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系統識別號 U0026-0812200914251593
論文名稱(中文) C型肝炎病毒核心蛋白與內質網壓力對脂肪代謝相關基因之調控
論文名稱(英文) Regulation of genes involving lipid metabolism by the core protein of hepatitis C virus and endoplasmic reticulum stress
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 96
學期 2
出版年 97
研究生(中文) 陳雅婷
研究生(英文) Ya-ting Chen
電子信箱 t3695403@mail.ncku.edu.tw
學號 t3695403
學位類別 碩士
語文別 英文
論文頁數 169頁
口試委員 口試委員-鄭如茜
指導教授-楊孔嘉
口試委員-張定宗
口試委員-賴明德
中文關鍵字 脂肪代謝  內質網壓力  C型肝炎病毒  核心蛋白 
英文關鍵字 core protein  lipid metabolism  HCV  endoplasmic reticulum stress 
學科別分類
中文摘要 C型肝炎病毒感染是目前慢性肝炎的主因,長期持續性感染會導致晚期肝臟疾病的發生。另外,脂肪代謝異常也被認為與肝癌的發生有關。C型肝炎病毒核心蛋白在內質網中成熟,目前被認為是C型肝炎病毒感染導致脂肪肝與肝癌的重要因子。C型肝炎病毒核心蛋白也被認為會造成內質網壓力 (ER stress),而內質網壓力的產生可能會導致肝臟病變。然而,對於C型肝炎核心病毒如何干擾脂肪代謝以及引起內質網壓力的相互關係仍然十分模糊。為釐清C型肝炎病毒核心蛋白與內質網壓力對脂肪代謝相關基因的影響。我們建立一個與脂肪代謝相關的基因表現模組 (Gene expression profile) 包含87個與脂肪代謝相關的基因,在轉染後表現C型肝炎病毒核心蛋白與受到內質網壓力刺激下的肝癌細胞中,分別分析這些脂肪代謝相關基因的表現。將全長191個胺基酸的C型肝炎病毒核心蛋白基因自感染不同基因型的C型肝炎病毒病患的血清中萃取得到,利用選殖技術 (Cloning) 將其構築於pEGFP-N1載體,建構出位在EGFP載體上表現不同基因型 (1a, 1b, 2a, 2b, 3a, 3b) 的C型肝炎病毒核心蛋白。再將C型肝炎病毒核心蛋白基因轉染至細胞中使細胞持續表現此蛋白質。蛋白質在細胞中的表現以西方墨點法 (western blot) 確認。利用即時偵測同步定量之聚合酶連鎖反應器 (real-time polymerase chain reaction) 來定量基因,比較在有表現C型肝炎病毒核心蛋白細胞中與只表現EGFP載體的細胞中這些基因表現的情況。在此部分的結果我們發現大部分基因表現受到調升,這些受到調升的基因多為脂蛋白 (lipoprotein) 與參與三酸甘油脂生合成 (triacylglycerol biosynthesis) 的相關基因。其中更有三個基因在不同基因型的C型肝炎病毒核心蛋白影響下皆受到調升。此三個基因分別為血清澱粉樣蛋白A4 (serum amyloid A4, SAA4), 脂蛋白元E (apolipoprotein E, APOE) 與甘油-3-磷酸轉酰酶 (glycerol-3-phosphate acyltransferase, mitochondrial, GPAM)。此外,在添加引發內質網壓力藥劑的肝癌細胞中,收集受到不同時間刺激的細胞並利用同步定量之聚合酶連鎖反應器來偵測基因表現的情況。在內質網壓力下,細胞中基因表現呈現調降趨勢,受到調降的基因主要涉及脂蛋白與三酸甘油脂生合成。因此,我們看到與脂肪代謝相關基因的表現在受C型肝炎病毒核心蛋白調控的情況與內質網壓力大不相同。我們進一步分析臨床肝癌組織檢體,發現在臨床檢體中的表現趨勢與在受到內質網壓力下的細胞中較相似,而非在表現C型肝炎病毒核心蛋白的細胞中。綜合以上結果,我們的研究提供了一個高效能的平台用於分析全面性脂肪代謝相關基因,並用以分析不同基因型C型肝炎病毒核心蛋白與內質網壓力及臨床肝癌病患組織檢體中對於調控這些基因的影響。
英文摘要 Hepatitis C virus (HCV) infection is the major cause of chronic hepatitis and HCV persistence over time can lead to end-stage liver disease. Disturbance of lipid metabolism might contribute to hepatocarcinogenesis. The HCV core protein, undergoing maturation in endoplasmic reticulum (ER), has been recognized as a causable factor of hepatic steatosis and hepatocellular carcinoma. On the other hand, HCV core protein could induce ER stress which might also lead to hepatic pathogenesis. However, the mechanism that how HCV core protein interfere lipid metabolism and the dependence on induction of ER stress, is still obscure. To elucidate the effects of HCV core protein and ER stress, the expression profile of 87 genes involving lipid metabolism was analyzed in Huh7 cells ectopically transfected with HCV-core protein and in Huh7 cells treated with ER stress inducers. The HCV core gene fragments encoding 191 a.a. were PCR-amplified from serum samples of patients infected with HCV genotype 1a, 1b, 2a, 2b, 3a and 3b, respectively, cloned into pEGFP-N1 plasmid and expressed as core-EGFP fusion protein. Huh7 cell lines stably expressing HCV core protein of different genotypes were established and confirmed by western blot