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系統識別號 U0026-3008201210302000
論文名稱(中文) 探討在檸檬素缺乏細胞的細胞質代謝變化
論文名稱(英文) Metabolic profiles in the cytosols of citrin-deficiency cells
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 100
學期 2
出版年 101
研究生(中文) 吳自強
研究生(英文) Zih-Ciang Wu
學號 T36994022
學位類別 碩士
語文別 英文
論文頁數 74頁
口試委員 口試委員-江美治
口試委員-蔡曜聲
口試委員-黃暉升
口試委員-凌斌
指導教授-謝淑珠
中文關鍵字 第二型瓜胺酸血症  串聯質譜儀  代謝物  檸檬素 
英文關鍵字 Type II citrullinemia  Tandem mass spectrometry  Metabolites  Citrin 
學科別分類
中文摘要 檸檬素(citrin)為一種位於粒線體內膜上的載體蛋白,其主要功能為交換粒線體內的天門冬胺酸(aspartate)及細胞質的穀胺酸(glutamate),而運送至細胞質的天門冬胺酸進一步用於尿素、胺基酸及蛋白質合成。檸檬素也是蘋果酸-天門冬胺酸路徑(malate-aspartate shuttle)的一員,負責將細胞質中的還原態nicotinamide adenine dinucleotide (NADH)送入粒線體中進一步合成三磷酸腺苷(ATP)。在檸檬素缺乏的病人身上常有代謝物失調及肝臟精胺丁二酸合成酶(argininosuccinate synthetase, ASS)缺乏,導致病人有高血氨甚至是猝死的情況發生。然而,檸檬素缺乏致成肝臟精胺丁二酸合成酶缺乏的分子致病機轉目前仍不明瞭。所以本研究目的為探討於檸檬素缺乏的人類肝癌細胞(Huh-7)及老鼠肝細胞(FL83B)中,其細胞質代謝變化,及這些代謝變化與ASS下降的關係;以及是否給予抗氧化劑或胺基酸得以回復細胞質代謝變化。我們使用高效能液相層析-串聯質譜儀建立一個可以同時測定細胞質天門冬胺酸、穀胺酸、蘋果酸、2-酮戊二酸 (α-ketoglutarate)及瓜胺酸(citrulline)的方法。我們利用專一性小髮夾RNA(shRNA)抑制檸檬素基因(SLC25A13)的表現,建立體外檸檬素缺乏的Huh-7及FL83B細胞來模擬檸檬素缺乏的肝臟。我們用西方墨點法來測定此細胞的檸檬素及ASS表現程度,而檸檬素及ASS在細胞內的分佈位置則利用免疫螢光染色及雷射共軛焦顯微鏡來進行觀測。本方法之偵測極限天門冬胺酸為1 μM,穀胺酸、蘋果酸、2-酮戊二酸及瓜胺酸為0.5 μM;標準曲線之測定上限天門冬胺酸及穀胺酸為500 μM,蘋果酸及2-酮戊二酸為250 μM,瓜胺酸為50 μM,其線性相關係數(r2)皆大於0.99。而方法同批次測定的變異係數(CV%)皆小於6.0% ,不同批次的變異係數皆小於11.8%,而平均回收率(recovery,N=4)天門冬胺酸為106.5%、穀胺酸為100.5%、蘋果酸為89.5%、2-酮戊二酸為117.5%、瓜胺酸為112.8%。於Huh-7細胞抑制SLC25A13後,其檸檬素幾乎完全不表現,然而與抑制LacZ的控制組細胞相比,其細胞質ASS沒有顯著下降。在免疫螢光染色方面顯示ASS和粒線體及檸檬素緊密相連,但抑制細胞檸檬素表現後並沒有看到ASS自粒線體脫離的現象。而抑制細胞檸檬素後,細胞質中天門冬胺酸顯著降低(8.0 vs 12.3 μmol/g, p<0.001),而其天門冬胺酸和穀胺酸的比值也顯著降低(61.0 vs 108.5, p<0.05)。另外,給予甲萘醌(menadione)提供超氧自由基後,細胞質代謝物有顯著變化,而在給予甲萘醌前若給予N-乙醯基半胱氨酸(N-acetylcysteine)或是甘胺酸(glycine),可以回復部分代謝變化。而在FL83B細胞株方面,抑制檸檬素表現後發現伴隨著細胞質ASS下降。而與控制組細胞相比,其細胞質的天門冬胺酸顯著降低(2.7 vs 3.8 μmol/g, p<0.05),瓜胺酸則顯著上升(3.8 vs 0.9 μmol/g, p<0.005)。總結,我們的研究數據顯示檸檬素為細胞質天門冬胺酸重要提供者,另外,檸檬素的有無存在不會顯著影響ASS與粒線體之間的作用。檸檬素的缺乏不是直接造成ASS下降的主要原因。
英文摘要 Citrin, an aspartate-glutamate carrier, is located on the mitochondria inner membrane for the exchanges of mitochondrial aspartate to the cytosolic glutamate for the synthesis of urea, nucleotide, and protein. Citrin also participates in the malate-aspartate shuttle to transport NADH-reducing equivalents into mitochondria for ATP production. Some patients with citrin deficiency presented metabolic disturbances and down-regulation of hepatic argininosuccinate synthetase (ASS), leading to hyperammonemia and death. However, the molecular mechanisms of citrin defect-induced down-regulation of hepatic ASS expression remain unknown. The aim of this study is to establish a method to simultaneously measure cytosolic metabolites, including aspartate, glutamate, malate, α-ketoglutarate, and citrulline by high performance liquid chromatography-tandem mass spectrometry and to investigate the metabolic profiles in citrin-knockdown Huh-7 and mouse hepatocytes, further to study the relationship between the metabolic changes and ASS and whether antioxidant (NAC), or amino acid supplementation would abrogate these changes. We had established an in vitro cell model to mimic citrin deficiency by specific knockdown of citrin using shRNA targeting to SLC25A13 in Huh-7 and FL83B cells. The expression of mitochondrial citrin and cytosolic ASS were assessed by Western blotting. The subcellular localization of citrin and ASS were evaluated by immunochemical staining with confocal microscopy. The calibration curves for the established method were linear up to 500 μM for aspartate and glutamate, 250 μM for malate and α-ketoglutarate, and 50 μM for citriulline (r2>0.99). Intra-run imprecision (CV%) of aspartate, glutamate, malate, α-ketoglutarate