臺灣博碩士論文加值系統

綜合前人及本實驗室對氧化炸油 (oxidized frying oil；OFO) 研究顯示，炸油在鼠類引起之反應類似PPARalpha (peroxisome proliferator-activated receptor alpha) 活化；加上有報告指出，linoleic acid氧化產物如9-HODE、13-HODE以及共軛亞麻油酸 (conjugated linoleic acid；CLA) 均可活化PPARalpha及PPARgamma，因此本研究假設炸油內含PPARa活化物。
為證明假說並鑑定炸油中的活化物成分，本研究進行以下四個實驗：一、大白鼠餵食炸油對PPARalpha下游基因表現之影響。二、為了解炸油對熱量代謝之影響，在上述動物實驗中同時偵測餵食炸油鼠組織中UCP (uncoupling protein) mRNA表現。三、利用transactivation assay證明炸油水解物可以活化PPARalpha，並將炸油進行區分，尋找與鑑定炸油中的PPARalpha活化物。四、以老鼠肝細胞株 (H4IIEC3) 為模式，證明來自炸油的活性區分物可促進細胞acyl-CoA oxidase (ACO) 活性。
在第一項實驗中將SD公鼠分為低 (5%, LF或LO) 或高 (20%, HF或HO) 劑量之新鮮大豆油 (LF或HF) 或炸油 (LO、HO) 組，探討油脂含量及種類對PPARalpha下游基因表現之影響；雌鼠亦分為高新鮮油 (HF-f) 或高炸油 (HO-f) 組，以便與HF及HO組公鼠比較，探討性別與油脂種類之影響。在公鼠另設正對照組 (PC)，給予已知的PPARalpha活化物clofibrate 0.5 %劑量處理一週。OFO製備自大豆沙拉油以205±5°C油炸麵片24小時。餵養六週後，鼠肝PPARalpha下游基因ACO及CYP4A1 mRNA隨著餵食炸油劑量增加，表現量顯著增加 (P<0.05)。HO組肝臟ACO活性增加為HF組六倍 (P<0.05)；炸油也會顯著增加肝臟微粒體CYP4A蛋白質量 (P<0.05)；攝食炸油的LO與HO組血漿總脂質、肝臟TG、膽固醇及總脂質均顯著低於新鮮油對照組 (P<0.05)。炸油在雌鼠亦有相同作用，但不如公鼠明顯。至於PC組正如預期的，血脂質顯著降低，且PPARalpha下游基因表現增加。
由於攝食炸油之大白鼠飼料效率顯著降低，推測炸油可能促進粒線體UCP 表現，增加熱量支出，因此偵測前述實驗動物各組織UCPs mRNA量。結果顯示不論公鼠或母鼠，攝食炸油六週並不影響棕色脂肪UCP-1、UCP-2與UCP-3 mRNA，也不影響肝臟UCP-2及骨骼肌的UCP-2與UCP-3 mRNA表現，但HF組棕色脂肪UCP-1表現顯著增加 (P<0.05)，為LF組之7.6倍。
在第三項實驗應用本實驗室所建立穩定表現GAL4-PPARalpha LBD chimeric receptor以及(UAS)4-alkaline phosphatase (ALP) reporter gene之CHO K1 細胞株，進行transactivation assay，發現炸油水解物比起新鮮油水解物有更好的促進ALP活性效果，尤其在50及100 mM (分別為14及28 mg/mL)劑量下二者間達顯著差異 (P<0.05)。此結果顯示炸油中含有比新鮮油一般脂肪酸更強之PPARalpha活化物。為尋找及鑑定炸油中的PPARalpha活化物成分，利用HP-20管柱流洗，將炸油水解物依極性高而低區分為RP1、RP12、RP2、RP23及RP3五個區分物，新鮮油水解物亦區分為RP12、RP2及RP23三個區分物。transactivation assay證實來自炸油之RP1有最大促進ALP活性能力。依據GC-MS提供之分子量線索及滯留時間，推測此區分物可能含有十八碳、具有cis, trans-共軛雙鍵之羥基化脂肪酸 (hydroxy fatty acid)。
將以上收得區分物 (來自炸油之RP1、RP2與RP3，或來自新鮮油之RP12、RP2與RP23) 及區分前水解物以28及140 mg/mL劑量處理大鼠肝癌細胞株 (H4IIEC3) 48及72小時，發現區分前的炸油水解物比起新鮮油水解物有較高的促進細胞ACO活性能力 (P<0.05)。區分因子 (P£0.0005) 及油脂種類 (P<0.05) 均會使細胞ACO活性顯著增加，因此來自炸油之RP1有最高的促進細胞ACO活性能力。
綜合以上結果，本研究提出以下結論：炸油含有PPARalpha活化物，會使大白鼠肝臟PPARalpha下游基因 (ACO及CYP4A1) mRNA表現顯著增加，影響大白鼠體內脂質代謝。此PPARalpha活化物應為極性脂肪酸，在HP-20管柱可以甲醇/水 (85/15，v/v) 沖堤出，在H4IIEC3細胞培養模式中證實此活性區分物的確可以促進細胞ACO活性。但炸油所導致體重降低似非經由促進組織UCP表現所致，反之高脂飲食的確可能藉由促進棕色脂肪UCP-1表現，增加生熱反應以達到調控熱量平衡。

It has been reported that rats fed an oxidized frying oil (OFO) containing diet show physiological effects like PPARalpha (peroxisome proliferator-activated receptor alpha) activation. Recently, conjugated linoleic acid (CLA), oxidized low density lipoprotein (oxLDL) and its component hydroxy fatty acids derived from linoleic acid are shown to activate PPARalpha and PPARgamma. It was hypothesized that lipid oxidation products in dietary OFO may activate PPARalpha and regulate the expression of its target genes. To test this hypothesis and, the following four experiments were conducted.
