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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 黃青真(Ching-jang Huang) | |
dc.contributor.author | Meng-Ting Wu | en |
dc.contributor.author | 吳夢婷 | zh_TW |
dc.date.accessioned | 2021-06-16T08:08:08Z | - |
dc.date.available | 2017-07-10 | |
dc.date.copyright | 2014-07-10 | |
dc.date.issued | 2014 | |
dc.date.submitted | 2014-06-02 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/58201 | - |
dc.description.abstract | 能量攝取大於消耗是肥胖形成的主因,肥胖係指體內累積過多的脂肪,會增加許多慢性疾病的風險,像是胰島素阻抗、第二型糖尿病、心血管疾病,甚至是癌症等。每年因肥胖相關疾病所造成的醫療費用越來越多,已成為全世界最重要的公衛問題之一。
藻褐素為褐藻特有的類胡蘿蔔素,其結構上具有獨特的 allenic bond 及 5,6-epoxy group。先前研究顯示藻褐素具有降低動物體脂的功能,然而其詳細機制尚未釐清,故本論文旨在探討藻褐素抗肥胖之機制,實驗共分三部分。 第一個部分以小鼠實驗探討藻褐素降體脂之機制。實驗一採用 C57BL/6J 雌鼠,每日腹腔注射藻褐素 (10 mg/kg BW) 或 vehicle (10% EtOH/10% BSA/0.9% NaCl) 共四週,結果顯示腹腔注射藻褐素的小鼠,其體脂未降低。實驗二採用 C57BL/6J 雄鼠,分成四組,分別餵食高蔗糖飼料 (50% 蔗糖,HS) 或高脂飼料 (7%大豆油+23%奶油,HF),兩種飼料再分為不含或含 0.2% 藻褐素的高蔗糖 (HS+F) 或高脂飼料 (HF+F),共餵食五週。結果顯示藻褐素顯著增加小鼠的能量消耗: 動物氧氣消耗量及二氧化碳排出量上升,並顯著減少內臟及皮下脂肪,但肝、心、脾及腎等臟器重量增加,因而體重並未改變。在尿液代謝體分析預測,HS+F 組尿液中 nicotinate D-ribonucleoside 及 pseudouridine 分別顯著高於 HS 組,HF+F 組尿液中 nicotinate D-ribonucleoside、5-acetamidopentanoate、1-methylhypoxanthine、6-succinoaminopurine、1-methylguanosine 及 L-phenylalanyl-L-hydroxyproline 顯著高於 HF。進一步分析基因表現,結果顯示藻褐素促進內臟和皮下脂肪中,褐化 (Cidea、Pgc-1α、Pparα、Errα、Adrb3、Dio2) 及粒線體融合 (Mfn1、Mfn2、Opa1) 基因表現,亦提高內臟脂肪粒線體生合成 (Nrf1、Nrf2) 基因表現,對於產熱 (Ucp1) 基因之影響未達顯著。藻褐素之上述效應,皆未與飲食產生顯著之交互作用,顯示無論高蔗糖或高脂飲食,藻褐素皆有降體脂作用。 另一方面,實驗二之結果也顯示飲食投予藻褐素 (HS+F 及 HF+F 組) 會增加血清三酸甘油酯、總膽固醇、HDL-C、LDL-C 濃度及肝臟膽固醇及游離脂肪酸含量,且與飲食類型無交互作用。進一步分析脂質代謝相關基因,顯示藻褐素增加內臟和皮下脂肪三酸甘油酯分解酵素 (Hsl)、脂肪酸合成酵素 (Acc) 及膽固醇代謝相關核受器及運輸蛋白 (Lxrα、Abca1、Abcg1) 之基因表現,降低白色脂肪及肌肉 Ldlr 基因表現,並顯著增加肝臟脂肪酸合成 (Acc) 及膽固醇合成 (Hmgcr) 基因表現,降低脂肪酸代謝 (Cpt1α、Aco) 和膽固醇代謝 (Lxrβ、Abca1) 相關基因表現。推測血清膽固醇增加可能與白色脂肪組織膽固醇逆運輸相關基因表現增加,且白色脂肪組織和肌肉 Ldlr 基因表現降低有關,可能減少了周邊組織胞吞 LDL 的活性,並且增加 HDL 逆運輸的活性。