臺灣博碩士論文加值系統

肝細胞核因子家族（hepatocyte nuclear factors, HNFs）為富含於肝臟中之轉錄因子，其能活化肝臟專一性基因之表現，亦於消化道、胰臟、肺臟及腎臟等器官中發現。近年來發現此類轉錄因子與類胰島素生長因子（insulin-like growth factors, IGFs）皆可表現於性腺（gonad），故性腺之發育及配子（gametes）之生成與成熟除受到傳統之下視丘（hypothalamus）-腦下腺（pituitary gland）-性腺之內分泌（endocrine）主軸之作用外，似亦受到性腺-固醇類荷爾蒙（steroids hormone）-HNFs-IGFs-性腺之自分泌（autocrine）或旁分泌（paracrine）之作用。本研究室先前已選殖並證實吳郭魚第一型之與型及第三型之型肝細胞核因子（HNF-1, -1及-3）與IGFs於其肝臟及性腺之表現，為明瞭HNFs系統之調控關係，故先選殖HNF-1及-3上游之第四型肝細胞核因子型（HNF-4），所選殖出之片段全長為2031 bp，其編碼區（coding region）胺基酸（amino acid）序列與其他物種（哺乳、鳥、兩棲及魚類等）比對後分別具80、81、79及89以上之相同度（identity）；另利用反轉錄酶-PCR反應（reverse transcription-PCR, RT-PCR）、PCR雜合反應（PCR hybridization）、西方墨點轉漬法（Western blot）及免疫化學染色分析法（Immunohistochemistry, IHC），分析其RNA及蛋白質之表現與分佈。結果顯示，HNF-4基因僅表現於腸（intestine）、腎（kidney）、肝（liver）及胃（stomach）等消化器官，且其表現量於肝最高，胃最低，而其蛋白多表現於此四者之上皮細胞核（epithelial nuclei）。雖HNF-4於性腺並無表現，但其可能於魚類消化生理代謝方面扮演重要角色；而另一方面HNFs家族間存在一複雜之相互調控關係，且HNF-4亦對遺傳代謝疾病—年輕型糖尿病（marturity onset diabetes of the young, MOD Y）極具相關性，如能釐清HNFs家族各因子間相互調控之情形，將有助於未來生醫研究之發展。

Hepatocyte nuclear factor (HNF)-4 is a liver-enriched transcription factor and belongs to the highly conserved member of the nuclear receptor superfamily. HNF-4 together with other factors play a key role in the tissue specific expression of a large number of genes involved in lipid and glucose metabolism. However, its function in fish is still poorly understood. In our previous study, RNAs and proteins of HNF-1, HNF-1, and HNF-3are detected in the liver, ovary, and testis of tilapia (Oreochromis mossambicus). And the expression of HNF-3 in the gonads could be induced by 17-estradiol and hydrocortisone in vitro. Besides, HNF-4 binding site on the promoter region of HNF-3 gene has also been found. However, there are only limited literatures dealing with HNFs in bony fish. The roles and their relation of HNFs in the physiology of fish remain to be explored. Here we report on the first cloning of full-length cDNA and protein localization of HNF-4from a tilapia (O. mossambicus). A total of 2,031 bp of tilapia HNF-4fhas been cloned and its deduced amino acid sequence of the coding region (340 amino acids) of tilapia HNF-4 has a 89% identity with that of zebrafish, over 84% with mammals (human, bovine, rat, and mouse), 81% with chicken, and 79% with Xenopus. RT-PCR detected HNF-4in liver, kidney, intestine and stomach, and the identity of the PCR fragments was confirmed by sequencing analysis and PCR hybridization. Its relative expression ratio was higher in the liver than in intestine and kidney, and lowest expression ratio was observed in stomach. The same result happened in both genders. Western blotting and immunohistochemical localization also detected HNF-4 protein in the tissues mentioned before. Expression of HNF-4 in the tilapia suggests that multi-HNFs may form a cascade to regulate physiology in the bony fish.

