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研究生:蕭尊先
研究生(外文):Tsun-HsienHsiao
論文名稱:探討10-甲醛四氫葉酸相關酵素之生理意義與調控
論文名稱(外文):Exploring the biological significance and regulation of 10-formyltetrahydrofolate related enzymes
指導教授:傅子芳
指導教授(外文):Tzu-Fun Fu
學位類別:博士
校院名稱:國立成功大學
系所名稱:基礎醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2018
畢業學年度:106
語文別:英文
論文頁數:97
中文關鍵詞:葉酸-單碳循環斑馬魚10-甲醛四氫葉酸去氫酶粒線體型亞甲基四氫葉酸去氫酶
外文關鍵詞:folate-mediated one-carbon metabolism (FOCM)zebrafishFDHMTHFD1L
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葉酸-單碳循環為生物體內相當重要且基礎的生化代謝路徑之一,在其中藉由各種酵素的催化而合成嘌呤、嘧啶、胺基酸與S-腺苷甲硫氨酸等生物分子參與在細胞複製、生物巨分子甲基化等重要的生理反應。先前的研究中指出,葉酸缺乏或單碳循環被擾亂可能和某些先天性缺陷、腫瘤生成、甚至是精神疾病有關,但其中詳細的分子機轉卻仍不是相當清楚。所以知道葉酸-單碳循環在葉酸缺乏或是其中葉酸衍生物不均的情況下如何被調控是需要的。因此,本研究分別以酒精處理與過量表現γ穀胺酸水解酶所造成的葉酸缺乏於斑馬魚動物模式中來探討此問題。在酒精處理而擾亂單碳循環的情況下,我們發現10-甲醛四氫葉酸去氫酶的表現量會經由C/EBPα所調控而大幅上升,進而增加細胞內四氫葉酸的濃度並藉以緩解酒精所引起的氧化壓力傷害;另一方面,於熱誘導過量表現γ穀胺酸水解酶之葉酸缺乏基因轉殖魚中,我們發現其眼睛發育有明顯地受到影響,包括眼睛大小與視覺能力,而此眼睛縮小的表徵可能和異常的細胞增生與凋亡有關,進一步分析其葉酸單碳循環中葉酸衍生物的組成與葉酸相關酵素的表現量後發現,在整個分析的發育週期內5-甲基四氫葉酸的含量皆十分低落,但相對的10-甲醛四氫葉酸含量就有逐漸上升且穩定的趨勢,此10-甲醛四氫葉酸濃度的上升可能是細胞藉由調控粒線體型亞甲基四氫葉酸去氫酶所用以補充生成去氧核醣核酸之原料所致。而5-甲基四氫葉酸的含量低落也使得視黃酸代謝酵素表現被異常調控,進而影響斑馬魚的視力與眼睛的分化。總和以上的發現,我們知道在細胞面對葉酸缺乏或干擾的情況下,葉酸-單碳循環會被有效地調控,進而使細胞有足夠且特定的葉酸衍生物來抵抗這些困境。
Folate-mediated one-carbon metabolism (FOCM) is an essential network of biochemical pathways in charge of nucleotide and amino acid synthesis and methyl donor production. Disturbance of FOCM and inadequate intracellular folate content have been reported to increase the risks of developmental defects, tumorigenesis, and mental disorders. However, the underlying mechanisms remain unclear. Herein, zebrafish, a widely used animal model for biomedical research, is used to investigate the regulation of disturbed FOCM, which was induced by ethanol treatment and folate deficiency (FD), and the resulting implications for fetal alcohol syndrome and ocular defects. Ethanol treatment increased the content of tetrahydrofolate (THF) but decreased that of 5-methyltetrahydrofolate (5-CH3-THF). The elevated content of THF resulted from up-regulated 10-formyltetrahydrofolate dehydrogenase that was transactivated by C/EBPα in order to alleviate the ethanol-induced oxidative stress. In the heat-shock-induced FD zebrafish model, ocular development was significantly impaired, including microphthalmia and visual inability. The reduced eye size of FD embryos may have resulted from abnormal cell proliferation and apoptosis. Analyzing the content of individual folate derivatives and mRNA expression of folate enzymes between control and FD embryos suggests that embryos that developed under the FD condition might have altered the FOCM with up-regulated mthfd1L at a late stage to maintain intracellular 10-formyltetrahydrofolate content for supporting cell proliferation. The consistently low level of 5-CH3-THF might have interfered with the expression of retinoic-acid-related enzymes and further contributed to the visual ability and eye differentiation of FD embryos. From above results, we concludes that cells flexibly regulate FOCM for maintaining particular folate derivatives against difficulties under conditions with an imbalanced or inadequate folate pool.