而肝臟本身之脂質合成基因表現增加及代謝脂肪基因表現減少,可能造成了脂質堆積在血液及肝臟的現象。 第二部分以細胞模式探討藻褐素及藻褐醇在個別組織的作用。實驗一採用HepG2 細胞,以 vehicle、ALA (18:3 n-3)、藻褐素+ALA (18:3 n-3) 分別處理 HepG2 肝細胞 48 小時。結果顯示藻褐素顯著增加細胞中 n-3 (EPA、DPA、DHA) 及 n-6 PUFA (AA) 含量且具劑量效應。接著以 U-13C-ALA 與藻褐素共同處理 0.5、3、6、24 或 48 小時,再次證明藻褐素增加肝細胞 n-3 脂肪酸的合成、D5D 酵素活性指標,對 D6D 酵素活性指標則無顯著影響。已知過氧化體 β-oxidation 為合成 DHA 最後一個步驟,實驗二以 H4IIEC3 肝細胞為平台,以 vehicle、藻褐素、藻褐醇、Wy14643 分別處理 H4IIEC3 細胞 72 小時,結果顯示藻褐素及藻褐醇顯著增加過氧化體 ACO 酵素活性,對 Pparα及 Aco mRNA 表現則無顯著影響。實驗三採用 3T3-L1 前脂肪細胞,藻褐素和藻褐醇分別於 DM2、分化全期、分化完成後等三個階段處理細胞。結果顯示藻褐素及藻褐醇於分化全期處理細胞,顯著增加其三酸甘油酯濃度,於 DM2 添加,則對三酸甘油酯濃度無顯著影響,於分化後處理,僅藻褐醇顯著增加三酸甘油酯濃度。最後於 3T3-L1 分化為成熟脂肪細胞後,處理藻褐素或藻褐醇 12 小時,再分析細胞攝取葡萄糖的能力,結果顯示藻褐素和藻褐醇均稍微增加脂肪細胞汲取葡萄糖的量 (p<0.05)。 第三部分在探討藻褐素及藻褐醇對於調控體內葡萄糖及脂質代謝重要的轉錄因子 PPARs 和 LXRs 之轉錄活性影響。使用 CHO-K1 細胞,短暫共同轉染 chimeric receptor of GAL4-rPPARα (或 rPPARγ, rPPARδ, hLXRα, hLXRβ) LBD 及 (UAS)4-tk-alkaline phosphatase reporter,將藻褐素、藻褐醇單獨或與各受器對應之 ligand 共同處理 48 小時,分析其轉錄活性。結果顯示藻褐素及藻褐醇均顯著拮抗 PPARs 和 LXRs 之 ligand 的轉錄活性且具劑量效應,藻褐醇的拮抗效果又比藻褐素明顯,藻褐醇的下一個代謝物 amarouciaxanthin A 之 PPARs 和 LXRs 轉錄活性值得進一步分析。 綜此,本研究結果顯示藻褐素須經消化道代謝、吸收始有降體脂的效果。並開啟探討飲食投予藻褐素抗肥胖機制的新方向,透過增加脂肪組織能量消耗及粒線體生合成/融合之 mRNA 表現,增加動物整體的代謝率,而降低白色脂肪塊重量。從動物及細胞實驗的結果可推測,飲食攝取藻褐素或其代謝產物對 PPARs/LXRs 影響似乎具組織特異性,詳細的調控機制值得進一步探討。 | zh_TW |
dc.description.abstract | Obesity, defined as excess accumulation of adipose, is a worldwide endemic health problem. Obesity and its related disorders are associated with increased morbidity, mortality and healthcare costs. Fucoxanthin (FX) is a major carotenoid in brown algae and has an unusual allenic structure. FX has a suppressive effect on adipose accumulation in genetically diabetic KKAy mouse, Wistar rat and diet-induced obese C57BL/6J mouse. However, the mechanism for how FX suppresses adipose accumulation is still unclear. This study thus aimed to explore the effect and mechanism of FX on body fat regulation.
