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系統識別號 U0026-2908201621540900
論文名稱(中文) 不同碳水化合物對氧化壓力與精胺丁二酸合成酶之影響
論文名稱(英文) Effects of carbohydrate nutrients on oxidative stress and argininosuccinate synthetase
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 104
學期 2
出版年 105
研究生(中文) 廖建勲
研究生(英文) Jun-Xun Liao
電子信箱 pe630418@hotmail.com.tw
學號 T36031044
學位類別 碩士
語文別 中文
論文頁數 56頁
口試委員 召集委員-陳炯瑜
口試委員-凌斌
口試委員-周言穎
指導教授-謝淑珠
中文關鍵字 第二型瓜胺酸血症  精胺丁二酸合成酶  超氧化物  碳水化合物 
英文關鍵字 citrullinemia type II  argininosuccinate synthetase  carbohydrate  oxidative stress  mitochondria 
學科別分類
中文摘要 精胺丁二酸合成酶(Argininosuccinate synthetase, ASS)是一個廣泛分布的酵素,大量表現在肝臟與腎臟中。ASS催化瓜胺酸和天門冬胺酸生成精胺丁二酸。在尿素循環、一氧化氮及精胺酸的合成中ASS皆扮演重要的角色。瓜胺酸血症是一種遺傳性疾病,第一型瓜胺酸血症(CTLN1)是由於ASS1基因突變造成ASS缺失所致; 第二型瓜胺酸血症(CTLN2)是由於檸檬素(citrin)的基因SLC25A13突變所致。CTLN2病患肝臟的ASS活性明顯降低。先前的報導指出,碳水化合物包含葡萄糖、果糖、半乳糖會對CTLN2患者造成毒性並加速死亡,然而其機制不清楚。目前採用乳糖限制的飲食及丙酮酸作為CTLN2的治療,顯示碳水化合物在CTLN2的病程中扮演重要的角色。因此,本研究探討碳水化合物對於肝細胞氧化壓力以及細胞質ASS的影響; 並且探討抗氧化物丙酮酸、N-乙醯半胱胺酸、或甘胺酸是否能回復碳水化合物造成的改變。肝細胞AML12培養在含有半乳糖、果糖或兩種低濃度(13.5 mM及9 mM)葡萄糖的培養基中,以18mM葡萄糖培養基的作為控制組。發現細胞在半乳糖、果糖或低濃度葡萄糖培養,會上升粒線體超氧化物,以及下降粒線體膜電位和細胞質ASS的表現量。在給予N-乙醯半胱胺酸或丙酮酸的處理下可以有效降低13.5 mM葡萄糖培養基致成的粒線體超氧化物增加(p<0.05),但是無法有效回復在9 mM葡萄糖所增加的粒線體超氧化物。在C57BL/6小鼠實驗方面,餵食半乳糖取代40 %或60 %原有糖分的飲食一個月,探討血清肝功能檢驗及肝臟氧化壓力與ASS的表現。小鼠在餵食40%或60%半乳糖後,體重與控制組相比明顯的下降(19.8, 17.8 vs. 21.2 g, p<0.001)。60%半乳糖會致成較高的血清AST(96 vs. 53 U/L, p<0.05)、ALT (33 vs. 20 U/L, p<0.05)、ALP活性 (113 vs. 93 U/L, p<0.05)及總膽汁酸濃度(3.59 vs. 1.14 μmol/L, p<0.001)。肝臟脂質的過氧化物在餵食40%的小鼠會上升 (118 vs. 100 nmol/g, p<0.05),在60%半乳糖的小鼠上升幅度更大(133 vs. 100nmol/g, p<0.01)發生。另一方面,我們也以腹腔注射的方式給予小鼠500 mg/kg半乳糖60天,注射半乳糖會上升血清AST活性與ALT活性以及肝臟脂質過氧化物的濃度。在肝切片染色中發現注射半乳糖小鼠會造成嚴重的肝臟損傷,包括包膜發炎及壞死。總結,我們的結果顯示,當葡萄糖不足的情況下會誘導肝細胞粒線體氧化壓力上升,並且使粒線體的膜電位與ASS表現量下降,而給予丙酮酸及N-乙醯半胱胺酸的治療可以有效的提供保護。動物實驗的結果中看到半乳糖會造成肝臟的損傷以及氧化壓力,這都指出半乳糖和氧化壓力與肝臟ASS的表現量有相關的。
英文摘要 SUMMARY

Argininosuccinate synthetase (ASS), catalyzing the synthesis of argininosuccinate from aspartate and citrulline, plays an important role in urea cycle and the synthesis of nitric oxide and arginine. Citrullinemia is an autosomal recessive urea cycle disorder, caused by defective ASS or citrin. Carbohydrate uptake exacerbates the symptoms of type II citrullinemia and leads to early death. Nutrient stress such as galactose and low glucose was shown to enhance oxidative metabolism and mitochondrial dysfunction, indicating carbohydrates may play an important role in the pathogenesis of citrin deficiency. Therefore, this study was aimed to examine the effects of carbohydrate nutrients on oxidative stress and cytosolic ASS levels in hepatocytes, and to investigate whether antioxidants wound alleviate these changes. AML12 hepatocytes were cultured in DMEM/F12 medium with different carbohydrate nutrients, including 18 mM glucose, 13.5 mM glucose, 9 mM glucose, 9 mM glucose plus 9 mM galactose and 9 mM glucose plus 9 mM fructose. C57BL/6 mice were fed with galactose diet for one month or injected intraperitoneally with galactose for two months. The results showed that glucose–insufficiency induced mitochondrial oxidative stress and decreased ASS levels in hepatocytes. NAC or pyruvate treatment decreased mitochondrial superoxide production in hepatocytes cultured in 13.5 mM glucose-containing medium. In vivo results showed that intake of galactose caused liver damage and oxidative stress in mice. In conclusion, carbohydrate nutrients are related to oxidative stress and ASS expression in vivo and in vitro.
Key words: citrullinemia type II; argininosuccinate synthetase; carbohydrate; oxidative stress; mitochondria.

