- 學位論文
山苦瓜葉萃取物對高果糖飲食誘導非酒精性肝病之保護作用
The protective role of wild bitter melon leaf extract against high-fructose diet induced NAFLD in mice
摘要
由飲食所引起的代謝症候群(Metabolic syndrome, MS)是現今盛行的流行病之一，攝食過多的果糖會引起非酒精性脂肪肝病(Nonalcoholic fatty liver disease, NAFLD)造成發炎反應和肝損傷，而具備抗發炎功效的天然萃取物有保護肝臟的潛力。山苦瓜葉(Momordica charantia L. var. abbreviate Seringe)的富含三萜類化合物萃取物(triterpenoid-enriched extract, TEE)含有生物活性成分，在先前研究發現能改善CCl4 誘導的小鼠肝纖維化現象。本研究欲探討 TEE 對高果糖飲食誘導肝損傷的保護機制。 細胞模式上發現 TEE 可緩解由 LPS 引起巨噬細胞的發炎現象，同時也能改善TGFβ 所引起的星狀細胞活化及纖維化，表示 TEE 具備抗發炎及抗纖維化的功效。另外也發現肝細胞在給予果糖處理後會提高脂肪酸生成與降低脂肪酸氧化相關蛋白質，使過多三酸甘油酯堆積形成油滴，引起發炎反應影響周遭細胞，如星狀細胞受到發炎因子的刺激活化，增加膠原蛋白的生成；此外果糖也會引起巨噬細胞活化，然而在給予 TEE 前處理皆有緩解效果。動物模式上則是將C57BL/6 公鼠給予三種不同的飲食條件，分別為 60%高果糖飼料、30%果糖飲用水、以及60%高脂飼料搭配 30%果糖飲用水，持續 14 週以引起 NAFLD 的相關症狀；同時每日餵食 TEE 並觀察其保護功效。本研究發現高果糖飲食會增加小鼠的體重變化量、提升血清中 AST 及 ALT 指標、增加尾靜脈血壓，並從組織蛋白與切片觀察到脂肪堆積形成脂肪肝、肝臟發炎及肝纖維化等損傷，而餵食TEE 皆能改善由高果糖飲食所引起的肝損傷現象。 由蛋白質表現量分析的結果，推測 TEE 是透過調控與發炎相關的 NLRP3 inflammasome 以及 STAT3 等途徑，降低三酸甘油酯生成與膠原蛋白堆積，藉此改善高果糖飲食誘導小鼠代謝性疾病及肝損傷的進展。由此可知，具抗發炎能力的 TEE 可做為治療高果糖飲食誘導非酒精性脂肪肝病的潛在天然萃取物。
並列摘要
Diet-induced metabolic dysfunction is one of the current epidemics. Excess fructose consumption can lead to nonalcoholic fatty liver disease (NAFLD), including inflammatory reactions and hepatic damages. Numerous natural extracts with anti-inflammatory effects may have potential to protect the liver. Triterpenoid-enriched extract (TEE) which obtained from leaves of wild bitter melon (Momordica charantia L. var. abbreviate Seringe) is previously found to have various biological functions and exhibit the hepatoprotection effect on CCl4-induced liver fibrosis in mice model. In this study, we aimed to investigate the mechanisms underlying the hepatic protective effects of TEE-against high fructose diet-induced liver injury in mice. The in vitro model showed that TEE had the anti-inflammatory function in LPS-induced Raw264.7 macrophages and anti-fibrosis effect in TGFβ-induced HSC-T6 hepatic stellate cells. Furthermore, HepG2 hepatocytes, treated with fructose, increased fatty acid production, caused inflammation, and released inflammatory factors to affect surrounding cells, such as activating HSC-T6 stellate cells to promote collagen synthesis and deposition. Meanwhile, fructose treatment on Raw264.7 led to the activation of macrophage, and there was a trend of improvement with TEE pretreatment. In the in vivo model, C57BL/6 mice were feed for 14 weeks with three different dietary conditions, including 60% high fructose diet, 30% fructose in drinking water or 30% fructose in drinking water plus 60% high fat diet. Fructose diet enhanced the ratio of body weight gain, increased AST and ALT level in serum, raised the blood pressure, fat accumulation and liver fibrosis. TEE prevented high-fructose diet induced hepatic damages. With the protein expression analysis, results suggested that TEE might ameliorate the progress of high-fructose diet-induced liver injury via reducing triglyceride production and collagen accumulation, and regulating inflammation-related NLRP3 inflammasome and STAT3 pathways in mice. TEE, with anti-inflammatory ability, could be a potential natural extract for the treatment of high fructose diet-induced non-alcoholic fatty liver disease.
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