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系統識別號 U0026-0502201416025400
論文名稱(中文) 營養壓力對於蘋果酸-天門冬胺酸運輸器剔除細胞影響之研究
論文名稱(英文) Effects of nutrient stress on malate-aspartate shuttle-silencing cells
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 102
學期 1
出版年 103
研究生(中文) 王貝慈
研究生(英文) Bei-Tzu Wang
學號 t36004039
學位類別 碩士
語文別 英文
論文頁數 72頁
口試委員 指導教授-謝淑珠
口試委員-陳炯瑜
口試委員-蕭廣仁
口試委員-凌斌
口試委員-周言穎
中文關鍵字 第二型瓜胺酸血症  精胺丁二酸合成酶  營養壓力  氧化壓力 
英文關鍵字 Type II citrullinemia  Argininosuccinate synthetase  Nutrient stress  Oxidative stress 
學科別分類
中文摘要 蘋果酸(malate)-天門冬胺酸(aspartate)(MA)運輸器位於粒線體的內膜上,主要將細胞質nicotinamide adenine dinucleotide reduced form (NADH)上的還原物質送入粒線體,進行氧化代謝以維持細胞能量的恆定。檸檬素(citrin)為MA運輸器的主要載體蛋白質之一,參與天門冬胺酸-榖胺酸(glutamate)的運輸,提供尿素、蛋白質和核酸生合成所需之物質;另外檸檬素在粒線體鈣離子的平衡也扮演著不可或缺的角色。檸檬素缺乏的臨床症狀表現為新生兒膽汁淤積症與第二型瓜胺酸血症。在新生兒檸檬素缺乏致成膽汁淤積症的患者中常被檢測出有半乳糖血症,但並非每位新生兒膽汁淤積症患者皆會在成年時期發生第二型瓜胺酸血症。因此本篇研究目的主要是探討葡萄糖與半乳糖對於檸檬素缺乏之HepG2細胞的影響,以及是否合併給予H2O2氧化壓力對細胞之影響;並且探討給予丙酮酸(pyruvate),甘胺酸(glycine)或是N-乙醯基半胱胺酸(N-acetylcysteine)是否對細胞有保護作用。我們利用shRNA抑制檸檬素基因(SLC25A13)的表現以阻斷蘋果酸-天門冬胺酸路徑;並以流式細胞儀檢測粒線體膜電位的變化,及細胞中三磷酸腺苷的濃度反映細胞存活率。氧化壓力的評估則利用液相層析串聯質譜儀檢測細胞質NADH/NAD+的比值以及螢光探針2,7-dichlorofluorescin dictate (DCFH-DA)檢測細胞內自由基含量。並且利用液相層析質譜儀測定細胞內代謝物天門冬胺酸及穀胺酸之變化。在檸檬素缺乏的細胞中,半乳糖會導致精胺丁二酸合成酶(argininosuccinate synthetase, ASS)明顯降低(p<0.01)而且提高自由基的產生(p<0.01)與細胞中的天門冬胺酸與穀胺酸比值上升 (0.06在半乳糖培養vs. 0.04在低葡萄糖培養, p<0.05)。半乳糖會使合併給H2O2的檸檬素缺乏細胞之粒線體膜電位下降(p<0.05);並且使其氧化壓力耐受能力降低,造成細胞質NADH/NAD+比值(p<0.05)、自由基(p<0.005)以及細胞天門冬胺酸與穀胺酸比值(p<0.005)的上升,最後致成細胞死亡的增加(p<0.005)。此現象在葡萄糖培養的檸檬素缺乏細胞中並不明顯,顯示半乳糖在第二型瓜胺酸血症的發病機制中可能扮演重要角色。給予丙酮酸,甘胺酸或N-乙醯基半胱胺酸則可以有效預防檸檬素缺乏細胞在半乳醣與氧化壓力作用下所產生的傷害,降低NADH的堆積、自由基的產生以及細胞中天門冬胺酸與穀胺酸比值並且提高粒線體膜電位與細胞存活率。其中丙酮酸更能有效回復營養壓力致成的精胺丁二酸合成酶表現下降(p<0.05)。總結來說,本研究結果顯示營養壓力與氧化壓力在第二型瓜胺酸血症的發病機制扮演重要角色,檸檬素缺失的病人應該避免含有半乳糖的飲食及氧化壓力;而丙酮酸,甘胺酸或N-乙醯基半胱胺酸則可以做為檸檬素缺乏病患的新治療策略。
英文摘要 Malate-aspartate (MA) shuttle, locating on the inner membrane of mitochondria, is essential for maintaining cellular bioenergetic states via the redox and transaminase reactions. The defect of citrin, a component of MA shuttle, is associated with neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2). NICCD patients present metabolic abnormalities including galactosemia. However, it’s unknown why symptoms of NICCD patients resolve within first year of life and some of patients develop CTLN2 decades later. Treating NICCD patients with lactose (galactose)-restricted formula has been shown to improve clinical symptoms. Therefore, we aimed to investigate the effects of high glucose-, low glucose- or galactose on MA shuttle-silencing HepG2 cells. The silencing was achieved genetically with SLC25A13 shRNA. Furthermore, we examined whether supplement of specific amino acids would alleviate these effects. Mitochondrial membrane potential (MMP) using Rhodamine 123 or JC-1 dye and cell viability by ATP levels were measured. Oxidative stress was assessed by cytosolic NADH/NAD+ ratio and intracellular reactive oxygen species (ROS) levels using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) and fluorescence spectrophotometer, respectively. The concentrations of intracellular metabolites were measured by LC-MS/MS. In citrin knockdown-(KD) cells, galactose-supplemented medium significantly caused reduced levels of cytosolic argininosuccinate synthetase (ASS) (p<0.01), and increased oxidative stress (p<0.01) and intracellular aspartate/glutamate ratio (0.06 in galactose supplement vs. 0.04 in low glucose supplement, p<0.05), compared to low glucose supplement. The addition of H2O2 induced the decrease of MMP (p<0.05) in galactose-supplemented citrin-KD cells. Furthermore, citrin-KD cells grown in galactose medium showed higher degree of vulnerability to H2O2, indicated by increased cytosolic NADH/NAD+ (p<0.05), ROS (p<0.005) and intracellular aspartate/glutamate (p<0.005), and decreased cell viability (p<0.005), compared to low glucose medium. The pretreatment of pyruvate, glycine or NAC was effective in increasing the cell viability and MMP, and decreasing the accumulation of cytosolic NADH, intracellular ROS and intracellular aspartate/glutamate; thus protecting citrin-KD cells against nutrient and oxidative stress. The supplement of pyruvate ameliorated the reduction of cytosolic ASS in galactose-treated citrin-KD cells (p<0.05). Taken together, our results suggest that patients with citrin defect should avoid galactose-containing food and oxidative stress, and pyruvate, glycine or NAC may be beneficial for patients with citrin deficiency.
論文目次 Index

