慢性肝病在台灣是一個極具挑戰性的臨床議題。肝纖維化的多重病原性是造成病患死亡 率增加的原因,而且肝纖維化往往會發展成肝癌。我們最近利用國民營養調查資料庫 (NAHSIT 2005-2008)分析國人血中鐵營養值標與代謝症候群的相關性.在全人口的分析 中,我們發現校正了血清發炎指標以及飲食的營養指標後, serum ferritin (鐵蛋白質) 高於最大三等分位的族群,得到代謝性症候群的危險對比值超過 1.6 倍. 目前並不清楚 過量的鐵蛋白質為何與代謝症候群的發生率有關。肝臟為重要的儲鐵器官但是臨床研究 也顯示過量的鐵質沉積與肝纖維化及肝癌有極大的相關性。血清中鐵蛋白質為反映體內 儲存鐵的生化質標。但是,發炎因子也會造成血清中鐵蛋白質的異常增加。證據顯示發炎 因子可以調控鐵蛋白質的基因表現量。但是慢性發炎如何造成鐵蛋白質代謝異常(組職 內沉積及釋放)? 血清中的鐵蛋白質又有何生理功能? 隨著國人代謝症候群及脂肪肝發生率的年輕化,這次研究的主題是以老鼠初代星狀肝細 胞來分析鐵蛋白質對內質網壓力機轉與肝纖維化的影響: 相關研究的主要目標為: 1. 釐清鐵蛋白質(serum ferritin)過量是否會造成星狀細胞內質網壓力增加與活化? 2. 何種鐵質(ferric, ferrous, ferritin, Apoferritin)較易增加內質網壓力? 3. 找出何種內質網壓力的轉錄因子 (ATF6,ATF4, XBP1 and CHOP)受到鐵質調控? 4. 分析鐵質誘導的內質網壓力機轉與肝臟纖維化的營響

Project: A - Government Institutionb - Ministry of Science and Technology

Project Details

Description

Elevated ferritin in circulation has recently been implicated in the pathogenesis of many diseases including chronic liver injury. Circulating ferritin reflects body iron store. However, increased ferritin levels are also associated with chronic liver fibrosis. Hemosiderin, oxidized and poorly available form of ferritin, deposition in the liver is a common form of hemochromatosis. Iron deposition is also the major cause of liver damage. In contrast to the cytosolic ferritin, serum ferritin is relatively iron-poor and its physiological function remains unclear. The activation of quiescent hepatic stellate cells to myofibroblasts is a key process in the development of hepatic fibrosis. Chronic hepatic iron overload has been known to activate the HSC and contribute to the development of liver fibrosis. However, the underlying mechanisms, which initiate this activation process, remain largely unknown. The primary goal of this study is to dissect the molecular targets of ferritin and iron metabolites in the development of liver fibrogenesis Specifically, we aim to: 1) Dissect molecular targets of ferritin and iron metabolites: which ER stress-associated transducers (ATF6,ATF4 and XBP1) is the primary target? 2) Do ER stress-associated mechanisms responsible for the activation of hepatic stellate cells? 3) Clarify the role of iron metabolites (ferritin, apoferritin, heme iron and ferric iron) on the liver fibrosis 4) Dissect genes promoter regulation of iron regulatory genes (e.g. hepcidin, ferritin) and genes involved in HSC activation (e.g. αSMA, IL6,TNF)
StatusFinished
Effective start/end date9/1/128/31/13