臺灣博碩士論文加值系統

細胞鐵的恆定取決於鐵的獲取（uptake）、鐵的儲存與鐵的利用。鐵的獲取與細胞膜上轉鐵蛋白受器（transferrin receptor, TfR）數目有關，鐵的貯存由鐵蛋白（ferritin）負責，鐵的利用則視各種含鐵酵素的需要而定。已知細胞內鐵貯存與利用相關蛋白質主要由IRPs (iron regulatory protein)：IRP1與IRP2 調控，細胞鐵量的高低會改變IRPs的活性，缺鐵時IRPs活性升高，可與鐵蛋白及粒線體aconitase（m-ACO）mRNA 5’端之IRE（iron responsive element）結合而減少兩者之蛋白質表現量，並且與TfR mRNA 3''UTR端之 IREs 結合而穩定其RNA；反之，高鐵時IRP1活性降低，IRP2降解，鐵蛋白及粒線體 aconitase（m-ACO）之表現不再受抑制，而TfR mRNA 穩定性降低。IRP1與IRP2之結構與功能雖相似，但調節機制卻有不同，除了鐵量之外，H2O2及NO等非鐵因子也會改變 IRP1與（或）IRP2的活性，進而對鐵代謝平衡有所影響，由細胞模式得知非鐵因子對IRP1與IRP2有分別調控（differential modulation）現象。
目前對非鐵因子之研究多侷限於細胞株，本研究乃以「動物實驗」探索膳食中可能影響IRPs活性之非鐵因子，研究中選擇炸油、魚油與降血脂藥物clofibrate為膳食因子，分三部份進行實驗。
第一部份以「炸油」為膳食因子，探討15% 炸油餵食時間（2-14天），並比較油脂種類（炸油和新鮮黃豆油）與膳食鐵量（控制組：35 ppm Fe與低鐵組：15 ppm Fe）對肝臟IRPs活性和鐵代謝相關蛋白質之影響。膳食低鐵會顯著降低血紅素濃度（9%），但對血清鐵、TIBC與Tf飽和度均無明顯影響；肝臟鐵濃度顯著降低，IRPs 活性上升，其中IRP1活性升高幅度未達顯著值，IRP2活性卻顯著升高62%，此時鐵蛋白含量已顯著降低，但m-ACO並無明顯下降，同時TfR mRNA含量顯著增加，有利於肝細胞鐵之攝入。
非鐵因子「炸油」餵食顯著降低大鼠血紅素、血清鐵、TIBC與Tf飽和度，且於低鐵因子並存時，鐵指標之降幅更為顯著，有增加貧血之危險性；炸油組降低肝鐵濃度，且於餵飼第2天起顯著活化IRP1，但不影響IRP2 活性，表示膳食炸油對IRP1與IRP2活性影響非同向，此現象與低鐵效應不同，乃炸油組之獨特效應。肝臟鐵蛋白濃度、總量與鐵濃度均受膳食炸油影響而降低，但m-ACO 活性與蛋白質量均顯著增加，鐵蛋白與m-ACO變化非同向表示除了IRPs之外，可能有其他未知訊息或機制參與調控。血清TIBC與肝臟Tf 降低現象一致，推測炸油餵食可能透過降低HNF-4αmRNA而負調控Tf基因表現於轉錄層次，使Tf mRNA減少。15% 炸油餵食的確會改變大鼠鐵代謝與其相關蛋白質表現，當低鐵因子並存時會劣化大鼠鐵營養狀況。
第二部份以「魚油」膳食因子。比較20% 魚油與椰子油結果顯示，肝臟鐵量與鐵蛋白濃度與總量因魚油餵食而顯著降低；15% 魚油與低鐵（15 ppm Fe）雙因子之2×2實驗顯示：魚油組之血清鐵、肝鐵與鐵蛋白總量均顯著降低，與低鐵因子並存時降幅更明顯，大鼠血紅素平均值更顯著減少了8%，表示於低鐵時，膳食魚油介入有劣化大鼠鐵營養狀況之虞。由two-way ANOVA統計結果得知IRP1活性顯著受膳食魚油影響而增加，IRP2活性不變；IRP2活性與TfR mRNA含量僅受低鐵影響而顯著增加；膳食魚油也顯著降低肝臟HNF-4αmRNA，以上魚油餵食引發大鼠肝臟鐵相關分子之變化均類似膳食炸油效應，唯一不同的是魚油組顯著升高血清銅、Cp活性與肝臟Cp mRNA 達50% 以上，不受膳食低鐵影響，此現象之生理意義有待進一步探討。
第三部份以降血脂藥「clofibrate」為非鐵因子，進行鐵量（控制組：35 ppm Fe與低鐵組：15 ppm Fe）和藥物（0 % 與0.5 % clofibrate）雙因子之2×2實驗。結果顯示clofibrate 組顯著降低血清鐵與TIBC約 50%，與肝臟 Tf mRNA表現一致，HNF-4αmRNA 亦顯著降低，推測clofibrate可能透過減少HNF-4α表現量，負調控Tf 基因表現。Clofibrate組之肝臟鐵蛋白含量不變，總鐵量顯著上升；膳食鐵量正常時，IRP1顯著受clofibrate因子影響而增加，與低鐵因子並存時，clofibrate會降低IRP2活性，同時肝臟TfR mRNA 亦顯著減少；m-ACO活性與蛋白質含量因clofibrate餵食而顯著增加一倍以上。Clofibrate處理除了影響鐵之外，也改變銅與鋅營養狀況，血清鋅、銅含量與Cp活性均顯著降低，肝臟Cp mRNA 降幅類似血清Cp活性，另外肝銅有明顯堆積現象，同時測得威爾遜氏症基因（ATP7B）mRNA顯著降低，表示銅自肝臟釋出機制有缺陷致使肝銅堆積。可見clofibrate餵食造成大鼠之鐵與銅代謝異常現象，其中以肝銅堆積最為顯著，以上結果具有臨床參考意義。
歸納低鐵與非鐵因子：炸油、魚油及clofibrate之主要結果如下：
1. 膳食低鐵明顯活化IRP2，顯著增加肝臟TfR mRNA含量，有利於細胞攝入鐵；當clofibrate與低鐵並存時，顯著抑制IRP2活性，同時TfR mRNA含量亦明顯降低，阻止細胞鐵之攝入，可緩和肝鐵堆積之程度。
2. 首次在動物體內証實︰IRP1與IRP2的確有分別調控之現象，肝臟IRP1活性受膳食非鐵因子影響，膳食炸油、魚油與藥物clofibrate均顯著活化IRP1，不影響IRP2活性；綜合膳食因子結果得知IRP2與TfR mRNA有明顯正相關，與鐵蛋白有負相關，因而推測IRP2可能是調控肝臟鐵恆定之主要因子。
3. 膳食炸油與魚油均造成大鼠缺鐵症狀，於膳食低鐵時更明顯，大鼠血紅素、血清鐵與Tf飽和度均顯著下降，肝臟總鐵量與鐵蛋白濃度和總量亦明顯降低。
4. 首次觀察到clofibrate餵食大鼠之肝臟有鐵與銅的堆積，血清Cp與Tf同時降低，兩者之肝臟 mRNA含量亦顯著減少，推測Tf與Cp同時下降可能干擾肝鐵外釋，因而導致血清鐵明顯降低。
