密度脂蛋白所含的三酸甘油脂會逐漸被血液中的脂蛋白酶(lipoprotein liapse, LPL)水解,而變成低密度脂蛋白。然而有關極低密度脂蛋白轉變成低密度脂蛋白過程中蛋白組成改變的研究卻很少。C型肝炎病毒的生活史與(極)低密度脂蛋白的代謝過程有極高的相關性。病毒脂質顆粒 (lipo-viral particles, LVP)是含有載脂蛋白、C型肝炎病毒RNA及C型肝炎病毒蛋白的低密度/極低密度脂蛋白,被認為是C型肝炎患者血液樣本中最具感染力的部分。研究指出脂蛋白酶不但參與(極)低密度脂蛋白的代謝過程,在細胞實驗中也會抑制C型肝炎病毒的感染。目前對於這些病毒脂質顆粒中的脂肪及蛋白對於C型肝炎病毒感染的功能的研究仍未清楚。因此,本研究著力於探討(極)低密度脂蛋白及病毒脂質顆粒的蛋白對於C型肝炎病毒感染所扮演的角色,1) 為了找出候選蛋白質,我們先建立極低密度脂蛋白轉變成低密度脂蛋白時的比較型脂蛋白質體資料庫;2) 找出載脂蛋白C家族成員在脂蛋白酶抑制C型肝炎病毒感染中所扮演的角色;3) 藉由RNA分解酶敏感性分析研究含有C型肝炎病毒的(極)低密度脂蛋白中的脂肪成份的功能。首先,在比較型脂蛋白質體資料庫中,我們找到了21個蛋白,並且依照其表現量差異將其分成三組:(1)極低密度脂蛋白>低密度脂蛋白 (載脂蛋白A-IV,載脂蛋白a,載脂蛋白CI-IV,載脂蛋白E, 載脂蛋白J, 及血清澱粉樣蛋白A4);(2)極低密度脂蛋白<低密度脂蛋白 (白蛋白,甲一型抗胰蛋白酵素,載脂蛋白D,載脂蛋白F,載脂蛋白M,及巴拉松酶);(3) 極低密度脂蛋白=低密度脂蛋白 (載脂蛋白A-I,載脂蛋白A-II,載脂蛋白B,載脂蛋白L-I,及烯化半胱胺酸分解酶)。藉由此蛋白質體資料庫,發現載脂蛋白C家族的表現量是最顯著的,此外此家族成員具有調控脂蛋白酶活性的功能。因此在第二部份的實驗,我們針對載脂蛋白C家族對於是否會藉由調控脂蛋白酶活性來影響C型肝炎病毒感染進行研究,結果顯示極低密度脂蛋白與來自(極)低密度脂蛋白的病毒脂質顆粒,均會透過載脂蛋白C-III及C-IV抑制脂蛋白酶活性;阻斷極低密度脂蛋白及C型肝炎病毒脂質顆粒上的載脂蛋白C-III及C-IV,會回復脂蛋白酶抑制C型肝炎病毒感染的功能。此外,正常血脂的C型肝炎病患血漿中的病毒量與脂蛋白酶活性成負相關,而與極低密度脂蛋白上的載脂蛋白C-III成正相關。除了探討病毒脂質顆粒所攜帶的蛋白對於C型肝炎病毒感染的功能外,我們進一步分析病毒脂質顆粒的蛋白質及脂質是否具有保護C型肝炎RNA的特性。使用表面活性劑去除脂質成分後,發現C型肝炎病毒RNA會被RNA分解酶水解,而去除蛋白成份則不會影響C型肝炎病毒RNA,結果推論C型肝炎病毒會隨著在極低密度脂蛋白生成而被包裹入其中,且在循環過程中極低密度脂蛋白的脂質成分可保護C型肝炎病毒RNA。
英文摘要 The very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) are two major classes of triglyceride (TG)-rich, apolipoprotein(apo)B-100-containing lipoproteins that deliver lipids from the liver to peripheral organs. The TG of VLDL is lipolyzed by lipoprotein lipase (LPL) and transformed into LDL during circulation.
However, the changes of protein compositions during conversion of VLDL to LDL are barely investigated. The hepatitis C virus (HCV) lifecycle is highly associated with VLDL and LDL. The low-density HCV fractions with the highest infectivity have been characterized as lipo-viral particles (LVPs) which contain apos, HCV RNA, and HCV viral proteins. Previous studies showed that LPL not only involves in lipoprotein metabolism but also suppresses HCV infection in cell-based model. Due to limited information, the function of lipid and protein components on HCV LVP s is still unclear. In the present study, we aimed to validate the function of apolipoproteins in VLDL/LDL or purified LVPs on HCV infection. 1) To identify the candidate protein, a comparative lipoproteomes of VLDL in the process of conversion to LDL is constructed firstly; 2) reveal the function of apoC proteins on LPL-mediated inhibition of HCV infection; 3) analyze the function of lipid components of low-density HCV containing particles by RNases sensitivity assay. First, the comparative lipoproteomes reveal 21 associated proteins and the proteins are classified into 3 groups based on the differential expression levels: (i) VLDL>LDL [apolipoprotein (apo) A-IV, apo(a), apoCs, apoE, apoJ and serum amyloid A-4]; (ii)VLDLmetabolic VLDL-to-LDL conversion. Next, we investigate whether the apoCs family influences LPL-mediated inhibition of HCVcc infection by regulating LPL activity.
The results show that the VLDL, as well as VLDL-LVP and LDL-LVP, suppress LPL activity and the inhibition of LPL activity can be restored by antibodies recognizing apoC-III and -IV. Also, the LPL-mediated inhibition can be reversed by the treatment with VLDL and HCV LVPs in an apoC-III and -IV dependent manner. Furthermore, plasma HCV viral loads correlates negatively with plasma LPL activity and positively with VLDL apoC-III from normolipidemic HCV-infected donors. Furthermore, the role of protein and lipid components of LVPs in protection of HCV RNA is examined.
The particles are subjected RNase digestion after removal of lipid compartment, but not protein component. The results suggest the lipid components of LVPs could protect HCV-RNA from RNase digestion and a substantial amount of low-density HCV containing particles is incorporated into low-density lipoprotein particles, which might protect circulating HCV genome.
論文目次 口試合格證明------------------------------- I
Abstract (In Chinese)--------------------- II
Abstract (In English) -------------------- IV
誌謝 --------------------------------------VI
Index ---------------------------------- VIII
Table/figure index ----------------------- XI
Abbreviations -------------------------- XIII
Compounds and reagents ------------------ XIV
Antibodies ------------------------------ XVI
Kits and apparatus --------------------- XVII
I. Introduction ---------------------------------- 1
1.Molecular biology of hepatitis C virus (HCV)--- 1
2. HCV experimental systems ----------------- 5
3. HCV and low-density lipoproteins ------- 7
4. Study goal --------------------- 12
II. Materials and methods------------------------ 13
1.Collection of blood samples and biochemical analysis -- 13
2.Preparation of low-density lipoproteins ----------- 14
3.Electrophoretic separation of lipoproteins in agarose gel ---- 15
4.iTRAQ labeling and strong cation exchange (SCX) chromatography -----16
5.2-DE, silver stain and in-gel tryptic digestion ---- 16
6.LC-MS/MS analysis --------------------- 17
7.Data processing --------------------- 18
8.Preparation of LVPs and HCVcc -------------- 19
9.Quantification of viral titer by real-time PCR ------ 19
10.In vitro LPL activity assay -------------- 20
11.Quantification of IgG, apoB and apoCs by ELISA --- 21
12.Evaluation of HCVcc infection/replication by NS3/4A protease-based reporter assay ------------------------ 22

