臺灣博碩士論文加值系統

非酒精性脂肪肝疾病為非過量攝取酒精或非特殊原因造成脂肪堆積於肝臟，其主要成因之一為不當日常飲食習慣，當飲食中過多脂肪被攝入時，因送入肝臟三酸甘油酯過多，過度增加肝臟粒線體β氧化產生活性氧屬，攻擊肝臟細胞，使脂肪酸氧化降低；且極低密度脂蛋白無法有效將三酸甘油酯運送出肝臟，使其堆積於肝臟內，最終造成非酒精性脂肪肝疾病。n-3多元不飽和脂肪酸為碳基端算起第3個碳含雙鍵之不飽和脂肪酸，其功能為穩定細胞膜、訊號傳遞及能量儲備等。過去針對n-3 多元不飽和脂肪酸研究發現，其可改善血脂組成、胰島素抗性、調節脂質代謝基因並降低發炎反應等功效。常見之n-3 多元不飽和脂肪酸為α-次亞麻油酸、二十碳五烯酸以及二十二碳六烯酸，本次實驗之油脂使用為磷蝦油、魚油及亞麻籽油；而磷蝦油與魚油富含二十碳五烯酸及二十二碳六烯酸，亞麻籽油則富含α-次亞麻油酸。
實驗目的為探討磷蝦油、魚油、亞麻籽油等富含n-3 多元不飽和脂肪酸油脂介入以45 %高脂飲食誘發非酒精性脂肪肝疾病之Sprague-Dawley (SD)大鼠，對其血脂、肝臟脂肪、脂肪酸生成酵素活性、抗氧化酵素活性及粒線體功能之影響。實驗共分8組：控制組－C，高脂組－HF，磷蝦油一、三倍劑量組－KO1、3，魚油一、三倍劑量組－FO1、3，亞麻籽油一、三倍劑量組－LO1、3。除C組外，其餘組別皆給予高脂飲食；除C、HF組外，其餘組別介入不同種類及劑量之油品；而一倍、三倍劑量組別分別將其n-3總量固定為每天每克飼料4.2及13.0 毫克。12週後犧牲，取其血液及肝臟樣本進行後續分析。其結果入下， FO及LO組於血漿三酸甘油酯濃度顯著低於HF組；而胰島素抗性部分則HF、KO3、FO3顯著高於C組。KO1、FO1及LO組於肝臟三酸甘油酯濃度與病理切片有顯著改善。脂肪酸生成酵素活性為KO3及FO3組顯著高於C組。抗氧化酵素、粒線體呼吸鏈複合體酵素活性及粒線體生合成則為KO1、FO1及LO組顯著高於HF組。
以45 %高脂飲食成功誘發大鼠非酒精性脂肪肝疾病模式下，同時額外添加富含n-3多元不飽和脂肪酸油脂磷蝦油每天每公斤體重273.4毫克、魚油每天每公斤體重149.6毫克、亞麻籽油每天每公斤體重147.0與466.5毫克，其可降低血脂、肝臟脂肪與脂肪酸生成酵素活性，提升肝臟抗氧化能力與粒線體功能，達到延緩或預防非酒精性脂肪肝疾病之進展。

Non-alcoholic fatty liver disease (NAFLD) is a condition of fat accumulatuin in the liver in the absent of excessive alcohol consumption (less than 20 g per day) and specific causes of hepatic steotosis. An improper dietary habit is one of the factors which induce NAFLD. When consuming too much fat, it will increase triglyceride into liver for metabolism. Meanwhile liver mitochondrial β oxidation increases and produces more reactive oxygen species, which may harm hepatic cells. On the other hand, very low-density lipoprotein can not bring triglyceride out of liver efficiently, and caused NAFLD eventually. n-3 polyunsaturated fatty acid (n-3 PUFA) is a polyunsaturated fatty acid which fist double bond is at third carbon from carbonyl tail. Its physiological functions include cell membrane maintenance, signal transduction, and energy storage. n-3 PUFA’s studies indicated that n-3 PUFA may ameliorate dyslipidemia, insulin resistance, regulate lipid metabolic genes, and reduce inflammatory response. α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) are the menbers of n-3 PUFA’s family. In our study, krill oil, fish oil, and linseed oil, which were rich in n-3 PUFA, were used for supplement. Krill oil and fish oil contain EPA and DHA, while linseed oil contains ALA. The purpose of this experiment is to evaluate supplement with oils rich in n-3 PUFA, such as krill oil, fish oil and linseed oil, on plasma and liver