analysis. Subsequently, real-time PCR analysis were used to quantify RNA levels of those lipid-metabolism-related genes in HCV core-expressing Huh7 cells as compared to those in vector control cells. The results showed a trend of up-regulation of genes responsible for lipoprotein and triacylglycerol biosynthesis. Remarkably, three genes were consistently increased in cells expressing different genotypes of HCV core proteins, including serum amyloid A4 (SAA4), glycerol-3-phosphate acyltransferase, mitochondrial (GPAM) and apolipoprotein E (APOE). Next, the Huh7 cells were treated with tunicamucin and thapsigargin, ER stress inducers, for 1, 3, 12 and 24 hours and subjected to real-time PCR analysis The results showed that ER stress might induce a trend of down-regulation of genes responsible for lipoprotein and triacylglycerol biosynthesis. Therefore, the regulation of lipid-metabolism-related genes responded to HCV-core and ER stress in divergent pathways. Furthermore, the expression of those genes in HCC tissues was analyzed, with the results showing a pattern more like that induced by ER stress but not HCV core expression. In conclusion, this study provided a high-throughput platform to analysis full-spectrum of lipid-metabolism-related genes and shed some light on the regulation of those genes by HCV core protein, ER stress in cultivated cells and also in patients’ tissue samples of hepatocellular carcinoma.
論文目次 Abstract (in Chinese) I
Abstract (in English) III
Acknowledgements V
Index VI
Table/Figure/Appendix Index VIII
Reagents and Instruments XI
Chapter 1 Introduction 1
A. Hepatitis C virus (HCV) 3
B. HCV core protein 15
C. Endoplasmic reticulum stress (ER stress) 20
D. Lipid metabolism 24
E. Study goal and experimental strategy 30
Chapter 2 Materials and Methods 31
A. Establishment of genes profile involving lipid metabolism 33
B. Expression of HCV core proteins in human hepatoma cell lines 33
C. Analysis of genes expression in HCV core-transfected
Huh7 cell lines 61
D. Analysis of genes expression in Huh7 cell lines treated
with ER stress inducer 64
E. Analysis of genes expression in hepatoma tissue samples 66
Chapter 3 Results 69
A. Establishment of genes profile involving lipid metabolism 70
B. Expression of HCV core proteins in Huh7 cell lines 70
C. Analysis of genes expression in HCV core-transfected
Huh7 cell lines 71
D. Analysis of genes expression in Huh7 cell lines treated
with ER stress inducers 74
E. Analysis of genes expression in hepatoma tissue samples 76
Chapter 4 Discussion 78
A. Previous remark of HCV core protein, lipid metabolism, ER stress and carcinogenesis 79
B. Analysis of different genotypes of HCV core proteins 80
C. Effect of HCV core protein on genes involving lipid metabolism 81
D. Effect of ER stress on genes involving lipid metabolism 83
E. The possible roles of amyloid A4 (SAA4), glycerol-3-phosphate acyltransferase, mitochondrial (GPAM) and apolipoprotein E (APOE) in HCV infection 84
Conclusions 87
References 88
Tables / Figures 95
Appendixes 165
Author 169
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