目錄
封面內頁
簽名頁
授權書 iii
中文摘要 iv
英文摘要 v
致謝
目錄 vii
圖目錄 x
表目錄 xi
附錄 xii

第一章 前言 1
第二章 文獻檢討 3
2.1肝細胞核因子（HNFs）簡介 3
2.2第四型肝細胞核因子 4
2.2.1第四型肝細胞核因子家族成 4
2.2.2第四型肝細胞核因子之結構與功能 5
2.3 第四型肝細胞核因子型 8
2.3.1 第四型肝細胞核因子型之簡介 8
2.3.2第四型肝細胞核因子型之結構與功能 9
2.4 研究目的 13
第三章 材料與方法 15
3.1 試驗材料 15
3.1.1試驗動物 15
3.2 試驗方法 15
3.2.1 吳郭魚HNF4-基因序列之選殖（cloning） 15
3.2.1.1吳郭魚肝臟核糖核酸（RNA）之抽取 16
3.2.1.2互補DNA（cDNA）之合成 16
3.2.1.3吳郭魚HNF-4部份（partial）cDNA序列之
選殖 17
3.2.1.4聚合酶連鎖反應（PCR） 18
3.2.1.5 RT-PCR產物電泳分析 18
3.2.1.6膠體萃取 19
3.2.1.7 連接反應與轉型作用（ligation reaction and
transformation） 19
3.2.1.8小量質體之抽取與定序 20
3.2.1.9選殖HNF-4全長序列 21
3.2.2 RT-PC觀察HNF-4於各組織之表現 21
3.2.3 南方點墨轉漬（Southern blot） 22
3.2.3.1 膠體轉印 22
3.2.3.2 探針（probe）之製備 23
3.2.3.3 雜合反應與壓片 23
3.2.4 西方點墨轉漬（Western Blotting） 23
3.2.4.1 蛋白質之萃取 24
3.2.4.2 蛋白質之定量 24
3.2.4.3 SDS-PAGE膠體之配製 25
3.2.4.3.1分離凝膠（separating gel）之配製 25
3.2.4.3.2堆積凝膠（stacking gel）之配製 25
3.2.4.4 電泳之進行 26
3.2.4.5 轉印 26
3.2.4.6 雜合與偵測 27
3.2.5 免疫組織化學法（Immunohistochemistry） 27
3.2.5.1 組織之石蠟包埋及切片 28
3.2.5.2 免疫組織化學分析 28
3.2.6 統計分析 29
第四章 結果 30
4.1第四型肝細胞核因子型（HNF-4）序列選殖 31
4.2 HNF-4序列分析 32
4.2.1 利用RT-PCR觀察 34
4.2.2 PCR-雜合反應 34
4.2.3 西方點墨轉漬 35
4.2.4 免疫組織化學法 35
第五章 討論 37
第六章 結論 43
參考文獻 86







圖目錄

圖一、肝細胞核因子家族間之調控路徑及其上、下游之相關因
子 44
圖二、各物種間第四型肝細胞核因子基因序列之比對 45
圖三、PCR選殖出吳郭魚第四型肝細胞核因子型之中段序列 47
圖四、PCR選殖出5’吳郭魚第四型肝細胞核因子型之序列 48
圖五、PCR選殖出3’吳郭魚第四型肝細胞核因子型之序列 49
圖六、吳郭魚之第四型肝細胞核因子型之序列及其RT-PCR
引子設計之位置 50
圖七、各物種間第四型肝細胞核因子型胺基酸序列之比對 54
圖八、吳郭魚第四型肝細胞核因子型之二級結構預測圖 56
圖九、吳郭魚第四型肝細胞核因子型之三維立體結構預測圖 58
圖十、各物種間第四型肝細胞核因子型胺基酸序列之比對 59
圖十一、各物種間第四型肝細胞核因子型胺基酸序列之比對 60
圖十二、各物種間第四型肝細胞核因子a型胺基酸DNA結合
區序列之比對 61
圖十三、各物種間第四型肝細胞核因子型胺基酸序列之雙
聚體/配位體結合區比對 62
圖十四、吳郭魚雄魚之RT-PCR及PCR-雜合反應 63
圖十五、吳郭魚雌魚之RT-PCR及PCR-雜合反應 65
圖十六、吳郭魚雄魚之第四型肝細胞核因子型西方墨點
法分析結果 67
圖十七、吳郭魚雄魚之第四型肝細胞核因子型西方墨點
法分析結果 68
圖十八、第四型肝細胞核因子型於腸道上皮細胞核之表現 69
圖十九、第四型肝細胞核因子型於腎小管上皮細胞核之表現 70
圖二十、第四型肝細胞核因子型於肝臟細胞核之表現 71
圖二十一、第四型肝細胞核因子型於胃上皮細胞核之表現 72
圖二十二、第四型肝細胞核因子型於腦、膽及鰓之表現 73
圖二十三、第四型肝細胞核因子型於心臟、肌肉、睪丸及卵
巢之表現 74









表目錄

表一、選殖吳郭魚HNF-4中段退化性引子之序列 76
表二、選殖吳郭魚HNF-4氮端專一性引子之序列 77
表三、選殖吳郭魚HNF-4碳端專一性引子之序列 78
表四、HNF-4之RT-PCR專一性引子 79
表五、吳郭魚HNF-4基因與其他物種間之序列比對 80
表六、各物種間第四型肝細胞核因子型胺基酸序列之比對 81
表七、各物種間第四型肝細胞核因子型胺基酸序列之比對 82










附錄

附錄一、各物種間HNF-4胺基酸序列比對之相似度及相同度
百分比 83
附錄二、各物種間HNF-4胺基酸DNA結合區之相似度及相同
度百分比 84
附錄三、各物種間HNF-4胺基酸序列雙聚體/配位體結合區之
相似度之相同度百分比 85

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