In the first part, the anti-obesity mechanism was studied in mice. C57BL/6J female mice were ip injected with FX (10 mg/kg/day) or vehicle for 4 weeks. FX did not reduce body fat through ip injection, suggesting the importance of intestinal digestion and absorption. Using a 2x2 factorial design, four groups of mice were respectively fed a high sucrose (50% sucrose) or a high-fat diet (23% butter + 7% soybean oil) supplemented with or without 0.2% FX. FX significantly increased O2 consumption and CO2 production, and reduced white adipose tissue (WAT) mass. The anti-obesity effect was further associated with significant up-regulation of mRNA expressions of PPARγ coactivator-1α (Pgc-1α), cell death-inducing DFFA-like effector a (Cidea), peroxisome proliferator-activated receptor (Ppar) α, PPARγ, estrogen-related receptor α (Errα), β3-adrenergic receptor (Adrb3), and type 2 deiodinase (Dio2) in inguinal WAT (iWAT) and epididymal WAT (eWAT) in FX fed mice. Mitochondrial biogenic genes, nuclear respiratory factor 1 (Nrf1) and Nrf2, were also up-regulated in eWAT of FX fed mice. Noticeably, FX up-regulated genes of mitochondrial fusion, mitofusin 1 (Mfn1), Mfn2, and optic atrophy 1 (Opa1), but not mitochondrial fission, Fission 1, in both iWAT and eWAT. In addition, FX increased predicted urinary metabolites including nicotinate D-ribonucleoside and pseudouridine in HS+F group compared to HS group and nicotinate D-ribonucleoside, 5-acetamidopentanoate, 1-methylhypoxanthine, 6-succinoaminopurine, 1-methylguanosine and L-phenylalanyl-L-hydroxyproline in HF+F group compared to HF group. The increases in the Ucp1 mRNA expression in WATs and BAT in FX fed mice were, nevertheless, not statistically significant. On the other hand, FX also significantly increased serum triglycerides, total cholesterol, LDL and HDL cholesterol. The up-regulated lipolytic (Hsl) and cholesterol reverse transport (Lxrα、Abca1 and Abcg1) genes, and down-regulated Ldlr mRNA in WATs as well as up-regulated lipogenic (Acc) and cholesterogenic (Hmgcr) genes, together with down-regulated fatty acid oxidation (Cpt1α and Aco) and cholesterol metabolism (Lxrβ and Abca1) genes expressions in liver might contribute to the higher serum lipids in FX-fed mice. Cell models were used in the second part of the study. HepG2 cells were treated with alpha-linolenic acid (ALA, 18:3 n-3, 100 μM) with FX (0~100 μM) or vehicle for 48 hr. FX increased EPA, docosapentaenoic acid (DPA, 22:5 n-3), DHA and AA but decreased eicosatetraenoic acid (ETA, 20:4 n-3) in HepG2 cells in a dose-dependent manner. Similar results were obtained when ALA was replaced by U-13C-labeled ALA (100 μM) to trace fatty acid metabolism. The delta-5 desaturase (D5D) but not delta-6 desaturase (D6D) activity index was increased. On the other hand, FX and and its metabolite, fucoxanthinol (FUOH) elevated the acyl-CoA oxidase (ACO) activity, but not the mRNA expression in H4IIEC3 hepatocytes. In