綜合本研究結果發現：於大鼠模式中，膳食非鐵因子會影響肝臟鐵代謝及其相關蛋白質表現，而且對IRP1與IRP2有分別調控現象，其中IRP2可能是鐵相關蛋白質改變之主要調控因子，至於非鐵因子造成IRP1顯著活化的生理意義則有待進一步探討。

Intracellular iron homeostasis maintained by iron uptake, functional uses, and storage is performed by transferrin receptor (TfR), iron-containing proteins, and ferritin. Iron regulatory proteins (IRPs: IRP1 and IRP2) are cytoplasmic RNA-binding proteins that are central components of a sensory and regulatory network of iron homeostasis by binding to iron responsive element(s) (IREs) in the 5’ or 3’ untranslated region of ferritin, mitochondrial aconitase (m-ACO) or TfR mRNAs. Although structurally and functionally similar, the two IRPs are different in their model of regulation by numerous factors such as iron, hydrogen peroxide and nitric oxide. Differential modulation of this two IRPs has been proposed in cellular models. We tested this hypothesis in a rat model using dietary treatment of non-iron components: oxidized frying soybean oil, fish oil and hypolipidemic drug clofibrate. Diets were formulated according to AIN-76 but oil content was increased to 15% (w/w). In all the experiments, Wistar rats were used unless specified otherwise. Blood parameters measured included: hemoglobin, serum iron, total iron binding capacity, serum copper and ceruloplasmin (Cp). RNA binding activities of IRP1 and IRP2 were measured using electrophoretic mobility-shift assays. Ferritin and m-ACO proteins were measured using Western blot analysis. Message RNA levels of transferrin, TfR, Cp and Wilson''s disease gene (ATP7B) were measured using Northern blot analysis.
First, in a time-course study of the effect of oxidized frying oil on IRPs, liver IRP1 but not IRP2 activity increased rapidly from day 2 of the treatment. The interaction of oxidized frying oil and dietary iron levels on IRPs were investigated in a 2×2 design, using two iron levels (control at 35 ppm Fe and low iron at 15 ppm Fe) and fresh soybean oil as reference oil for 6-wks feeding. Rats fed the diet of low iron in combination with oxidized oil had the lowest levels of hemoglobin, serum iron and transferrin saturation among the four groups. Based on results of two-way ANOVA, IRP1 activity was significantly increased by oxidized frying oil treatment, IRP2 activity was increased at low dietary Fe level. In response to IRP2, TfR mRNA increased significantly. Hepatic Tf and HNF-4mRNA levels also decreased by oxidized oil. It is concluded that consumption of high level of oxidized frying oil will aggravate iron deficiency in rats fed low iron diet.