INTRODUCTION

Argininosuccinate synthetase (ASS), catalyzing the conversion of argininosuccinate, plays an important role in urea cycle and synthesis of nitric oxide and arginine. ASS is expressed mainly in liver and kidney. Decrease hepatic ASS enzyme activity is associated with citrullinemia, a genetic urea cycle disorder. Citrullinemia type I (CTLN1) is caused by mutations of ASS gene, and type II (CTLN2) or neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) by mutations of SLC25A13 gene, which encodes citrin protein. Patients with CTLN2 had decreased liver-specific ASS activity. Previous studies showed carbohydrate intake, including glucose, fructose, and galactose exacerbates the symptoms of CTLN2 patients and leads to early death. However, the mechanism is unclear. CTLN2 patients are treated with lactose-restricted formula and sodium pyruvate. Nutrient stress such as galactose and low glucose has been shown to enhance oxidative metabolism and mitochondrial dysfunction, indicating that carbohydrates may play an important role in the pathogenesis of CTLN2.

MATERIALS AND METHODS

In vitro experiment, to investigate the effects of carbohydrate nutrient, AML12 hepatocytes were grown in DMEM/F12 medium with different carbohydrate nutrients, including 18 mM glucose, 13.5 mM glucose, 9 mM glucose, 9 mM glucose plus 9 mM galactose and 9 mM glucose plus 9 mM fructose. After 72 hours, we analyzed mitochondrial superoxide production and mitochondrial membrane potential by FACSCalibur flow cytometer (BD Biosciences, CA, USA).We measured ASS protein levels by western blotting.
In vivo experiment, C57BL/6 mice were fed with galactose diet for one month. In the other hand, mice were injected with galactose or glucose by intraperitoneal injection for 60 days. The mice were sacrificed and collected the liver. After anesthetizing by Zoletil, blood samples were obtained from inferior vena cava. Samples were stored at -80℃ freezer. Serum samples were analyzed for AST, ALT, ALP, and ALB by cobas system. We measured hepatic lipid peroxidation by MDA assay, iNOS and ASS expression by western blotting.

RESULTS AND DISCUSSION

Hepatocytes cultured in 13.5 mM had increased mitochondrial superoxide levels (76 vs. 57 %, p<0.01), as well as in 9 mM (86 vs. 57 %, p<0.001) glucose-containing medium. In addition, cells cultured in 13.5 mM glucose-containing medium exerted impaired mitochondrial membrane potential (MMP) and decreased ASS protein levels. Similarly, cells cultured in 9 mM glucose-containing medium had decreased MMP and decreased ASS protein levels. These data demonstrate that low glucose condition caused ROS in hepatocytes. NAC or pyruvate treatment reversed the decreased mitochondrial superoxide resulting from 13.5 mM glucose-containing culture medium, but not 9 mM glucose-containing medium. In animal experiment, C57BL/6 mice were fed standard chow diet, 40 %, or 60% galactose diet for one month to examine the changes of liver function and ASS expression. Mice fed with 40 % or 60% galactose diet lost a significant body weight (19.8, 17.8 vs. 21.2 g, p<0.001). Mice fed with 60% galactose diet had elevated serum AST (96 vs. 53 U/L, p<0.05), ALT (33 vs. 20 U/L, p<0.05), ALP (113 vs. 93 U/L, p<0.05), and total bile acid (3.59 vs. 1.14 μmol/L, p<0.001). Mice fed with 40 % or 60 % galactose diet also caused increased liver lipid peroxidation (118, 133 vs. 100 nmol/g, p<0.05, p<0.01). On other hand, mice were daily injected with galactose (500mg/kg) intraperitoneally for 60 days to examine the changes of liver functions. Mice injected with galactose had elevated serum AST (p<0.05) and ALT (p<0.05). Galactose injection caused bile acid profile change and increased liver lipid peroxidation (MDA 104 vs. 93 nmol/g, p<0.05), compared with control. Haematoxylin–eosin staining liver sections confirmed greater liver injury in galactose injection group with capsule inflammation, hepatocyte necrosis, and portal inflammation.

CONCLUSION

Our results indicate that the glucose–insufficiency induced mitochondrial oxidative stress and decreased MMP and ASS protein levels in hepatocytes. The treatment of pyruvate or NAC may provide protection against these changes. In mouse model, the results indicate that high galactose caused liver damage and oxidative stress. Galactose injection further led to liver histopathology changes. In conclusion, galactose is related to oxidative stress and ASS expression.
論文目次 索引
中文摘要 I
英文摘要 III
致謝 VII
索引 VIII
圖目錄 IX
縮寫索引 X
緒論 1
精胺丁二酸合成酶 1
瓜胺酸血症 2
瓜胺酸血症與碳水化合物 3
氧化壓力 5
一氧化氮合酶 6
N-乙醯基半胱胺酸 6
丙酮酸 7
甘胺酸 7
目的與實驗策略 8
材料和方法 9
細胞培養 9
細胞粒線體萃取 10
蛋白質定量 10
正十二丙烷硫酸鈉-聚丙醯胺凝膠電泳及西方墨點法 11
粒線體超氧化物測定 12
粒線體膜電位的測定 12
動物實驗 13
肝臟的丙二醛測量 13
血清生化檢驗 15
病理切片檢查 15
統計分析 15
結果 16
討論 20
總結 24
參考資料 25
圖表 37
附錄 49

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