and citrulline was 2.5, 2.0, 6.0, 3.6,1.9, respectively. Inter-run imprecision (CV%) was 4.9, 5.6, 5.4, 11.8, 2.7 for aspartate, glutamate, malate, α-ketoglutarate, and citrulline, respectively. Mean recovery of aspartate, glutamate, malate, α-ketoglutarate and citrulline was 106.5 %, 100.5 %, 89.5 %, 117.5 %,and 112.8 %, respectively (N=4). Citrin was almost 100% suppressed in Huh-7 cells, but cytosolic ASS level was not significantly decreased, in comparison with shLacZ-treated cells. In Huh-7 cells, ASS was closely located with mitochondria and citrin, but knockdown of citrin did not cause the dissociation of ASS from mitochondria. The cytosolic aspartate decreased in citrin-knockdown Huh-7 cells, compared to shRNA control cells (8.0 vs 12.3 μmol/g, p<0.001). The ratio of cytosolic aspartate/glutamate was decreased in citrin-knockdown Huh-7 cells, compared to shRNA control (61.0% vs 108.5%, p<0.05). Administration of menadione changed the cytosolic metabolites, and pre-treatment of NAC or glycine would recovery part of them. In FL83B cells, citrin was partially suppressed and cytosolic ASS was decreased after knockdown of citrin. There were significant decreases on cytosolic aspartate concentrations (2.7 vs 3.8 μmol/g, p<0.05) and increase on cytosolic citrulline (3.8 vs 0.9 μmol/g, p<0.005) in citrin-knockdown FL83B cells, in compared with shRNA control cells. Also, knockdown of citrin didn't change the association of ASS from mitochondria in FL83B cells. Taken together, our data suggest that citrin is an important provider of cytosolic aspartate, while knockdown of citrin would not significantly dissociate of ASS from mitochondria. Moreover, citrin deficiency may not be the direct contributor to the reduction of ASS.
論文目次 Abstract (in Chinese)................................................................................... I
Abstract (in English)…………………………………………………….... II
Acknowledgement....................................................................................... IV
Index……………………………………………………………………… V
Table list…………………………………………………………………... VII
Figure list……………………………………………………………….… VIII
Appendix list……………………………………………………………… IX
Introduction
Citrullinemia and urea cycle………………………………………… 1
Classic citrullinemia (CTLN1).....…………………………………... 1
Type II citrullinemia ….………………………...............…………… 2
Characteristics of citrin......................……………………………….. 3
Treatment of citrin deficiency ……………………………………..... 4
Characteristics of argininosuccinate synthetase…..………………… 6
Citrin and ASS……………………….………...............................….. 8
Effects of N-acetyl-cysteine............................………………………. 9
Effects of glycine…………………………………………………….. 9
Aims and strategies………………………………………………………... 11
Materials and methods
1. Cell culture……………………………………………………… 12
2. Lentivirus mediated citrin-knockdown stable clone cells………. 12
3. Separation of cytosolic and mitochondria-rich fractions..…….... 13
4. Total protein analysis ……………………………………............ 14
5. Western blotting ……………………………………………........ 14
6. Protein visualization by confocal microscopy...……………….... 16
VI
7. Metabolites measurement by LC-MS/MS …………………......... 17
8. Detection of intracellular hydrogen peroxide by DCFH-DA……. 19
9. Menadione-induced oxidative stress ………………………........ 20
10. Statistical analysis ………………………………………………. 20
Results……………………………………………………………………... 21
Discussion…………………………………………………………………. 26
Conclusion………………………………………………………………… 30
References………………………………………………………………… 31
Tables……………………………………………………………………… 43
Figures…………………………………………………………………….. 44
Appendixes………………………………………………………………... 66
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