addition, FX and FUOH promoted TG accumulation in 3T3-L1 preadipocyte under treatment during the whole differentiation period but not within the DM2 or after maturatuion. Furthermore, 12hr treatment of FUOH increased glucose uptake of mature 3T3-L1 adipocyte. The inconsistency between the in vitro and in vivo experiments implied the bioactive compound might be the metabolites from FUOH, i.e., amarouciaxanthin A. PPARs and LXRs are master regulators of glucose and lipid metabolism. Transactivation assay was employed to examine FX and FUOH on PPARs and LXRs in CHO-K1 cells were transiently co-transfected with vectors of chimeric receptors containing the ligand-binding domain of PPAR or LXR and reporter and treated with FX or FUOH. Both FX and FUOH showed antagonistic activity to PPARs and LXRs and the suppressive effect of FUOH were more pronounced than that of FX. In conclusion, dietary FX enhanced the metabolic rate and lowered adipose mass irrespective of the diet. These effects are associated with the up-regulation of PGC-1α network involved in energy expenditure, lipid metabolism/transport and mitochondrial biogenesis/fusion in eWAT and iWAT. The concomitant increases in serum and liver lipids together with observations in the in vitro studies led to a speculation that FX, FUOH and its further metabolites might act, at least in part, as tissue selective PPARs/LXRs modulators. Further investigations are worth to confirm the speculation. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T08:08:08Z (GMT). No. of bitstreams: 1 ntu-103-D98b47301-1.pdf: 8664073 bytes, checksum: e7adf393e172c58dd8bf8e6a1cb806a5 (MD5) Previous issue date: 2014 | en |
dc.description.tableofcontents | 中文摘要 I
英文摘要 IV 縮寫對照表 VII 總目錄 XI 圖目錄 XVIII 表目錄 XXI 第一章 緒言 1 第一節 前言 1 第二節 文獻回顧 2 一、肥胖 2 (一) 定義 2 (二) 盛行率 2 二、脂肪組織 3 (一) 白色脂肪組織 (White adipose tissue, WAT) 3 (二) 棕色脂肪組織 (Brown adipose tissue, BAT) 3 (三) 白色脂肪褐化 (Browning of WAT) 4 三、粒線體 6 (一) 粒線體功能缺失與肥胖代謝異常 6 (二) 粒線體生合成 (Mitochondrial biogenesis) 7 (三) 粒線體融合 (Fusion) 與分裂 (Fission) 8 四、膽固醇之恆定 9 (一) 合成 9 (二) 代謝 10 五、多元不飽和脂肪酸之合成 12 六、PGC-1α (Peroxisome proliferator-activated receptor γ coactivator-1α) 14 (一) 與 PGC-1α 作用相關之因子 16 1. PPARs 17 2. ERRα (Estrogen-related receptor α) 17 3. LXR (Liver X receptor) 18 4. TR (Thyroid receptor) 20 5. CIDEA (Cell death-inducing DFFA-like effector a) 20 七、代謝體學 (Metabolomics) 20 八、藻褐素 (Fucoxanthin) 23 (一) 化學結構及自然界中之分布 23 (二) 生體可用率與安全性 24 (三) 抗肥胖及抗糖尿病之功能 26 第三節 研究假說及架構 37 一、研究假說 37 二、實驗架構 37 (一) 藻褐素降低小鼠體脂之機制探討 37 (二) 以細胞模式評估藻褐素及藻褐醇對個別組織之影響 38 (三) 評估藻褐素及其代謝物藻褐醇之 PPARs 與 LXRs 轉錄活性 38 第二章 腹腔注射或飲食投予藻褐素對小鼠抗肥胖之機制 39 第一節 前言 39 第二節 材料與方法 40 一、大綱 40 (一) 實驗一 40 (二) 實驗二 41 二、動物飼養 41 三、飼料 43 (一) 藻褐素 43 1. 棲狀褐茸藻 43 2. 藻褐素之純化 44 3. 