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研究生:戴米雪
研究生(外文):Mi-Hsueh Tai
論文名稱:薑黃素影響肝細胞PCSK9基因表達與低密度脂蛋白接受器之分子研究
論文名稱(外文):Molecular Effects of Curcumin on Modulation of PCSK9 and LDL Receptor Expression in HepG2 Cells
指導教授:顏瑞鴻顏瑞鴻引用關係
指導教授(外文):Jui-Hung Yen
口試委員:吳明娟江信仲
口試委員(外文):Ming-Jiuan WuShinn-Jong Jiang
口試日期:2014-07-08
學位類別:碩士
校院名稱:慈濟大學
系所名稱:分子生物暨人類遺傳學系碩士班
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:中文
論文頁數:83
中文關鍵詞:高膽固醇血症薑黃素低密度脂蛋白接受器PCSK9HNF-1αstatin藥物
外文關鍵詞:curcuminLDLRPCSK9HNF-1αstatin
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血液中含有過量的低密度脂蛋白膽固醇(low density lipoprotein cholesterol, LDL-C )被認為是造成高膽固醇血症、動脈粥狀硬化及心血管疾病的因素之一。肝臟為合成及代謝低密度脂蛋白的器官,血液循環中的低密度脂蛋白膽固醇會運送到肝臟,與肝細胞表面的低密度脂蛋白接受器(low density lipoprotein receptor, LDLR)結合,低密度脂蛋白膽固醇經由內吞作用(endocytosis)進入肝臟代謝,低密度脂蛋白接受器則循環回到細胞膜表面。Proprotein convertase subtilisin/kexin type 9 (PCSK9)也會與肝細胞膜上的低密度脂蛋白接受器結合,然而PCSK9主要功能為促使低密度脂蛋白接受器送往溶小體降解,PCSK9量過多將導致低密度脂蛋白接受器過度降解,促使低密度脂蛋白堆積在血液循環中,進而造成高膽固醇血症。因此, PCSK9抑制劑的開發為近幾年來治療高膽固醇血症與粥狀動脈硬化的重要方向。薑黃素(curcumin)從薑黃植物地下莖萃取出來的多酚類化合物,在先前研究中已證實具有抗氧化、抗發炎以及降低血液膽固醇的功效。本論文的主要研究目的,為探討薑黃素影響肝臟細胞中PCSK9基因表達,以及進一步影響低密度脂蛋白接受器之間的分子機制,並且探討臨床降膽固醇藥物statin與薑黃素合併使用,對於PCSK9基因表達與肝細胞吸收低密度脂蛋白的影響。
從本論文的研究結果中,我們發現薑黃素顯著增加HepG2細胞內以及細胞膜上低密度脂蛋白接受器的量,並且促進細胞外低密度脂蛋白之吸收。然而,薑黃素並不影響低密度脂蛋白接受器啟動子活性、mRNA表達與mRNA穩定度,因此我們推測curcumin藉由後轉譯方式調控低密度脂蛋白接受器的表達量。接下來,我們探討薑黃素對於PCSK9基因表達之影響。我們證明了薑黃素藉由抑制PCSK9啟動子活性、降低細胞內PCSK9 mRNA及蛋白質的表達、以及減少釋放於胞外成熟型PCSK9蛋白量,並且促進HepG2細胞吸收更多的低密度脂蛋白。我們也進一步確定PCSK9啟動子薑黃素作用的DNA區域,此DNA區域包含一段DNA序列為hepatocyte nuclear factor 1α (HNF-1α)的結合位。接下來,我們進一步證明薑黃素藉由降低細胞核內HNF-1α蛋白量進而減低細胞內HNF-1α蛋白與PCSK9啟動子結合,藉此抑制PCSK9啟動子活性,降低PCSK9轉錄作用。此外,我們也探討參與薑黃素抑制PCSK9基因表達可能的分子訊息路徑。由實驗結果發現,薑黃素可能經由影響ERK、JNK、或PI3-K訊息路徑抑制PCSK9之轉錄作用。最後,我們想探討合併使用statin藥物與薑黃素對於PCSK9表達及肝細胞吸收低密度脂蛋白之影響。實驗結果發現,HepG2細胞共同處理薑黃素與lovastatin藥物,薑黃素可以有效降低lovastatin所引起過多的PCSK9基因表達,並且促進肝細胞吞噬更多的低密度脂蛋白。
總結本論文的實驗結果,我們認為薑黃素是一種新的PCSK9小分子化合物抑制劑,薑黃素可以有效抑制PCSK9基因表達,增加膽固醇被肝細胞吸收進入細胞內進行代謝,並且可以作為臨床降膽固醇statin藥物的輔助治療藥物。本論文的研究成果,提供了開發預防或治療高膽固醇血症重要的保健食品或藥物的新方向。