中文摘要 I
Abstract II
Acknowledgement III
Contents IV
Contents of tables and figures VII
Abbreviations IX
I. Introduction 1
1.1 Folate 1
1.2 Absorption of reduced folate and folic acid 1
1.3 Folate-mediated one-carbon metabolism 2
1.4 Intracellular compartmentation of FOCM 3
1.5 Folate deficiency 4
1.6 10-formyltetrahydrofolate dehydrogenase 5
1.7 Methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like 6
1.8 Zebrafish 7
1.9 FOCM-related studies using zebrafish as model organism 7
II. Rationale and Aims 9
III. Materials and methods 10
3.1 Materials 10
3.2 Fish stock and maintenance 10
3.3 Cell culture 10
3.4 Bacterial stains and vector plasmids 11
3.5 Induction of folate deficiency 12
3.6 Eye size measurement and histological analysis 12
3.7 Whole-mount immunostaining 13
3.8 Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay 13
3.9 Flow cytometry for cell cycle analysis 13
3.10 Quantification of gene expression levels 14
3.11 Embryonic folate content analysis 14
3.12 Zebrafish mthfd1l cloning 15
3.13 Knockdown and rescue of zebrafish mthfd1L 15
3.14 Primary culture from zebrafish embryos 16
3.15 Immunofluorescent staining of cultured cell 16
3.16 Compound treatment 17
3.17 Optomotor response (OMR) assay 17
3.18 Mitofraction and Western blotting 17
3.19 Liver area quantification 18
3.20 Statistical analysis 18
IV. Results 19
4.1 Ethanol-induced up-regulation of FDH helps alleviate ethanol-induced oxidative stress 19
4.2 Folate deficiency affects eye development including microphthalmia and impaired visual ability 19
4.2.1 Folate deficiency induces microphthalmia 19
4.2.2 Folate deficiency impairs visual ability 20
4.3 Folate deficiency decreases proliferation at early stage and increases apoptosis at late stage 20
4.3.1 Folate deficiency interferes with cell proliferation and apoptosis during embryogenesis 20
4.3.2 Folate deficiency affects cell cycle 21
4.4 Folate-deficiency-induced eye size reduction and vision inability may result from different mechanisms through disturbance of FOCM 21
4.4.1 Folate-deficiency-induced microphthalmia may result from inadequate nucleotides but not oxidative stress 21
4.4.2 Folate deficiency disturbs contents of different folate derivatives 22
4.4.3 mthfd1L is up-regulated in folate-deficient embryos 23
4.5 Overexpressed mthfd1L at early stage improves eye size and visual ability of folate-deficient embryos 24
4.5.1 Zebrafish Mthfd1L is localized in mitochondria 24
4.5.2 Knocking down of mthfd1L induces microphthalmia 25
4.5.3 Mthfd1L participates in FOCM regulation 25
4.5.4 Overexpressed mthfd1L at early developmental stage can rescue eye size reduction of folate-deficient embryos 26
4.6 mthfd1L expressional level interferes with endogenous mthfr expression 26
4.7 Folate-deficiency-induced 5-CH3-THF decrease contributes to defects of ocular differentiation by interfering with retinoic acid metabolism 28
4.7.1 Folate deficiency affects ocular differentiation 28
4.7.2 Retinoic acid supplementation can rescue both eye size and ocular differentiation of folate-deficient embryos 28
4.7.3 aldh1a3 is down-regulated in folate-deficient embryos 29
4.8 Folate deficiency induces hepatomegaly 29
4.8.1 Folate deficiency may affect liver development 29
4.8.2 Folate-deficiency-induced hepatomegaly can be independent from affecting liver development 30
4.8.3 Folate supplementation can rescue enlarged liver of folate-deficient larvae 30
4.9 Folate deficiency or folic acid supplementation leads to fluctuation of folate derivatives in different tissues 31
V. Discussions 32
5.1 Folate acts as natural anti-oxidant 32
5.2 Dysregulation of 5-CH3-THF and 10-CHO-THF content implies folate-deficiency-induced microphthalmia and eye misdifferentiation 32
5.3 Fluctuation of folate composition of folate-deficient zebrafish embryos implies priority of FOCM regulation in folate limiting environment 34
5.4 Regulation of mthfd1L 35
5.5 FA supplementation needs more consideration 36
5.6 Folate composition is tissue-heterogeneous 37
VI. Conclusion 39
VII. References 40
VIII. Tables 47
IX. Figures 49
X. Appendices 69
XI. Author 86
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