In the first experiment, 4 groups of male weanling Sprague-Dawley rats were respectively fed diets containing either high (20% wt/wt, HO and HF) or low (5% wt/wt, LO and LF) levels of OFO (HO and LO) or fresh soybean oil (FSO) (HF and LF), based on a 2 × 2 factorial design, to test the significance of the effect of fat quality, fat quantity and their interaction. Two groups of female rats fed the HF (HF-f) and HO (HO-f) diets respectively were also included to observe the gender effect. Another group of male rats were fed the LF diet but supplemented with 0.5 % clofibrate for the last 7 days, to serve as the positive control (PC). The OFO sample was prepared by frying wheat dough sheets in soybean oil at 205±5°C for 24 hr. After 6 week of feeding, OFO resulted in dose-dependent and significant increases (P＜0.05) in mRNA of acyl-CoA oxidase (ACO) and cytochrome P450 4A1 (CYP4A1) in the liver of rats. Dietary OFO also dose-dependently increased liver microsomal CYP4A protein (P＜0.05). The activity of hepatic ACO of the HO group was 6 times that of the HF group (P＜0.05). Plasma total lipids, liver TG, cholesterol and total lipids, were reduced in rats fed LO and HO diets (P＜0.05). These effects of OFO were also observed in female rats fed the HO diet, albeit with less significant effect. As expected, a significant hypolipidemic effect and increased expression of PPARalpha target genes were observed in PC group.
Since the feed efficiency was reduced in rats feeding dietary OFO, it was proposed that the thermogenesis effect was increased by stimulating the expression of uncoupling protein (UCP) in OFO feeding rats. In the second experiment, UCPs mRNA in tissue samples obtained from the first experiment were detected by Northern blot analysis. No significant effects of OFO on the expression of UCP-1, UCP-2 and UCP-3 mRNA in brown adipose tissue (BAT), UCP-2 mRNA in liver and UCP-2 and UCP-3 in skeletal muscle were observed. However, the UCP-1 mRNA in BAT was significantly increased in HF group (P＜0.05) which was 7.6 times that of the LF group.
In the third experiment, a transactivation assay using a CHO cell clones stably expressing GAL4-PPARa chimeric receptor and (UAS)4-alkaline phosphatase (ALP) reporter was conducted to test the PPARalpha activating potency of the OFO. It was found that the hydrolyzed OFO enhanced the expression of ALP reporter gene to a significantly higher extent (P＜0.05) than the hydrolyzed FSO at 50 and 100 mM (14 mg/mL and 28 mg/mL, respectively).To further explore the PPARalpha activators in OFO, HP-20 column chromatography was used to fractionate the hydrolyzed OFO and FSO. Five fractions (RP1, RP12, RP2, RP23 and RP3) were collected from OFO following from high to low polarity. Accordingly, three fractions (RP12, RP2 and RP23) were collected from FSO. In the transactivation assay, the RP1 fraction isolated from OFO showed the highest activation potency as indicated by the highest ALP activity in the treated stable transfected cell clone. From the molecular weight and retention time shown in GC-MS, it was speculated that 18C-hydroxy fatty acids with cis, trans-conjugated double bond were present in the fraction of RP1.
In the last experiment, rat hepatoma cell line H4IIEC3 was treated with hydrolyzed OFO or FSO before and after fractionation (RP1, RP2 and RP3 from OFO or RP12, RP2 and RP23 from FSO) at concentrations of 28 or 140 mg/mL for 48 and 72 hr. Similar to results obtained in transactivation assay, hydrolyzed OFO also increased the ACO activity in H4IIEC3 cell line to a significantly higher extent than the hydrolyzed FSO. Results of two-way ANOVA indicated that both the fractions (P £0.0005) and fat source (P＜0.05) significantly affected ACO activity in this cell line. Since there was no significant interaction between these two factors, RP1 separated from OFO had the highest enhancing effect on the ACO activity.
