臺灣博碩士論文加值系統

　　諾麗(Morinda citrifolia)以往研究多以抗癌、抗氧化為主，近年在降血糖、降血脂有進一步探討。高脂飲食可能引發後天性高血脂症進而導致心血管與肝臟相關疾病，本研究探討諾麗果粉在高脂飲食誘導動物模式，是否具調節血脂暨體脂功效。本研究中，將雄性C57BL/6JNal小鼠分成六組，分別為正常之控制組(C)及果粉餵食組(CN)、高脂誘導之對照組(H)及合併餵食三種果粉劑量之試驗組(H-NL、H-NM、H-NH)。結果顯示，諾麗果粉對高脂飲食誘導肥胖之小鼠，在體脂方面可減少增重百分率及內臟脂肪含量，進而改善肥胖。血清生化分析顯示可降低TG、TC、LDL-C及動脈硬化指數，進而改善血脂異常；亦可改善小鼠受高脂飲食誘導的高血糖及胰島素阻抗。經肝臟脂質含量測定與肝臟組織切片H&E及油紅染色發現，因高脂飲食造成的膽固醇、三酸甘油酯堆積以及油滴蓄積、組織排列異常現象，在餵食諾麗果粉後有顯著改善。基因表現量方面與活性分析顯示，餵食諾麗果粉可抑制調控三酸甘油酯生成之SREBP-1c、FAS，並提升三酸甘油酯代謝之PPARα、CPT1a之活性；同時抑制調控膽固醇生成之SREBP2、HMGCR，並提升膽固醇代謝之SR-B1、LDL-R、LDLRAP1及CYP7A1之活性。而在葡萄糖代謝方面，諾麗果粉之餵食可抑制PEPCK與提升GLUT2、IR、PI3K之活性，亦促進Akt及AMPK磷酸化活化訊號。綜合上述結果，諾麗果粉可改善小鼠因高脂飲食造成脂質代謝異常現象，降低高血脂、減少脂肪細胞之增大及肝臟脂質的堆積，以及降低因高脂飲食造成的高血糖與胰島素阻抗現象，整體具調控血脂、體脂及血糖之作用。

　　In the past studies, Noni (Morinda citrifolia) has mainly recognized for its anticancer and antioxidants activities, whereas its hypoglycemic and hypolipidemic activities were only recently mentioned. High-fat diet may lead to hyperlipidemia and in turn cause cardiovascular and hepatic diseases. Our specific aim was to investigate whether feeding with noni fruit powder can regulate adipogenesis and lipidemia in obese mice induced by high-fat diet. In current study, male C57BL/6JNarl mice were divided into six groups, the control-diets groups fed without (C) or with the co-presence of noni fruit powder (CN), high-fat-diet groups fed without (H) or with supplementations of low (HN-L), medium (HN-M) and high (HN-H) doses of noni fruit powder. Our results indicated that the mice fed with noni fruit powder showed lower percent weight gain and visceral fat weight, serum triglycerides (TG), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) and atherosclerosis index (AI), also lower blood glucose levels and insulin resistance. Furthermore, mice fed with noni fruit powder processed lower amounts of hepatic cholesterol and triglycerides, which could also be manifested by H&E and Oil-Red-O staining of hepatic tissue sections. Based on the analysis of expression and activation levels of key molecules in metabolism pathway of triglycerides, cholesterol and glucose, mice fed with noni fruit powder show suppressed SREBP1c, FAS, SREBP2, HMGCR expressions, and PEPCK activity, which might reduce hepatic lipid and glucose production. At the same time, the activity of PPARα,CPT1a, SR-B1, LDL-R, LDLRAP1, CYP7A1, GLUT2, IR, PI3K, Akt and AMPK were enhanced, which may promote hepatic lipid and glucose metabolism. In summary, feeding with noni fruit powder significantly improved the regulation of adipogenesis, lipidemia and hyperglycemia in obesity mice.

