脂締素透過活化PPARα誘發HO-1/COX-2的表現及對肝細胞鐵過度沉載之保護機制

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题名:	脂締素透過活化PPARα誘發HO-1/COX-2的表現及對肝細胞鐵過度沉載之保護機制 Adiponectin inhibits iron-induced hepatic damage through the activation of PPARα mediated HO-1/COX-2 expression
作者:	任治宇 Chih-YU Jen
贡献者:	醫學科學研究所
关键词:	脂締素過氧化增生活化受體第一型血紅素氧化第二型環氧鐵 Adiponectin PPAR HO-1 COX-2 Iron
日期:	2009
上传时间:	2009-08-27 17:24:55 (UTC+8)
摘要:	鐵質的沉積常發生在地中海型貧血或酒精性肝炎的病患體內，因為鐵質無法被正常代謝與再利用，而使得細胞中出現過多的鐵離子。過多的鐵離子將造成不正常的氧化作用與細胞傷害，它會造成細胞發炎反應、粒線體功能異常及細胞凋亡的發生。在許多研究中已指出：第一型血紅素氧化?? (HO-1)及第二型環氧?? (COX-2)在許多不同的組織當中，具有抗發炎及抗細胞凋亡的功能。透過誘發這些蛋白的表現，能保護細胞防止來自氧化壓力或發炎反應的傷害。在我們的實驗中，證實透過給予肝細胞脂締素 (adiponectin)可明顯增加HO-1及COX-2的RNA及蛋白質的表現量。透過轉染帶PPARα的質體處理後，可更明顯的提高蛋白表現量達6.5倍。而相對的，減少細胞中PPARα的表現量將會反轉脂締素誘發其表現的效果。顯示了這個誘發作用是必須依賴PPARα的。此外，脂締素所誘發的HO-1及COX-2可以減輕過多鐵質所造成的肝細胞的凋亡和發炎反應。透過給予不同的抑制劑，我們發現了脂締素的細胞保護功能主要是建立在HO-1的抗細胞凋亡及COX-2的抗發炎反應的功能上。在本實驗中，證明了脂締素透過活化PPARα誘發HO-1及COX-2表現的分子機轉；以及脂締素保護肝細胞防止細胞凋亡效果。 Iron deposition usually occurs in Thalassemia or alcoholic liver injury patients, of which the process of iron transportation or utilization is suppressed. Overloaded iron in cells causes oxidative injury and mitochondria dysfunction. It elicits inflammatory response and the activation of apoptotic pathway in various cell types, thereby leading to cell death and tissue damage. Many studies have shown that heme oxygenase-1 (HO-1) and cyclooxygenase-2 (COX-2) have important anti-inflammatory and anti- apoptotic roles in various tissues. Induction of these enzymes has been shown to protect various cells from oxidative or inflammatory insults. In this study, we demonstrated that hepatocytes treated with adiponectin caused significant increases in HO-1/COX-2 RNAs and protein expressions. It was further increased by approximately 6.5 fold in cells transfected with pcDNA3.1-PPARα. Conversely, PPARα knock down reversed APN-mediated HO-1/COX-2 induction, suggesting that induction of HO-1/COX-2 is dependent on PPARα. Additionally, adiponectin mediated HO-1/COX-2 induction is essential for the elimination of iron-mediated apoptosis and inflammation in hepatocytes. Using pharmaceutical inhibitors, we further demonstrated that the anti-apoptotic effect of HO-1 and anti-inflammatory effect of COX-2 synergistically contributed to the protection of adiponectin against iron-mediated hepatic injury. Taken together, we illustrated the effects and molecular mechanism of adiponectin mediated PPARα activation, in a concomitant induction of HO-1/COX-2 in the protection of hepatic apoptosis in vitro.
数据类型:	thesis
显示于类别:	[醫學科學研究所] 博碩士論文

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