Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/23291
標題: 內臟脂肪素在人類內皮細胞經由NF-κB轉錄因子誘發發炎介質之研究
Visfatin induced expression of inflammatory mediators in human endothelial cells via NF-κB pathway
作者: 吳承修
Wu, Cheng-Shiu
關鍵字: visfatin;內臟脂肪素;HUVECs;adipocytokine;inflammation;adhesion molecule;人類臍帶內皮細胞;脂肪素;發炎;黏著分子
出版社: 生命科學院碩士在職專班
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摘要: 
過多脂肪累積所造成的肥胖是造成代謝症候群的主要原因之一,脂肪組織所分泌的荷爾蒙和胞泌素統稱為脂肪素(adipocytokines或adipokines),內臟脂肪素(visfatin)是最近被發現新的脂肪素,可與胰島素接受器結合而具有類似胰島素的功能。許多文獻指出,在肥胖及第二型糖尿病人血中的內臟脂肪素濃度較正常人高。然而有關內臟脂肪素的生理功能,特別是在參與代謝症候群引起有關的內皮細胞功能失調所扮演的角色,目前仍不清楚。
本研究,利用內臟脂肪素刺激人類臍帶內皮細胞的模式,觀察此脂肪素是否會引起增生、發炎現象和黏附因子的產生,由觀察內皮細胞的細胞存活率變化,及藉由同步定量聚合酶鏈反應、酵素免疫分析、流式細胞儀分析發炎分子和黏附因子的表現量及人類單核球細胞黏著在內皮細胞上之能力,以及是否經由改變轉錄因子NF-κB的活性路徑。研究結果發現,內臟脂肪素(50 ng/ml)可誘導IL-6、IL-8、ICAM-1、VCAM-1及E-selectin之基因表現增加,分別增加為2.72倍、1.93倍、2.96倍、3.97倍、2.80倍(相較於對照組皆p<0.05)。在蛋白質層次,相較於對照組IL-6有1.41倍(10ng/ml)、1.76倍(50ng/ml)增加,IL-8有1.22倍(10ng/ml)、1.23倍(50ng/ml)增加,ICAM-1有1.11倍(10ng/ml)增加,VCAM-1有1.06倍(50ng/ml)增加,sE-selectin有1.78倍(50ng/ml)增加(皆p<0.05)。同時發現內臟脂肪素處理1小時後,可增加核轉錄因子NF-κB的活化,分別為1.56倍(10ng/ml)、1.38倍(50ng/ml)(皆p<0.05),亦表示內臟脂肪素增加發炎反應和黏附因子表現可能是經由調控NF-κB的活性。此外內臟脂肪素對於人類單核血球細胞與內皮細胞的黏附,分別有1.22倍(10ng/ml)、1.22倍(50ng/ml)顯著增加(皆p<0.05)。
本研究結果證實內臟脂肪素在體外實驗可能造成內皮細胞功能失調,而此資料可能可解釋內臟脂肪素在肥胖及心血管疾病之相關聯性,並且做為將來開發新治療方法的標的之一。

Obesity, the excessive accumulation of fat, is a risk factor for development of metabolic syndrome. The adipose tissue itself has proven to be an important endocrine organ, secreting several hormones and cytokines, usually referred as adipocytokines or adipokines. Visfatin can bind to and activate the insulin receptor, exerting insulin mimetic effects both in vitro and in vivo. In addition, visfatin, found to identical to pre-B-cell colony-enhancing factor (PBEF), a novel inflammatory cytokine that plays a requisite role in the delayed neutrophil apoptosis , and it levels in blood levels have been reported higher in subjects with obesity and/or type 2 diabetes mellitus. It is currently unclear the pathophysiological role of visfatin and it association with endothelial dysfunction related inflammatory and adhesion molecule expression has been largely unexplored.
Primary human umbilical vein endothelial cells (HUVECs) pretreated with visfatin (1, 10, 50 ng/ml) were used to study the relationship between visfatin and endothelium dysfunction. Expression of cytokine (IL-6 and IL-8) and adhesion molecules (VCAM-1 and E-selectin) affected by visfatin were investigated by real-time PCR and ELISA. Activity of NF-κB was examined by electrophoretic mobility shift assay (EMSA).At a visfatin concentration of 50 ng/ml, significant increases in IL-6 (2.72 folds), IL-8 (1.93 folds), ICAM-1 (2.96 folds), VCAM-1 (3.97 folds) and E-selectin (2.80 folds) gene expression (all p<0.05) along with increased IL-6 (1.76 folds), IL-8 (1.23 folds) and sE-selectin (1.78 folds) protein levels (all p<0.05) in the conditioned medium were detected. Visfatin significantly increased ICAM-1 (1.11 folds) expression on 10 ng/ml, and VCAM-1 (1.06 folds) expression on 50 ng/ml detected by flow cytometry. Results from EMSA confirmed that visfatin (10, 50 ng/ml) increased DNA binding activity of NF-κB (1.56 folds, 1.38 folds respectively) (p<0.05). In addition, increased human monocyte cell line THP-1 attaching to HUVECs when pretreated with visfatin (10, 50 ng/ml) was also demonstrated(1.22 folds, 1.22 folds respectively) (p<0.05).
We demonstrated that visfatin increased inflammatory and adhesion molecule expression, at least partly via up-regulated of NF-κB activity, that might contribute to increased endothelial dysfunction. In addition, visfatin enhanced THP-1 adherence to HUVECs. Our findings provide direct evidence that visfatin causes endothelial dysfunction, which may help establish a link between obesity and cardiovascular disease, as well as a novel approach to target the development of new therapeutic strategies.
URI: http://hdl.handle.net/11455/23291
其他識別: U0005-2106200708210500
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