藻褐素純度 44 四、動物犧牲及樣品收集 46 五、代謝速率 46 六、血清分析 46 (一) 葡萄糖 46 (二) 胰島素 47 (三) 胰島素抗性指標 HOMA-IR index 計算 47 (四) 三酸甘油酯 47 (五) 總膽固醇 48 (六) 高密度脂蛋白膽固醇 48 (七) 低密度脂蛋白膽固醇 48 (八) 非游離脂肪酸 48 (九) Thyroxine (T4) 及Triiodothyronine (T3) 49 (十) 正腎上腺素 (Norepinephrine) 及腎上腺素 (Epinephrine) 49 (十一) Corticosterone 50 七、肝脂及脂肪酸組成分析 51 八、糞便脂質含量分析 52 九、基因表現分析 52 十、尿液代謝體分析 54 十一、統計分析 56 第三節 結果 57 一、實驗一 57 (一) 體重變化、飼料/熱量攝取及利用率、血糖及血脂 57 (二) 新陳代謝速率 57 (三) 器官組織相對重量 57 (四) 血清及肝臟脂肪酸組成 57 (五) 子宮周圍白色脂肪組織、棕色脂肪組織及肌肉 mRNA 表現量 57 二、實驗二 58 (一) 體重變化、攝食量及飼料利用率 58 (二) 糞便脂質排出量 58 (三) 新陳代謝速率 58 (四) 黑暗期新陳代謝與脂肪組織相對重量之相關性 59 (五) 組織器官絕對及相對重量 59 (六) 血清分析 59 (七) 肝臟脂質分析 60 (八) 肝臟、附睪及鼠蹊周圍白色脂肪組織、棕色脂肪組織及肌肉之褐化、粒線體生合成/恆定及脂質代謝相關基因表現量 61 (九) 尿液代謝體 63 第四節 討論 104 一、腹腔注射藻褐素未有降體脂效果 104 二、高蔗糖或高脂飲食誘導肥胖之差異 105 三、藻褐素之影響 110 (一) 增加棕色脂肪組織重量 110 (二) 降低白色脂肪組織重量 110 1. 促進能量消耗基因表現 111 2. 促進粒線體生合成及融合基因表現 112 (三) 降體脂但不改變體重 114 (四) 增加血脂及肝脂 115 (五) 尿液代謝體之影響 116 第五節 結論 117 第三章 藻褐素及藻褐醇對肝細胞脂質代謝及脂肪細胞分化與葡萄糖汲取之影響 118 第一節 前言 118 第二節 材料與方法 118 一、試劑與耗材 118 (一) 藻褐素 118 (二) 製備藻褐醇之試劑藥品 119 (三) 細胞株 119 (四) 血清及細胞培養用試劑 119 (五) 脂肪酸組成實驗用試劑 121 (六) ACO 酵素活性分析用試劑 121 (七) 葡萄糖汲取試驗用試劑 123 二、儀器設備 124 (一) Preparative HPLC 124 (二) 氣相層析儀 124 (三) 其他 124 三、實驗方法 124 (一) 藻褐醇之製備流程 124 (二) 細胞培養、分化方法 125 (三) HepG2 肝細胞脂肪酸組成試驗 126 (四) 以 U-13C-ALA 追蹤藻褐素對 HepG2 肝細胞脂肪酸代謝試驗 127 (五) H4IIEC3 肝細胞 ACO 酵素活性及 mRNA 表現量分析 127 (六) 3T3-L1 脂肪細胞分化試驗 129 (七) 3T3-L1 成熟脂肪細胞汲取葡萄糖試驗 129 (八) 統計分析 130 第三節 結果 131 一、藻褐素對 HepG2 肝細胞株脂肪酸組成之影響 131 二、藻褐素及藻褐醇對 H4IIEC3 肝細胞株 ACO 酵素活性之影響 131 三、藻褐素及藻褐醇對 H4IIEC3 肝細胞株 Aco 及 Pparα mRNA 表現量之影響 132 四、藻褐素及藻褐醇對 3T3-L1 脂肪細胞分化之影響 132 五、藻褐素及藻褐醇對成熟脂肪細胞汲取葡萄糖之影響 132 第四節 討論 143 一、藻褐素及其代謝物對肝細胞脂肪酸代謝之影響 143 二、藻褐素及藻褐醇對 3T3-L1 脂肪細胞分化之影響 144 三、藻褐素及藻褐醇對成熟脂肪細胞汲取葡萄糖之影響 144 第五節 結論 145 第四章 藻褐素及藻褐醇對 PPARs 與 LXRs 轉錄活性之拮抗作用 146 第一節 前言 146 第二節 材料與方法 146 一、試劑與器材 146 (一) 藻褐醇之製備 146 (二) 細胞株 146 (三) 培養基 146 (四) 血清 147 (五) 細胞培養用試劑 147 (六) 短暫轉染用質體 147 (七) 短暫轉染用試劑 147 (八) 分析 ALP 之試劑與器材 148 二、細胞培養方法 148 三、短暫轉染試驗 149 四、ALP 活性分析 150 五、細胞存活率之分析- MTT染色法 150 六、統計分析 150 第三節 結果 151 一、藻褐素對 CHO-K1 細胞存活率之影響 151 二、藻褐素及藻褐醇之 PPARα 轉錄活性 151 三、藻褐素及藻褐醇之 PPARγ 轉錄活性 151 四、藻褐素及藻褐醇之 PPARδ 轉錄活性 151 五、藻褐素及藻褐醇之 LXRα 轉錄活性 152 六、藻褐素及藻褐醇之 LXRβ 轉錄活性 152 七、GGPP 與 LXRα 或 LXRβ agonist 共處理之轉錄活性分析 152 第四節 討論 160 一、藻褐素代謝物之製備 160 二、藻褐素、藻褐醇之 PPARα/γ/δ轉錄活性 160 三、藻褐素、藻褐醇之 LXRα/β 轉錄活性 162 第五節 結論 163 第五章 綜合討論與總結論 164 第一節 綜合討論 164 一、相關文獻之異同 164 二、藻褐素透過 PPAR/LXR 調節體脂代謝? 167 三、藻褐素透過調節粒線體促進能量消耗 171 第二節 總結論 172 第六章 參考文獻 174 附錄- 氫譜 199 一、藻褐素 (溶於 CDCl3) 199 二、藻褐醇 (溶於 CDCl3) 199 | |
dc.language.iso | zh-TW | |
dc.title | 藻褐素抗肥胖之機制探討 | zh_TW |
dc.title | The Study on Anti-obesity Mechanism of Fucoxanthin | en |
dc.type | Thesis | |
dc.date.schoolyear | 102-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 周宏農(Hong-Nong Chou),魏耀揮(Yau-Huei Wei),胡淼琳(Miao-Lin Hu),趙蓓敏(Pei-Min Chao),蘇慧敏(Hui-Min Su) | |
dc.subject.keyword | 藻褐素,脂肪,代謝率,PGC-1α,粒線體生合成及融合,PPARs,LXRs, | zh_TW |
dc.subject.keyword | Fucoxanthin,Adipose tissue,Metabolic rate,PGC-1α network,Mitochondrial biogenesis and fusion,PPARs,LXRs, | en |
dc.relation.page | 199 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2014-06-03 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 生化科技學系 | zh_TW |
顯示於系所單位: | 生化科技學系 |
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