目錄
摘要 1
Abstract 2
第一章、前言 3
第二章、文獻回顧 4
2-1 諾麗 4
2-1-1 諾麗(Noni)之簡介 4
2-1-2 諾麗果粉 4
2-1-3 諾麗之生理活性 5
2-1-3.1抗微生物 5
2-1-3.2抗發炎與鎮痛 5
2-1-3.3抗腫瘤與抑癌 6
2-1-3.4抗氧化與保肝 6
2-1-3.5降血糖與抗糖尿病 7
2-1-3.6降血脂 7
2-2 代謝症候群 8
2-2-1代謝症候群定義 8
2-2-2代謝症候群判定標準 9
2-2-3代謝症候群成因與發展 10
2-3 肥胖 12
2-3-1 肥胖定義 12
2-3-2 肥胖種類 13
2-3-3肥胖成因 14
2-3-4 肥胖的影響及併發症 15
2-4 胰島素阻抗 17
2-4-1 胰島素功能 17
2-4-2 胰島素阻抗定義及成因 18
2-4-3 胰島素阻抗機制 19
2-5 肥胖與胰島素阻抗的關聯與影響 19
2-5-1 血中脂質相關指標 20
2-5-1.1三酸甘油酯(Triglyceride, TG) 20
2-5-1.2膽固醇(Cholesterol, CHOL) 21
2-5-1.3高密度脂蛋白膽固醇(High density lipoprotein-cholesterol, HDL-C) 21
2-5-1.4低密度脂蛋白膽固醇(Low density lipoprotein-cholesterol, LDL-C) 22
2-5-2 脂肪組織產生之細胞激素 22
2-5-2.1腫瘤壞死因子α(Tumor necrosis factor alpha, TNF-α) 23
2-5-2.2瘦體素(Leptin) 23
2-5-2.3抗素(Resistin) 23
2-5-2.4脂聯素(Adiponectin) 24
2-5-3 肝臟與腎臟功能指標 24
2-5-3.1天門冬胺酸轉胺酶(Aspartate aminotransferase, AST) 24
2-5-3.2丙胺酸轉胺酶(Alanine aminotransferase, ALT) 25
2-5-3.3肌酸酐(Creatinine, CRE) 25
2-5-3.4尿酸(Uric acid, UA) 25
2-5-4 三酸甘油酯生成與代謝調控 25
2-5-4.1固醇調節元件結合蛋白1c (Sterol regulatory element-binding protein 1c, SREBP1c) 26
2-5-4.2脂肪酸合成酶(Fatty acid synthase, FAS) 27
2-5-4.3磷酸腺苷激活蛋白激酶(AMP-actived protein kinase, AMPK) 27
2-5-4.4過氧化物酶體增殖物激活受體α(Peroxisome proliferator-activated receptor alpha, PPARα) 28
2-5-4.5肉鹼棕櫚醯基轉移酶1 a (Carnitine palmitoyl transferase І a, CPT1a) 28
2-5-5 膽固醇生成與代謝調控 29
2-5-5.1固醇調節元件結合蛋白2 (Sterol regulatory element-binding protein 2, SREBP2) 30
2-5-5.2 3-羥基-3-甲基戊二酰輔酶A還原酶(HMG-CoA reductase, HMGCR) 30
2-5-5.3低密度脂蛋白受體(Low-density lipoprotein receptor, LDL-R) 31
2-5-5.4清道夫受體B1 (Scavenger receptor class B member 1, SR-B1) 32
2-5-5.5膽固醇7α-羥化酶(Cholesterol 7 alpha-hydroxylase, CYP7A1) 32
2-5-6 胰島素傳訊與葡萄糖轉運蛋白 32
2-5-6.1胰島素受體(Insulin receptor, IR) 33
2-5-6.2磷脂基醇-3-激酶(Phosphatidylinositol-3-kinases, PI3K) 34
2-5-6.3蛋白質激酶B (Protein knase B, PKB/Akt) 34
2-5-6.4葡萄糖轉運蛋白(Glucose transporter, GLUTs) 35
2-5-6.5 磷酸烯醇丙酮酸羧化激酶(Phosphoenolpyruvate carboxykinase, PEPCK) 35
2-6 高脂肪飲食誘發肥胖 36
第三章、研究目的與實驗架構 37
3-1 研究目的 37
3-2 實驗架構 38
第四章、材料與方法 39
4-1 實驗試劑與藥品 39
4-1-1 藥品與試劑 39
4-1-2儀器與設備 40
4-2 實驗方法 41
4-2-1 動物飼養與分組 41
4-2-1.1 高脂飲食引發肥胖之實驗模式塑造 42
4-2-2 實驗動物觀察與體重測量 42
4-2-3 攝食量及攝水量計算 42
4-2-4血清分離與其分析項目 43