Second, the effect of fish oil and coconut oil on liver iron was compared in weanling male Sprague-Dawley rats, and it was observed that liver iron and ferritin concentration decreased significantly in rats fed fish oil. The interaction of fish oil and dietary iron levels on IRPs were investigated in a 2×2 design, using two iron levels (35 ppm and 15 ppm Fe) and fresh soybean oil as reference oil for 6-wks feeding. In rats fed fish oil, serum iron, hepatic iron and ferritin concentration were significantly lower; hepatic IRP1 but not IRP2 activity increased significantly; serum copper content and Cp activity were significanly elevated in consistent with the increase mRNA level of heaptic Cp regardless of iron status.
Finally, the effects and interaction of clofibrate (0.5%) and dietary iron levels (35 ppm and 15 ppm) on proteins related to iron and copper metabolism were studied in a rat model using 2 x 2 experimental design. Wistar rats (6 each group) were assigned to the four diets and fed for 6 wks. In clofibrate-treated rats, serum iron and total iron binding capacity, and serum copper and Cp were significantly reduced by 50% and 20%, respectively, which were consistant with the reduced mRNA levels of transferrin and Cp in the liver. Reduced Tf and Cp may be resposible for impaired hepatic iron release. Hepatic iron and DFO-chelatable iron concentrations were significantly elevated by clofibrate treatment. In clofibrate-treated rats, the RNA-binding activity of IRP1 but not IRP2 were significantly elevated even in the presence of increased iron concentration, indicating differential modulation of IRP1 and IRP2 activities. Hepatic TfR mRNA was increased by low dietary iron but inhibited by clofibrate. The activity and protein of m-ACO were elevated by clofibrate treatment regardless of dietary iron levels. Copper accumulated in the liver of clofibrate-treated rats, which may result from impaired coppper efflux due to reduction of Wilson’s disease gene (ATP7B) mRNA. We conclude that clofibrate treatment altered molecular regulation of iron and copper metabolism in the liver and resulted in impaired iron and copper transport. These observations may have clinical implications.
In summary, dietary factors other than iron affect RNA binding activities of hepatic IRP1 and IRP2. IRP2 but not IRP1 activity increased in response to moderately decreased dietary iron and plays an essential role in the regulation of iron homeostatsis. IRP1 activity was significantly elevated in the liver of rats fed oxidized frying oil or clofibate even though their hepatic iron concentrations were not depleted or higher than that of the normal rats. The physiological implication of this phenomenon is not understood. These results support that differential modulation of hepatic IRP1 and IRP2 activities occurs in vivo.

縮寫對照表 vii
組別代號涵義 viii
中文摘要 I
英文摘要 IV
緒言 VI
第一章 文獻回顧
第一節、細胞鐵平衡之調控
一、IRPs與IRE之特性 1
二、IRPs 作用機制與鐵代謝相關蛋白質 5
三、影響IRPs的因素 9
第二節、飲食模式：炸油 11
第三節、鐵、銅及鋅代謝受過氧化體增殖劑影響
一、過氧化體增殖劑的效應與作用機制 13
二、過氧化體增殖劑改變鐵、銅、鋅平衡 17
第四節、銅與鐵的代謝相關性 19
第一章 材料與方法
第一節、動物飼養與飼料組成 22
第二節、分析項目與方法 23
第三章 膳食炸油對大鼠 IRPs 活性的影響
第一節、實驗 A — 膳食炸油攝食時間對 IRP1 及 ferritin 之影響
一、 實驗設計 43
二、 分析項目 45
三、 結果 45
第二節、實驗 B — 膳食炸油與鐵量影響鐵代謝相關蛋白質表現
一、實驗設計 60
二、分析項目 61
三、結果 61
第三節、綜合討論 73
第四章、膳食魚油與鐵代謝調節相關分子
第一節、實驗 A - 膳食魚油改變肝臟鐵含量與鐵儲存
一、實驗設計 79
二、分析項目 80
三、結果與討論 81
第二節、實驗 B - 膳食魚油與鐵量對肝鐵調控蛋白質的影響
一、實驗設計 85
二、分析項目 86
三、結果 86
第三節、綜合討論 100
第五章 降血脂藥 clofibrate 影響大鼠鐵與銅代謝及其相關蛋白質
第一節、 實驗設計 104
第二節、 分析項目 105
第三節、 結果 106
第四節、 討論 122
第六章 討論與結論 127
第七章 參考文獻 141
附錄一 構築 rat L-ferritin cDNA 156
附錄二 實驗方法之建立與評估 162
附錄三 構築實驗所需之質體 174
謝誌 184

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