關鍵字:高膽固醇血症; 薑黃素; 低密度脂蛋白接受器; PCSK9; HNF-1α; statin藥物

Elevated low-density lipoprotein cholesterol (LDL-C) in the plasma is a major risk factor for hypercholesterolemia, atherosclerosis and cardiovascular disease. The hepatic cells are the major site of synthesis and clearance of cholesteryl ester-rich lipoproteins. Most of circulating LDL is removed from the blood through hepatic LDLR-mediated endocytosis. LDLs bound to the LDLR are internalized in clathrin-coated pits and subsequently undergo lysosomal degradation, whereas the LDLR is recycled back to the cell membrane. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease bound the extracellular domain of LDLR and triggers its degradation in lysosome, resulting in increasing plasma cholesterol levels which is associated with hypercholesterolemia. Thus, PCSK9 inhibition is a promising therapeutic strategy for the prevention or treatment of hypercholesterolemia and atherosclerosis. Curcumin is a polyphenolic phytochemical obtained from the dried rhizome of the turmeric plant, which has been reported to possess the antioxidant, anti-inflammatory, anti-carcinogenic and anti-atherogenic properties. The aim of this study is to investigate the molecular mechanisms underlying the hypocholesterolemic effects of curcumin, with a special focus on PCSK9 expression and its subsequent influence on LDLR expression in HepG2 cells. The effects of combining statin and curcumin on PCSK9 expression and LDL uptake were also examined.
In the present study, we found that curcumin increases the level of total LDLR protein, cell-surface LDLR, and extracellular LDL uptake in HepG2 cell. However, the LDLR promoter activity, mRNA expression, and mRNA stability were not changed in curcumin-treated HepG2 cells. These results indicated that curcumin may regulate LDLR expression at post-translational level. Next, we investigated the effect of curcumin on the PCSK9 gene expression. We found that curcumin decreases the activity of PCSK9 promoter and attenuates the levels of PCSK9 mRNA, intracellular protein and secreted mature protein, resulting in increasing LDL uptake in HepG2 cell. We also identified the curcumin-responsive element of the PCSK9 promoter, a binding site for hepatocyte nuclear factor 1α (HNF-1α). We further demonstrated the curcumin decreased the level of nuclear hepatocyte nuclear factor-1α (HNF-1α), resulting in its attenuated interaction with the PCSK9 promoter and leading to a down-regulation of PCSK9 gene expression. Moreover, we investigated the signaling pathways involved in curcumin-mediated PCSK9 reduction. Our results showed that curcumin may be via ERK-, JNK- or PI3/Akt-dependent pathways to down-regulate PCSK9 expression. Finally, we examined the effect of a combination of curcumin and lovastatin on PCSK9 expression and LDL uptake in HepG2 cells. Our results showed that curcumin decreases the statin-induced PCSK9 gene expression, enhances LDL uptake and potentially synergizes with statin administration. Our findings demonstrate that curcumin is a novel, small molecule inhibitor of PCSK9 gene expression and may be a beneficial supplement to statin therapy for hypercholesterolemia.


Key words: curcumin; LDLR; PCSK9; HNF-1α; statin

中文摘要 I
Abstract III
目錄 V
圖表目錄 VII
緒論 1
1. 膽固醇(cholesterol)的功能、運送與量的調控 1
2. 低密度脂蛋白與心血管疾病 2
3. 家族性高膽固醇血症 2
4. Proprotein convertase subtilisin/kexin type 9 (PCSK9)基因與高膽固醇血症 4
5. 影響PCSK9基因表達之分子 5
6. 抑制PCSK9在治療高膽固醇血症之重要性 6
7. Statins藥物與PCSK9基因 6
8. 天然物影響脂質代謝之研究文獻 7
9. 薑黃素(Curcumin)影響膽固醇代謝之研究文獻 8
10. 研究動機與目的 9
材料與方法 10
1. 試劑與藥品 10
2. 細胞培養及藥物處理 12
3. 細胞存活率的分析(MTT assay) 13
4. 定量反轉錄聚合酶鏈鎖反應(Quantitative Reverse Transcription PCR; qRT- PCR) 13
5. 西方墨點法(Western blotting) 15
6. Reporter assay 17
7. 以流式細胞儀( flow cytometry)偵測細胞膜上低密度脂蛋白接受器(LDL receptor) 18
8. DiI-LDL uptake的測定 19
9. mRNA穩定性的測定 19
10. 染色質免疫沈澱分析技術 (Chromatin immunoprecipitation (ChIP) assay 20
11. siRNA轉染HepG2細胞 21
12. 建立HNF-1α knockdown之HepG2細胞 21
13. 統計分析Statistical Analysis 21
結果 22
1. 薑黃素(curcumin) 對於 HepG2 細胞存活之影響 22
2. Curcumin對低密度脂蛋白接受器(LDL receptor, LDLR)量之影響 22
3. Curcumin對於細胞膜表面上低密度脂蛋白接受器量與功能之影響 22
4. Curcumin對於低密度脂蛋白接受器基因表達之影響 23
5. Curcumin對於PCSK9基因表達量之影響 24
6. 降低PCSK9基因表達量對低密度脂蛋白接受器活性之影響 25
7. Curcumin對於PCSK9 mRNA穩定度與啟動子活性之影響 26
8. Curcumin對於HNF-1α與SREBP2影響PCSK9 轉錄作用之分析 27
9. Curcumin對於細胞核內HNF-1α蛋白之影響 28
10. 降低HNF-1α表達量對PCSK9基因表達之影響 29
11. Curcumin對HNF-1α基因表達之影響 30
12. 影響PCSK9轉錄調控之可能分子訊息路徑 30
13. 合併使用statins藥物與curcumin對於PCSK9基因表達之影響 31
14. 合併使用statins藥物與curcumin對於HepG2細胞吸收LDL之影響 32
討論 33
參考文獻 38


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