NQ-1 降血糖分子機制探討：體外及體內試驗

Studies of molecular mechanisms of NQ-1 on the hypoglycemic effect in vitro and in vivo

陳乃琦(Nai-Qi Chen)

指導教授 ： 梁有志

臺北醫學大學/醫學院/醫學科學研究所/碩士(2008年)

摘要

過氧化物酶體增殖物激活受體(peroxisome proliferator-activatived receptors，簡稱PPARs)是一群需要配體(ligand)激活的轉錄因子，屬於核激素受體超家族，在許多生理作用中扮演重要的角色，例如：提高胰島素的敏感性、調節脂質代謝、維持體內葡萄糖平衡、細胞週期的調控與發炎反應的調節。在過去幾年中，對於天然和合成的過氧化物酶體增殖物激活受體配體的開發，及其相關的功能之鑑別，已經成為糖尿病病人血糖控制重要的研究目標之一。NQ-1是從中草藥純化出來的一種疏水性化學物質。首先，我們從細胞轉染(transition transfection assay)實驗中發現隨著NQ-1劑量的提高細胞中PPARa及g的活性亦顯著地增加。接著，以西方墨點法觀察，NQ-1可以分別在3T3-L1脂肪細胞及人類肝癌細胞(HepG2)中誘導PPARa/g產生。除此之外，NQ-1也可顯著地誘導3T3-L1脂肪細胞之脂肪標的基因表現(adipocyte marker gene)，例如:脂肪酸結合蛋白(adipose fatty acid-binding protein, aP2)、脂蛋白脂解酶(lipoprotein lipase, LPL)、脂肪酸合成酶(fatty acid synthase, FAS)和CCAAT/enchancer binding protein-a(C/EBPa)。第三，NQ-1同樣地誘導HepG2肝癌細胞表現PPARa標的基因增加，例如: CPT-1與ACS。最後，在動物實驗方面，糖尿病小鼠(db/db mice)以腹腔注射的方式投予NQ-1，發現NQ-1能夠降低血糖卻無法降低血漿中胰島素與三酸甘油脂的濃度。由上述的實驗結果顯示，NQ-1為PPARa/g的雙重配體，並且具有治療第二型糖尿病的可能性。

關鍵字

過氧化物酶體增殖物激活受體 ； 胰島素抗性 ； 第二型糖尿病

並列摘要

Peroxisome proliferator-activatived receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-dependent transcription factors. PPARs play a central role in insulin sensitivity, lipid metabolism, glucose homeostasis, cell cycle progression, and inflammation. For the control blood glucose level of diabetes mellitus patient, searching PPAR activators from natural and synthetic chemicals, and discovering their associated functions is one of the most important works in the field. NQ-1 is a hydrophobic chemical and extracted from Chinese herb medicine. First, NQ-1 significantly activated both of PPARa and PPARg in a dose-dependent manner by transition transfection assay. Second, NQ-1 markedly induced the expression of PPARa and PPARg in HepG2 cells and 3T3-L1 respectively. In addition, NQ-1 significantly induced the expression of adipogenic factors such as aP2, LPL, C/EBPa and fatty acid synthase in 3T3-L1cells. Third, NQ-1 also induced the expression of PPARa target genes such as CPT-1 and ACS in HepG2 cells. Finally, obese diabetic mice (db/db mice) were treated with NQ-1, and found that NQ-1 markedly reduced plasma glucose level, however did not change the plasma insulin level and serum triglyceride level. These results suggest that NQ-1 is a dual PPARa/g activator and may have a beneficial effect on the therapy of typeⅡdiabetes mellitus.

並列關鍵字

PPAR dual agonist ； typeⅡdiabetes mellitus ； insulin resistance

參考文獻

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