4-2-4.1 天門冬胺酸轉胺酶(AST)濃度測定 43
4-2-4.2 丙胺酸轉胺酶(ALT)濃度測定 43
4-2-4.3肌酸酐(CRE)濃度測定 44
4-2-4.4尿酸(UA)濃度測定 44
4-2-4.5血清三酸甘油酯(TG)濃度測定 44
4-2-4.6 血清總膽固醇(TC)濃度測定 44
4-2-4.7 高密度脂蛋白膽固醇(HDL-C)濃度測定 45
4-2-4.8 低密度脂蛋白膽固醇(LDL-C)濃度測定 45
4-2-4.9 口服葡萄糖耐受性試驗(Oral glucose tolerance test, OGTT) 45
4-2-5 肝臟病理分析 46
4-2-5.1 肝臟外觀病理分析 46
4-2-5.2 肝臟組織蘇木紫-伊紅染色(Haematoxylin-Eosin stain, H&E stain) 46
4-2-5.3 肝臟組織油紅染色(Oil-Red-O stain) 46
4-2-6 肝臟脂質分析 47
4-2-6.1 肝臟三酸甘油酯(TG)濃度測定 48
4-2-6.2 肝臟總膽固醇(TC)濃度測定 48
4-2-7 肝臟基因表現量分析 48
4-2-7.1 肝臟RNA萃取與cDNA製備 48
4-2-7.2 同步定量聚合酶連鎖反應 49
4-2-8 肝臟蛋白質分析 50
4-2-8.1 肝臟蛋白質萃取 50
4-2-8.2 肝臟蛋白質濃度定量 50
4-2-8.3 西方轉漬 51
4-2-9 體內脂肪重量 51
4-2-10脂肪組織基因表現量分析 51
4-2-10.1腹部脂肪RNA萃取與cDNA製備 51
4-2-10.2同步定量聚合酶連鎖反應 52
4-2-11 脾臟與腎臟重量 52
4-2-12 統計分析 52
第五章、結果 53
5-1 諾麗果粉對高脂飲食誘導肥胖小鼠之影響 53
5-1-1 小鼠之體重變化、攝食攝水量及食物利用率 53
5-1-2小鼠之肝臟、脾臟、腎臟重量 54
5-1-3 小鼠之腹部、副睪、腎周及內臟脂肪組織重量 54
5-1-4小鼠之血清肝腎功能指標 55
5-1-5小鼠誘導後及餵食諾麗果後之血脂指標濃度 55
5-1-6 小鼠之肝臟脂質含量累積 56
5-1-7小鼠之空腹血糖檢測 57
5-1-8 小鼠之口服葡萄糖耐受性試驗 57
5-1-9 小鼠脂聯素mRNA相對表現量 58
5-2 肝臟與脂肪組織外觀與病理切片 58
5-2-1 肝臟外觀病理型態圖 59
5-2-2 肝臟蘇木紫與伊紅染色 59
5-2-3 肝臟油紅(Oil-Red-O)染色 59
5-2-4 腹部脂肪蘇木紫與伊紅染色 60
5-3三酸甘油酯生成代謝路徑基因表現及蛋白質含量 60
5-3-1 SREBP-1c mRNA相對表現量 61
5-3-2 FAS mRNA相對表現量 61
5-3-3 PPARα mRNA相對表現量 61
5-3-4 CPT1a mRNA相對表現量 62
5-3-5 SREBP1蛋白質相對含量 62
5-3-6 PPARα蛋白質相對含量 62
5-4膽固醇生成代謝路徑基因表現及蛋白質含量 63
5-4-1 SREBP2 mRNA相對表現量 63
5-4-2 HMGCR mRNA相對表現量 63
5-4-3 SR-B1 mRNA相對表現量 63
5-4-4 LDL-R mRNA相對表現量 64
5-4-5 CYP7A1 mRNA相對表現量 64
5-4-6 HMGCR蛋白質相對含量 64
5-4-7 SR-B1蛋白質相對含量 65
5-4-8 LDLRAP1蛋白質相對含量 65
5-5胰島素傳訊路徑基因表現及蛋白質含量 65
5-5-1 GLUT2 mRNA相對表現量 66
5-5-2 IR mRNA相對表現量 66
5-5-3 PI3K mRNA相對表現量 66
5-5-4 Akt mRNA相對表現量 67
5-5-5 PEPCK mRNA相對表現量 67
5-5-6 PI3K蛋白質相對含量 67
5-5-7 Akt蛋白質相對含量 68
5-5-8 pAkt蛋白質相對含量 68
5-5-9 pAkt/total Akt蛋白質相對含量 68
5-5-10 AMPK蛋白質相對含量 68
5-5-11 pAMPK蛋白質相對含量 69
5-5-12 pAMPK/total AMPK蛋白質相對含量 69
第六章、討論 122
6-1 諾麗果粉對體重及攝食、攝水量之影響 122
6-2 諾麗果粉對臟器重量之影響 123
6-3 諾麗果粉對體脂肪之影響 123
6-4 諾麗果粉對肝機能之影響 124
6-5 諾麗果粉對血脂之影響 126
6-6 諾麗果粉對肝臟脂質恆定之影響 127
6-7 諾麗果粉對胰島素調控血糖恆定能力之影響 127
6-8 諾麗果粉對能量調控樞紐之影響 129
6-9 諾麗果粉對三酸甘油酯生成代謝之影響 130
6-10 諾麗果粉對膽固醇生成代謝之影響 131
6-11 諾麗果粉對葡萄糖代謝之影響 133
第七章、結論 136
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