In conclusion, these results support the hypothesis that dietary OFO contained the PPARalpha activators, which could up-regulate the expression of PPARalpha target genes and alter lipid metabolism in rats. The activators should be polar fatty acids which could be eluted from HP-20 chromatography by a solvent system of methanol/H2O (85/15, v/v). This polar fraction (RP1) separated from OFO had very high potency in increasing ACO activity in H4IIEC3 cell line. On the other hand, the lowered body weight gain in OFO fed rats was unlikely to be due to an increased expression of UCPs mRNA in tissues, although the higher expression of UCP-1 in BAT was observed in rats fed the high FSO diet.

中文摘要 I
英文摘要 IV
縮寫對照表 VII
第一章 緒言 1
第一節 前言 1
第二節 文獻回顧 2
一、 PPAR 2
1. PPAR發現緣起 2
2. PPAR下游基因與PPRE 4
3. PPAR的活化劑與結合子 6
4. PPARa與PPARγ的生理效應 11
二、 氧化炸油 34
1. 油脂在油炸時的化學變化 34
2. 炸油及其分離物對生物體之影響 35
第三節 實驗假說與設計 38
第二章 大白鼠餵食炸油對PPARα下游基因表現之影響 40
第一節 前言 40
第二節 材料方法 42
一、 炸油的製備 42
二、 試驗飼料的配製 42
三、 動物飼養 44
四、 動物犧牲及樣品收集 44
五、 血漿脂質分析 45
六、 肝臟脂質分析 48
七、 肝臟Total cytochrome P-450含量分析 50
八、 肝臟過氧化體Acyl-CoA Oxidase (ACO)活性分析 52
九、 肝臟Catalase活性分析 54
十、 以西方轉漬法（Western blot）分析CYP4A蛋白質含量 55
十一、北方轉漬法（Northern blot）分析 PPARα 及其下游基因之 mRNA 表現量 58
十二、以半定量逆轉錄聚合酶連鎖反應（RT-PCR）分析肝臟PPARαmRNA含量 63
十三、油脂品質分析 64
十四、統計分析 69
第三節 結果 70
一、 炸油品質 70
二、 炸油對生長攝食影響 70
三、 炸油對組織相對重量影響 71
四、 炸油對血脂質與肝脂質影響 72
五、 炸油對肝臟ACO與Catalase活性影響 73
六、 炸油對肝臟微粒體Cytochrome P-450含量及CYP 4A蛋白質量影響 74
七、 炸油對肝臟PPARa下游基因mRNA表現之影響 75
八、 炸油對周邊組織PPARa下游基因mRNA表現之影響 75
九、 炸油對肝臟PPARa mRNA表現之影響 76
第四節 討論 100
第三章 大白鼠餵食炸油對組織中UCP mRNA表現之影響 104
第一節 前言 104
第二節 材料方法 104
一、 棕色脂肪取樣 104
二、 以北方轉漬法（Northern blot）分析各組織UCP mRNA 表現量 105
三、 以半定量逆轉錄聚合酶連鎖反應（RT-PCR）分析棕色脂肪 PPARg mRNA含量 105
四、 統計分析 106
第三節 結果 107
一、 棕色脂肪UCP mRNA表現 107
二、 其他組織UCP mRNA表現 107
三、 棕色脂肪PPARg mRNA表現 108
第四節 討論 116
第四章 利用transactivation assay證明及篩選炸油中的PPARa活化物 119
第一節 前言 119
第二節 材料方法 119
一、 新鮮大豆油與油炸大豆油之水解 119
二、 炸油及新鮮油之區分 120
三、 Transactivation assay 122
四、 MTT試驗 123
五、 薄層層析法 (thin layer chromatography) 123
六、 氣相層析質譜 (GC-MS) 124
七、 統計分析 125
第三節 結果 126
一、 穩定轉染細胞株 126
二、 炸油與新鮮油之冷皂化 126
三、 炸油與新鮮油對PPARα活化效果 126
四、 比較炸油與新鮮油中可能的PPARα活化劑 127
五、 炸油/新鮮油以矽膠管柱 (silica gel chromatography) 區分 132
六、 炸油/新鮮油水解物以HP-20管柱區分(不含BHT) 137
七、 炸油/新鮮油水解物以HP-20管柱區分(含BHT) 142
八、 炸油水解物以矽膠管柱區分 160
第四節 討論 164
第五章 炸油活性區分物促進H4IIEC3細胞株ACO活性 168
第一節 前言 168
第二節 材料方法 168
一、 細胞培養 167
二、 細胞處理 169
三、 過氧化體ACO活性分析 169
四、 統計 171
第三節 結果 173
第四節 討論 180
第六章 總討論與總結 182
一、 總討論 182
二、 總結 184
第七章 參考文獻 187
附錄一 選殖大鼠CYP4A1、UCP-1、UCP-2、UCP-3 cDNA片段 202

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