天然化合物對脂蛋白解脂梅表現之影響

脂蛋白解脂酶(lipoprotein lipase, LPL)座落於人類第八條染色體上，全長大約30kb，由十個exon以及九個intron構成，LPL在身體許多組織中合成，如脂肪組織、骨骼肌、腦以及腎臟等等。LPL被製造後會分泌至附近的微血管，與細胞表面的heparan sulfate proteoglycans (HSPG)結合而附著在微血管壁上。LPL在脂質代謝方面佔有重要的角色，其主要的功能是水解乳糜微粒和極低密度脂蛋白中的三酸甘油酯，而形成游離型脂肪酸及甘油。游離型脂肪酸可燃燒作為能量使用，或者以脂肪形式貯存。當脂蛋白解脂酶基因發生變異時會造成高脂血症，導致脂質代謝失去平衡。 Peroxisome proliferator-activated receptors (PPAR) 是一種nuclear receptor，當被活化時會結合retinoid X receptor形成heterodimer，直接結合到DNA上一段特殊的序列，而調控基因的表現，而此段序列稱為peroxisome proliferators response element (PPRE)，LPL的promoter序列中也具有PPRE。近年研究指出白藜蘆醇(resveratrol)是最具增強sirtuin活性的物質，而SIRT 1可以調節哺乳動物體內葡萄糖、胰島素生成，以及脂肪代謝等，另外也有研究提出柚皮素(naringenin)可以降低primary rat hepatocytes生成三酸甘油酯，提高PPARα和PPARγ活性。此外亦有研究指出厚朴酚(magnolol)可以藉控制具有第二型糖尿病老鼠體內的血糖而抑制慢性腎病的形成。同時厚朴酚也是PPARγ的ligand，可提高脂肪細胞攝取葡萄糖。本論文目的為探討resveratrol、naringenin和magnolol這三種天然化合物是否透過PPARs 刺激LPL的生成並增加其活性，進而提供臨床治療高脂血症用藥的方向。實驗利用HEK293、Huh7、U937以及3T3-L1細胞測試不同濃度的resveratrol、naringenin和magnolol是否可提高LPL活性。由收集細胞培養液以及細胞溶解液，分析結果顯示這三種化合物皆可以提高細胞中內源性LPL的活性。利用Real-time PCR定量3T3-L1細胞中基因表現，發現resveratrol可以提高pparα、pparγ、lpl及sirt1基因表現，而naringenin可以提高pparγ基因表現，magnolol則是提高pparγ、lpl基因表現。目前結果證明了resveratrol、naringenin和magnolol可以促進細胞中LPL的表現量增加，pparγ表現量也增加，以上結果是否為PPARs的作用還需要更多實驗證實。

關鍵字

脂蛋白解脂酶高三酸甘油脂血症；白藜蘆醇；柚皮素；厚朴酚

並列摘要

Lipoprotein lipase ( LPL ) gene located at human chromosome 8. The human LPL gene comprises of 10 exons and 9 introns spanning approximately 30 kb. LPL is synthesized in many tissues, such as adipose tissue, skeletal muscle, brain and kidney,etc. The synthesized LPL is secreted to capillary upon binding with HSPG which is localized on cell surface. LPL plays an important role in plasma lipid metabolism. It catalyzes the hydrolysis of triglycerides from chylomicrons and very low density lipoprotein into glycerol, diacylglycerol and free fatty acids. Free fatty acids are supplied to tissues as sources of metabolic energy or stored as triglycerides after re-esterification. Defects in LPL gene can cause hyperlipoproteinemia and affect lipid homeostasis. Peroxisome proliferator-activated receptors (PPAR) is a nuclear receptor，PPAR/RXR heterodimers bind to specific response elements (PPREs) present in the promoters of their target genes.The PPREs is present in the promoters of LPL genes. Recent research about Sirtuin family shows that SIR1 can regulate glucose synthesis and insulin and adipose metabolism, etc. Resveratrol , the most potent molecule that enhances SIRT1 activity. There are reports showing that naringenin could reduce triglyceride production in primary rat hepatocytes and it also regulates nuclear receptors PPARα and PPARγ activities. Moreover, magnolol has been reported to control blood glucose and prevent or retard development of diabetic nephropathy in type 2 diabetic rats and it also increases glucose uptake in 3T3-L1 adipocytes as a weak PPARγ ligand. In this research, we investigated whether resveratrol, naringenin and magnolol could enhance LPL synthesis and activity through PPARs pathway. HEK293, Huh7, U937 and 3T3-L1 cells were treated with resveratrol, naringenin and magnolol.The data shoewed that three compounds enhanced endogenous LPL expression. By observing other genes expressed in 3T3-L1 cells, we detected resveratrol cound enhance pparα, pparγ, lpl and sirt1gene expression, naringenin could enhance pparγ gene expression, and magnolol could enhance pparα, pparγ and lpl gene expression. This result indicated that hypolipidemic effects of those natural compounds could be by enhancing LPL expression.Moreover, those compounds also enhanced pparγ gene expression. However, we could not prove whether resveratrol, naringenin and magnolol could enhance LPL synthesis and activity through PPARs pathway so far.

並列關鍵字

Lipoprotein lipase ； Hyperlipoproteinemia ； Resveratrol ； Naringenin ； Magnolol

參考文獻

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天然化合物對脂蛋白解脂梅表現之影響

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