以動物模型探討中國橄欖乙醇萃取物延緩高血糖與高血脂作用之機制

Study on mechanisms underlying the preventive effects of the Chinese olive ethanol extract on modulation of hyperglycemia and hypercholesterolemia in animal model

高郁涵(Yu-Han Kao)

指導教授 ： 謝淑貞

共同指導教授 ： 姜安娜(An-Na Chiang)

國立臺灣大學/生物資源暨農學院/食品科技研究所/碩士(2016年)

https://doi.org/10.6342/NTU201603277

摘要

中國橄欖(Canarium album L.)屬於橄欖科植物，廣泛栽種於台灣新竹縣, 中國東南方以及亞洲其他區域。擁有多種藥理性質，包含保肝、抗微生物、抗病毒與抗毒性。中國橄欖富含多酚化合物與三萜類也被證實與抗代謝疾病間具有強關聯性，然而其確切之相關機制仍未盡明確。因此本篇研究將透過第二型糖尿病大鼠探討中國橄欖乙醇萃取物的介入對於第二型糖尿病之高血糖與高血脂之代謝路徑影響。第二型糖尿病大鼠之誘導模式採高脂飲食輔以低劑量(35 mg/kg BW) STZ腹腔注射，模擬實驗動物在肥胖導致慢性發炎下使胰臟細胞受損的病理症狀。大鼠經四週中國橄欖乙醇萃取物介入後，藉提升肝臟GLUT2以及GK表現量促進葡萄糖攝取、降低PEPCK表現抑制糖質新生。此外更能增加肌肉組織Akt磷酸化，而促進胰島素敏感度，故推測中國橄欖可能藉由促進肝臟與肌肉組織之葡萄糖攝取能力，並抑制肝臟糖質新生而益於調降高血糖。在血脂代謝方面，中國橄欖可顯著降低血清中的總膽固醇、總膽酸。在膽固醇代謝方面，體內的膽固醇80%來自內生性膽固醇。中國橄欖主要藉降低肝臟SREBP-2與HMGCR表現量，抑制內生性膽固醇生成。另外，樣品介入後提升肝臟LDLR與ABCG-8表現量，分別提升肝臟攝取以及排除膽固醇的能力，綜合上述兩者的影響，顯著降低血清中之總膽固醇。而在膽酸代謝方面，體內95%膽酸來自迴腸端的再吸收，5%來自肝臟的內生性製造。中國橄欖藉由抑制NTCP的表現，可調控膽酸回收至肝臟的量。此外，經由抑制運輸蛋白BSEP、MRP3/4表現，降低肝臟中膽酸排出至膽管及週邊循環的量，最後藉由影響FXR、SHP及CYP7A1之表現量，抑制肝臟中內生性膽酸生成，因而使血清中的總膽酸低於疾病組。綜合上述實驗結果，推測中國橄欖可改善因肥胖及糖尿病而造成之肝臟膽固醇及膽酸調節失衡的現象，對於第二型糖尿病血糖、血脂與膽酸代謝失衡之調節，均有正向的貢獻。

關鍵字

中國橄欖乙醇萃取物 ； 第二型糖尿病 ； 膽固醇 ； 膽酸

並列摘要

Chinese olive (Canarium album L.), a plant in the Burseraceae family is widely cultivated in Hsinchu (Taiwan), the southeast area of China and other Asian regions. It has several pharmacological effects including hepatoprotective, antimicrobial, detoxic and antivirus. Phytochemical studies have shown that Chinese olive fruit is rich in polyphenols. These phytochemcals appear to be responsible for the pharmacological activity of Chinese olive fruit and have properties that may reduce the risk of metabolic diseases. Diabetes can be controlled through the reduction of hyperglycaemia. However, the exact mechanism of protection is not real understood. Thus, the objective of this study was to investigate the effects of an ethanol extract of Canarium album L. (COE) on the regulation of glucose and lipid metabolism in type 2 diabetic rats and L6 muscle cell line. Type 2 diabetes was induced in rats by feeding a 60% high-fat diet (HFD) and a low dose (35 mg/kg.BW) of streptozotocin injection. COE significantly reduced the elevated blood glucose levels, epididymal fat, serum FFA, total cholesterol and bile acid level elevated by HFD. Moreover, treatment of COE elevated deoxyglucose uptake in differentiated L6 muscle cells. Our findings demonstrate that COE improves glucose metabolism and in type 2 diabetes by decreased hepatic gluconeogenesis via its regulation on GK and PEPCK expressions. COE could attenuate the hepatic expression of SREBP-2 with a subsequent decrease in hepatic HMGCR mRNA expression and an increase in hepatic LDL receptor to decreased serum cholesterol concention. Also, COE represses hepatic BA synthesis via a FXR/SHP/CYP7A1 signaling pathway. Thus, COE could act as adjuvant therapeutics for metabolic disorders via attenuating obesity, epididymal fat, and improving serum parameters with cholesterol clearance and bile acid regulation of liver.

並列關鍵字

Chinese olive ethanol extract ； type 2 diabetes ； cholesterol ； bile acid

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