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)
|Effective start/end date||9/1/12 → 8/31/13|
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