PPARα在內生性DHA合成之角色及生理意義

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题名:	PPARα在內生性DHA合成之角色及生理意義 The role and physiological relevance of PPARα in endogenous DHA synthesis
作者:	蕭雯婷;Wen-Ting Hsiao
贡献者:	營養學系碩士班
关键词:	多元不飽和脂肪酸;脂肪酸代謝;Polyunsaturated fatty acid;DHA;PPARα;Fatty acid metabolism
日期:	2018-08-21
上传时间:	2018-12-25 10:18:07 (UTC+8)
出版者:	中國醫藥大學
摘要:	二十二碳六烯酸 (Docosahexaenoic acid, DHA)是一種n-3多元不飽和脂肪酸，具有重要的生理功能。DHA非必需脂肪酸，人體可藉由攝取α-次亞麻油酸 (α-Linolenic acid, ALA)經由一連串延長與去飽和酶反應生成，近年研究發現除了原有路徑外，有另一條替代路徑涉及 Peroxisome proliferator-activated receptor α (PPARα)-dependent β-oxidation，但PPARα在內生性DHA合成重要性尚無定論。本研究欲探討PPARα在內生性DHA合成之角色及生理意義。實驗分為兩部分，實驗一欲了解PPARα含量的多寡 (+/+、+/–、–/–)對內生性DHA之影響，實驗二欲探討活化PPARα是否會影響內生性DHA合成。為了解PPARα在內生性DHA合成之重要性，須避免外源性DHA干擾實驗，採行的策略為於母鼠懷孕及哺乳期間提供sunflower oil diet （n-6/n-3 ratio極高），此種飼料不含DHA前驅物，遂可使母體內DHA耗竭而無法傳與子代，子代斷乳後提供soybean oil diet（n-6/n-3 ratio恰當），此種飲食含有DHA前驅物-ALA，故子代可立即啟動內生性DHA合成，為達成PPARα活化的目的，實驗二於實驗組飼料中添加PPARα agonist clofibrate。實驗結果顯示在欠缺PPARα情況下，斷乳後4周肝臟內生性DHA合成酵素Acox、Fads2、Fads1及Elovl5基因表現量會下降，活化PPARα會使肝臟內生性DHA合成酵素Acox、Fads2、Fads1及Elovl5基因表現量被上調，表示PPARα會調控內生性DHA合成酵素活性；欠缺PPARα會使斷乳後4周肝臟DHA、AA（Arachidonic acid ）含量及大腦皮質AA含量百分比下降；活化PPARα會使肝臟、大腦皮質及視網膜中DHA含量百分比降低，但AA增加；大腦及視網膜DHA運輸蛋白Mfsd2a、發育及功能性基因表現Bdnf、Ngf、Ntrk2、Pax6、Crx、Opn1sw、Opn1mw、Rho並未受到PPARα活化影響。本研究證實PPARα確實參與了2個內生性DHA合成路徑，且缺乏PPARα或活化PPARα都會降低體內DHA堆積，但並不會影響大腦與視網膜的發育及功能性相關基因表現。 Docosahexaenoic acid (DHA) is a n-3 polyunsaturated fatty acid which has important physiological functions. DHA is a non-essential fatty acid and can be synthesized through a series of elongation and desaturation by ingesting α-Linolenic acid (ALA). In recent years, it has been found that in addition to the original pathway, endogenous DHA has another alternative pathway involving peroxisome proliferator-activated receptor α (PPARα)-dependent β-oxidation, but whether PPARα involved in the endogenous DHA synthesis is not clear. In this study, we aim to investigate the physiological role and its significance of PPARα in endogenous DHA synthesis. Our study was divided into two parts. First is to investigate the effect of PPARα (PPARα+/+, PPARα+/–, PPARα–/–) on endogenous DHA. Second is to explore whether the activation of PPARα would affect endogenous DHA synthesis. In order to examine the importance of PPARα in endogenous DHA synthesis, the interference of exogenous DHA should be avoided. Pregnant C57BL/6J mice were administered sunflower oil diet during pregnancy and lactation to deplete the DNA precursor, ALA. After weaning, offsprings were fed on soybean oil diet with or without clofibrate (CF, a PPARα agonist) for 2 or 4 weeks. Results showed that in the absence of PPARα, the hepatic mRNA level of Acox, Fads2, Fads1 and Elovl5 were decreased at 4 weeks after weaning. However, activation of PPARα upregulates the mRNA level of endogenous DHA synthase Acox, Fads2, Fads1 and Elovl5, indicating that PPARα modulates the activity of endogenous DHA synthase. Lack of PPARα decrease the percentage of DHA, AA in liver and AA in cerebral cortex at 4 weeks after weaning. Activation of PPARα decrease the percentage of DHA in liver, cerebral cortex and retina, but increase the AA content. However, the mRNA level of brain and retina DHA transport protein Mfsd2a, developmental and functional genes includes Bdnf, Ngf, Ntrk2, Pax6, Crx, Opn1sw, Opn1mw, Rho were not affected by PPARα. Our study demonstrates that PPARα is indeed involved in two endogenous DHA synthesis pathways, and that lack of PPARα or activation of PPARα both reduces DHA accumulation in vivo, but PPARα activation does not affect brain and retina development and functionally related gene expression.
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