13.FACS analysis of HCV infected cells ------------ 23
14.Binding assay of HCVcc ---------------- 23
15.RNase sensitivity assay ---------------- 24
16.Transmission electron microscopy (TEM) observation--- 24
17.In situ hybridization of HCV RNA with anti-sense oligonucleotide -----------25
(ASON) conjugated nano-gold particles
18.Silver staining of SDS-PAGE--------------- 26
19.Statistical analysis--------------- 26
III. Results ---------- ------------------------------- 28
1. Comparative proteome of VLDL and LDL from volunteers with normolipidemia 28
1.1 Isolation of VLDL/LDL from pooled plasma -------- 28
1.2 iTRAQ labeling coupled with LC-MS/MS analysis of differential VLDLand LDL lipoproteomes ------- 29

1.3 VLDL- and LDL-associated protein maps -------- 29
2.The apoC proteins in VLDL and LVPs reversed LPL-mediated inhibition of HCV infection ------- 30

2.1 Purification and characterization of VLDL, LDL and HCV LVPs ------------30
2.2 The LPL activity was inhibited by VLDL and HCV LVPs----32
2.3 LPL activity was inhibited by apoC-III and apoC-IV present on LVPs ------33
2.4 The expression level of apoC-III and apoC-IV was increased in purified LVPs ------33

2.5 The LPL-mediated inhibition of HCV infection was restored by apoC-III and apoC-IV present on VLDL and LVPs -------- 35

2.6 Correlations of plasma HCV viral load with LPL activity and VLDL’s apoC-III ------ 36

3.The RNA protection effect of lipid component on low-density HCV RNA containing particles------- 37

3.1 Characterization of low-density fraction from HCV-infected plasma -----37
3.2 The low-density lipoproteins from HCV-infected patients displayed heterogeneous morphology and contained enlarged particles ------- 38

3.3 In situ hybridization of HCV RNA in low-density lipoproteins from HCV-infected plasma --------- 39

3.4 The HCV RNA was protected by lipid component of low-density lipoproteins----------- 40

IV. Discussion ------------------------ 42
1. The function of proteins associated with low-density lipoproteins ------ 42
2. The role of protein and lipid components of LVPs -----44
3. The putative mechanism of LPL-mediated inhibition of HCVcc infection (Supplementary figure 6) ----- 46

4. The regulation of HCVcc infection by apoCs on low-density lipoproteins ------ 47
5. Conclusion -----49
V. References ------------------ 50
Tables --------------------- 60
Figures ------------------ 67
Supplementary tables --------- 92
Supplementary figures --------- 94
作者簡歷 ----------------------- 104
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