Abstract (in Chinese)……………………………………………………………………………………………I
Abstract (in English) …………………………………………………………………………………………III
Acknowledgement……………………………………………………………………………………………………………V
Index………………………………………………………………………………………………………………………………………VI
Figure list………………………………………………………………………………………………………………………VIII
Appendix list…………………………………………………………………………………………………………………X
Abbreviation……………………………………………………………………………………………………………………XI

Introduction
Malate aspartate shuttle……………………………………………………………………………………1
Citrin……………………………………………………………………………………………………………………………………1
Neonatal intrahepatic cholestasis caused by citrin deficiency…………………………………………………………………………………………………………………………2
Adult-onset type II citrullinemia……………………………………………………………3
Prevalence…………………………………………………………………………………………………………………………4
Citrin deficiency and argininosuccinate synthetase………………4
Citrin deficiency and carbohydrates………………………………………………………5
Citrin deficiency and oxidative stress………………………………………………6
Therapeutic strategies for patients with citrin deficiency…………………………………………………………………………………………………………………………7
Pyruvate………………………………………………………………………………………………………………………………8
Glycine…………………………………………………………………………………………………………………………………9
N-acetylcysteine…………………………………………………………………………………………………………10

Aims and strategies…………………………………………………………………………………………………11
Material and methods
1. Cell culture………………………………………………………………………………………………12
2. Lentivirus-mediated transient citrin knockdown……………………………………………………………………………………………………………………………12
3. Separation of cytosolic and mitochondria-rich fraction………………………………………………………………………………………………………………………………13
4. Total protein analysis……………………………………………………………………13
5. Western blot analysis………………………………………………………………………14
6. Mitochondrial membrane potential…………………………………………16
7. Cell viability assay…………………………………………………………………………17
8. Measurement of cytosolic NADH and NAD+ by LC-MS/MS………………………………………………………………………………………………………………………………………17
9. ROS detection by 2’,7’-dichlorofluorescin diacetate……………………………………………………………………………………………………………………………19
10. Measurement of intracellular metabolites by LC-MS/MS………………………………………………………………………………………………………………………………………19
11. Statistical analysis…………………………………………………………………………20

Results…………………………………………………………………………………………………………………………………22
Discussion…………………………………………………………………………………………………………………………27
Conclusion…………………………………………………………………………………………………………………………31
References…………………………………………………………………………………………………………………………32
Figures…………………………………………………………………………………………………………………………………47
Appendixes…………………………………………………………………………………………………………………………64
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