lipid profiles, liver fatty acid synthesis enzyme activities, antioxidant enzyme activities, and mitochondrial function in the animal model of NAFLD induced by 45 % high fat diet. 80 Sprague-Dawley (SD) rats were divided into 8 groups, including control group (C), high fat diet group (HF), high fat diet supplied with krill oil, fish oil or linseed oil in one or triple dosage respectively (KO1, KO3, FO1, FO3, LO1, LO3). Except C, rests of the groups were fed with Adjusted Calories Diet (45/Fat) fodder. Except C and HF, rests of the groups were supplied with different oil and different dosage. One and triple dosage were used to control their supplement n-3 PUFA amount, which were 4.2 and 13.0 mg/g fodder/day respectively. After 12 weeks, SD rats were sacrified and analyzed plasma lipid profiles and glucose homeostasis, hepatic lipid profiles, biopsies, fatty acid synthesis enzyme acitivities, antioxidant enzyme activites, mitochondrial respiratory chain complex enzyme activities, and mitochondrial biogenesis. FO1, FO3, LO1, and LO3’s plasma triglyceride were significantly lower than HF. Furthermore, HF, KO3, and FO3’s HOMA-IR increased significantly. KO1, FO1, LO1, and LO3’s hepatic triglyceride content and biopsies were ameliorated significantly. Fatty acid synthesis enzyme activities in KO3 and FO3 were significantly higher than C. Antioxidant enzyme activities, mitochondrial respiratory chain complex enzyme activities, and mitochondrial biogenesis in KO1, FO1, LO1, and LO3 were significantly higher than HF. Supplement with oils rich in n-3 PUFA, such as krill oil 273.4 mg/kg b.w./day, fish oil 149.6 mg/kg b.w./day, and linseed oil 147.0 or 466.5 mg/kg b.w./day may reduce plasma and hepatic lipid profiles, fat accumulation in liver, and fatty acid synthesis; while elevating mitochondrial function, eventually ameliorate NAFLD in animal model induced by 45 % high fat diet.

中文摘要 I
Abstract III
致謝 V
縮寫表 VII
表目次 XIX
圖目次 XX
第一章 序論 1
第二章 文獻回顧 3
第一節 非酒精性脂肪肝疾病 3
第二節 粒線體功能與脂肪酸β氧化 5
一、 粒線體功能 5
二、 粒線體與脂肪酸β氧化 6
第三節 粒線體與非酒精性脂肪肝疾病 8
一、 粒線體架構損壞 8
二、 粒線體DNA斷裂 8
三、 粒線體β氧化受損 9
第四節 n-3多元不飽和脂肪酸（n-3 polyunsaturated fatty aicd, n-3 PUFA） 10
一、 n-3 PUFA代謝 10
二、 n-3 PUFA與脂質代謝基因 11
第五節 富含n-3多元不飽和脂肪酸之油脂 12
一、 魚油（fish oil） 12
二、 亞麻籽油（linseed oil） 13
三、 磷蝦油（krill oil） 13
第三章 研究目的 16
第四章 材料與方法 17
第一節 實驗設計 17
一、 實驗動物 17
二、 飼育環境與方法 17
三、 實驗分組 17
第二節 飼料與介入物組成 20
第三節 實驗流程 21
第四節 血液生化分析 23
一、 血漿三酸甘油酯 23
二、 血漿總膽固醇 24
