藥物對變異型脂蛋白元A5 c.553G>T之影響

高三酸甘油酯血症(HTG)在人類族群中的盛行率高，且以列為致死疾病中心血管疾病的危險因子，所以發展對其有效治療的方式日益受到關注與重視。血液中脂質由脂蛋白所運輸攜帶，然而脂質的代謝主要受到脂蛋白表面各式各樣且功能各異的脂蛋白元所調控。脂蛋白元AV為近年新發現的脂蛋白元，據先前基因轉殖小鼠實驗中顯示出其含量與三酸甘油脂(TG)的濃度呈負相關。同時APOA5的許多基因多型性(SNPs)與HTG具有統計學上的相關性。其降TG功能於近期的發表研究中指出可能藉由間接提升脂蛋白解脂酶(LPL)的活性、降低體內VLDL-TG的形成與加速其透過LPL水解的代謝途徑，除此之外並可作為一個ligand透過LDL受體結合的方式使富含TG的脂蛋白被細胞內吞後而加以代謝清除。APOA5可被影響TG代謝的轉錄因子(e.g. PPAR-α、PPAR-γ,TR-β )所調控，顯示於TG代謝與TG恆定中扮演著不可或缺的角色。近期研究更指出APOA5也會影響著膽固醇的?琠w，可能也在與糖尿病和發炎相關的HTG中參予要角。本實驗室所發現華人特有的c.553G>T多型性與HTG具有統計學上的相關性，會造成脂蛋白元AV的第185個胺基酸由甘胺酸（glycine）變為半胱胺酸（cysteine），並且後續的研究指出其亦是罹患心血管疾病的危險因子之ㄧ。故本論文為針對華人中帶有特有之APOA5 c.553G>T而好發HTG的治療法中探討此多型性是否可作為新的藥物標的，及有效的治療策略，以提供臨床上作為用藥的參考。首先我們觀察到APOA5的驅動子在有PPAR-α的激活物Fibrates、TR-β的激活物T3、T4與調節發炎反應的Curcumin、Esculetin等等藥物的作用下，其轉錄活性皆有所提升，其提升百分比從118.4 %至453.9 %不等。又於藥物作用後，所轉譯出的野生型及變異型脂蛋白元AV的蛋白表現量，分別有62.5 %~208.9 %與39 % ~273.1 %不等的提升。然而初步實驗結果顯示藥物激活後的野生型與變異型apoAV強化LPL的水解能力與對照組相比並無差異，雖然此結果需待更佳的實驗設計後才能確認，但是否暗示不同的調控機制亦值得討論。

關鍵字

高三酸甘油酯血症；三酸甘油脂；脂蛋白元A5 ；脂蛋白元A5c.553G>T ；脂蛋白解脂酶

並列摘要

Hypertriglyceridemia (HTG) is an independent risk factor for the development of cardiovascular disease and is often associated with diabetes, inflammation and the metabolic syndrome. Recently, apolipoprotein A5 (APOA5) was identified as a novel member of the APOAI/CIII/AIV gene cluster. Data from mice over-expressing or lacking apoAV provide direct evidence that this apolipoprotein plays a crucial role in triglyceride metabolism. Moreover, plasma triglyceride levels were found to be strongly associated with APOA5 polymorphisms. We previously identified genetic variant in Chinese people, c.553G > T in the APOA5 gene which causes a substitution of a cysteine for a glycine residue at amino acid residue 185 is associated with increased TG levels, also a risk factor for coronary artery disease. The human APOA5 gene is regulated by transcription factors known to affect triglyceride metabolism such as PPARα, RORα, LXR ,SREBP-1c and thyroid receptorβ and this supports its function. To date, the triglyceride lowering action of apoA5 is attributed to the activation of lipoprotein lipase (LPL) and an acceleration of very low density lipoprotein catabolism. Recent findings indicate that APOA5 could also influence cholesterol homeostasis and probably play a role in hypertriglyceridemia associated with diabetes and inflammation. Considering clinical application, we want to examine whether APO A5 is the new drug target for HTG. For that, we examined drugs and chemicals effects on APOA A5 promoter activity. Further, whether these new strategies for curing HTG are practicable therapies. All drugs and chemicals increased the expression of APOA5 promoter from 118.4 % to 453.9 % . While drugs or chemicals increased the wild type and variant apoAV concentractions from 62.5 % to 208.9 % and 39 % to 273.1 % respectively, the LPL-activating abilities of drugs-treated apoAV remained the same among wild type, variant and control. Maybe proper methodology of LPL activity assay is needed for further studies. Further studie is needed to explore the mechanism.

並列關鍵字

Hypertriglyceridemia ； triglyceride ； apolipoprotein A5 ； apolipoprotein A5 c.553G >T ； lipoprotein lipase

參考文獻

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藥物對變異型脂蛋白元A5 c.553G>T之影響

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