臺灣博碩士論文加值系統

四氫薑黃素（tetrahydrocurcuin；THC）是薑黃素的主要無色代謝產物之一。已有許多文獻證實具有抗糖尿病、抗氧化、抗發炎、抗癌等功效，因此本研究欲進一步探討 THC 對於抑制肝臟脂質堆積是否也有相似功效。本研究主要以細胞模式（in vitro）和動物模式（in vivo）探討 THC 對於減少肝臟脂肪堆積之功效與機制。實驗模式分別以油酸及高脂飲食（high fat diet；HFD）誘導細胞及動物實驗之肝臟脂質堆積。在細胞實驗結果顯示，以 Oil Red O 染色發現 THC 有效降低油酸誘導細胞內脂質的堆積並呈現 dose-dependent 趨勢，利用 trypan blue 結果也能得知 THC 細胞內脂質堆積並不是因為具有細胞毒性所導致。進一步利用 Western blot 探討相關肝臟脂質生合成蛋白質分子機制研究，發現給予 THC 後能活化 adenosine 5’-monophosphate（AMP）-activated protein kinase（AMPK）訊息傳遞，抑制其下游標的分子 acetyl-CoA carboxylase（ACC），減少細胞內 TG 的累積﹔THC亦能抑制細胞內脂質合成轉錄因子 sterol regulatory element binding proteins-1c（SREBP-1c）、peroxisome proliferator-activated receptor gamma（PPARγ）、fatty acid binding protein 4（FABP4）及 fatty acid synthase（FAS）蛋白質表現，並能促進脂質代謝酵素及其轉錄因子 Carnitine palmitoyltransferase 1a（CPT-1a）及peroxisome proliferator-activated receptor alpha（PPARα）的表現，達到降低肝臟脂質堆積的效果。進一步探討 IRS1/PI3K/AKT signaling，實驗證實 THC 有效改善胰島素抗性問題。在動物實驗結果顯示，肥胖小鼠給予 THC 後有效降低HFD所誘導之肥胖現象，且體重增加的情形明顯較 HFD 組低，其白色脂肪（性腺脂肪與腸膜脂肪）的重量亦有顯著性的減少。在血清生化值方面，餵食 THC 可降低 GOT、GPT、TG 及 TCHO。在肝臟、脂肪及腎臟組織切片中發現，餵食 THC 可有效改善 HFD 所造成肝臟脂肪的堆積、脂肪細胞的大小、脂肪組織發炎現象及腎纖維化的現象。而 Western blotting 結果中發現，於肝臟及脂肪組織中 THC 可透過調控 AMPK pathway 以降低下游相關脂質生合成因子的表現。綜合以上結果可以顯示 THC 具有預防和治療由肥胖所引起的非酒精性脂肪肝之功效。

Tetrahydrocurcumin (THC) is one of the major active colorless metabolites of curcumin. THC exhibited beneficial effects in metabolic syndromes such as diabetic mellitus and dyslipidemia. In vitro study, we investigated the effect of THC on oleic acid (OA)–induced hepatic lipogenesis in hepatocarcinoma cells (HepG2 cells). To investigate the effects of THC in vivo, high fat diet (HFD) fed C57BL/6J mice were orally administered THC (20 or 100 mg/kg body weight) or vehicle for 10 weeks. The cell viability and lipid accumulation was analyzed by trypan blue and oil Red O stain. THC also activated adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK) signaling and reduced acetyl-CoA carboxylase (ACC) in HepG2 cells, reduce the accumulation of intracellular TG. THC also decreased hepatic lipogenesis through down-regulated sterol regulatory element binding proteins-1c (SREBP-1c), peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid binding protein 4 (FABP4) and fatty acid synthase (FAS). Besides, we found THC increased the expression of carnitine palmitoyltransferase 1a (CPT-1a) and peroxisome proliferator-activated receptor alpha (PPARα) that may contribute to up-regulation of fatty acid oxidation. Furthermore, we also investigated IRS1/PI3K/AKT signaling, experiments confirmed THC can improve insulin resistance. In the in vivo study, THC (20 or 100 mg/kg body weight) decreased HFD induced weight gain and relative perigonadal and mesenteric fat weight in C57BL/6 mice. Administration of THC reduced serum GOT, GPT, TG and T-CHO in high-fed mice. Hepatic, fat and kidney histological result demonstrated THC supplementation both improved HFD-induced morphological change of hepatocytes, reduced fat accumulation in liver, THC also reduced perigonadal adipose tissues size and improved slight kidney fibrosis. Based on these results, we suggested that THC may have a potential benefit in preventing and treating obesity induce NAFLD.

目錄
附圖目錄
附表目錄
誌謝
中文摘要
英文摘要
縮寫表
第一章、緒論
第一節、非酒精性脂肪肝定義
第二節、肝臟二次打擊學說
第三節、非酒精性脂肪肝（NAFLD）致病機轉
第四節、調控脂質代謝相關蛋白質
一、Adenosine monophosphate-activated protein kinase（AMPK）
二、脂肪酸合成酶（fatty acid synthase；FAS）
三、乙醯輔酶A羧化酶（acetyl-CoA carboxylase；ACC）
四、固醇調節結合蛋白（sterol regulatory element biding-protein；SREBPs）
五、過氧化體增殖活化受體（peroxisome proliferators activated receptors；PPARs）
六、肉鹼醯基轉移酶 1 （carnitine palmitoyltransferase 1；CPT 1）
七、脂肪酸結合蛋白4 （fatty acid binding protein 4；FABP4）
第五節、非酒精性脂肪肝與肝臟胰島素抗性
一、肝臟脂質代謝與肝臟胰島素抗性
二、內臟肥胖與肝臟胰島素抗性
第六節、胰島素與葡萄糖生理恆定作用
一、葡萄糖之生理恆定作用
二、胰島素的分泌
三、胰島素的功用
四、胰島素訊息傳遞路徑
五、胰島素抗性及其分子機制
第七節、非酒精性脂肪肝之預防及治療
第八節、薑黃素（curcumin；CUR）
一、薑黃活性成分
二、Curcumin
第九節、四氫薑黃素（tetrahydrocurcumin；THC）
第二章、研究目的
第三章、研究架構
第四章、實驗材料與方法
第一節、儀器與廠牌
第二節、藥品與廠牌
第三節、實驗方法
第五章、結果與討論
第六章、結論
第七章、圖表
第八章、參考文獻

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