三、 血漿天門冬胺酸轉胺酶（aspartate aminotransferase, AST） 25
四、 血漿丙胺酸轉胺酶（alanine aminotransferase, ALT） 25
五、 血漿高密度脂蛋白膽固醇（high-density lipoprotein-cholesterol, HDL-c） 26
六、 血漿低密度脂蛋白膽固醇（low-density lipoprotein-cholesterol, LDL-c） 27
七、 血漿葡萄糖濃度 28
八、 血漿胰島素濃度 28
第五節 肝臟脂質含量分析 30
一、 肝臟組織切片 30
二、 肝臟脂質萃取 30
三、 肝臟三酸甘油酯 30
四、 肝臟總膽固醇 32
第六節 肝臟抗氧化分析 33
一、 肝臟樣品處理 33
二、 肝臟超氧歧化酶（superoxide dismutase, SOD） 33
三、 肝臟過氧化氫酶（catalase, CAT） 34
四、 肝臟麩胱甘肽氧化酶（glutathione peroxidase, GPx） 34
五、 肝臟麩胱甘肽還原酶（glutathione reductase, GR） 35
六、 肝臟麩胱甘肽濃度（glutathione, GSH） 36
七、 肝臟脂質過氧化-丙二醛（malonadialdehyde, MDA）含量 37
第七節 肝臟脂肪酸合成酵素分析 38
一、 肝臟去核上清液（post nuclear supernatant, PNS） 38
二、 肝臟脂肪酸合成酶（fatty acid synthase, FAS） 38
三、 肝臟乙醯輔酶A羧化酶（acetyl-CoA carboxylase, ACC） 39
第八節 肝臟粒線體功能分析 40
一、 肝臟粒線體萃取 40
二、 肝臟總DNA萃取 40
三、 粒線體呼吸控制速率及比值（mitochondrial respiratory control ratio, RCR） 41
四、 粒線體電子傳遞鏈複合體酵素活性-Nicotinamide adenine dinucleotide (NADH)-cytochrome c reductase (NCCR)活性測定 41
五、 粒線體電子傳遞鏈複合體酵素活性-Succinate-cytochrome c reductase (SCCR)活性測定 42
六、 粒線體DNA套數（mitochondrial DNA copy number） 42
第九節 統計分析 44
第五章 結果 45
第一節 進食量與體重分析 45
一、 進食量及三大營養素比例 45
二、 體重與體重變化量 47
第二節 臟器重量分析 49
一、 肝臟重量 49
二、 心臟重量 49
三、 腓腸肌重量 49
四、 內臟脂肪重量 50
第三節 血液生化分析 51
一、 血漿三酸甘油酯（TG） 51
二、 血漿總膽固醇（TC） 51
三、 血漿高密度脂蛋白膽固醇（HDL-c） 52
四、 血漿低密度脂蛋白膽固醇（LDL-c） 52
五、 血漿天門冬胺酸轉胺酶（AST） 52
六、 血漿丙胺酸轉胺酶（ALT） 53
七、 血漿葡萄糖（glucose） 53
八、 血漿胰島素（insulin） 53
九、 胰島素抗性（HOMA-IR） 54
第四節 肝臟脂質及肝臟組織病理切片分析 55
一、 肝臟脂質 55
二、 肝臟組織病理切片 55
第六節 肝臟脂肪酸生合成酵素比活性分析 57
一、 脂肪酸合成酶比活性（fatty acid synthase, FAS） 57
二、 乙醯輔酶A羧化酶比活性（acetyl-CoA carboxylase, ACC） 57
第七節 肝臟抗氧化酵素活性分析 58
一、 超氧歧化酶活性（superoxide dismutase, SOD） 58
二、 過氧化氫酶（catalase, CAT） 58
三、 麩胱甘肽氧化酶（glutathione peroxidase, GPx） 58
四、 麩胱甘肽還原酶（glutathione reductase, GR） 59
五、 麩胱甘肽濃度（glutathione, GSH） 59
六、 脂質過氧化-丙二醛（malonadialdehyde, MDA） 59
第八節 肝臟粒線體生合成分析 60
第九節 肝臟粒線體電子傳遞鏈複合體酵素活性 61
一、 NCCR活性 61
二、 SCCR活性 61
第十節 肝臟粒線體呼吸速率與呼吸控制比值（RCR） 62
一、 呼吸控制比值（RCR） 62
二、 質子滲漏（proton leak） 62
三、 基礎呼吸率（basal respiration） 62
四、 最大呼吸速率（maximal respiration） 63
第六章 討論 64
第一節 45 %高脂飲食誘發大鼠非酒精性脂肪肝疾病 64
第二節 高脂飲食添加磷蝦油、魚油及亞麻籽油對於進食量與熱量、體重與臟器重之影響 65
一、 進食量與熱量之影響 65
二、 體重與臟器重之影響 66
第三節 高脂飲食添加磷蝦油、魚油及亞麻籽油對於血脂組成之影響 67
第四節 高脂飲食添加磷蝦油、魚油及亞麻籽油對於胰島素抗性之影響 69
第五節 高脂飲食添加磷蝦油、魚油及亞麻籽油對於脂肪酸生成酵素之影響 71
第六節 高脂飲食添加磷蝦油、魚油及亞麻籽油對於脂質過氧化之影響 73
第七節 高脂飲食添加磷蝦油、魚油及亞麻籽油對於肝臟粒線體功能及粒線體生合成之影響 75
第八節 各一倍劑量與三倍劑量組別對非酒精性脂肪肝疾病之影響比較 77
一、一倍劑量組別對非酒精性脂肪肝疾病之比較 77
二、三倍劑量組別隊非酒精性脂肪肝疾病之比較 78
第七章 結論 80
第八章 參考文獻 81

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