Iron accumulation in alcoholic liver diseases
Iron accumulation in alcoholic liver diseases
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DOI：
10.1097/01.alc.0000189274.00479.62
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发表时间：
2005-11-01
影响因子：
3.2
通讯作者：
Kato, J
中科院分区：
文献类型：
--
作者：
Kohgo, Y;Ohtake, T;Kato, J
肝脏铁含量的增加是酒精引起肝脏活性氧自由基中毒的重要因素之一。在酒精性肝病（ALD）患者中，肝脏铁增加，产生的脂质代谢产物4-羟基壬烯醛-蛋白质加合物也增加。一般来说，ALD患者的铁沉积在实质细胞和枯否细胞中。然而，在轻度ALD患者中，实质铁沉积而不是网状内皮铁沉积占主导地位，而后者在重度ALD中占主导地位，可能是由于内毒素血症和炎性细胞因子的过度产生。我们推测轻度ALD时肝实质铁沉积是乙醇引起肝细胞损伤的一个重要因素，而肝实质铁沉积的可能原因是乙醇暴露后肝细胞通过血清转铁蛋白增加了细胞铁摄取。通过免疫组织化学研究肝活检标本，转铁蛋白受体1（TfR 1），介导细胞铁的吸收血清转铁蛋白的表达增加。通过使用HepG 2细胞和原代大鼠肝细胞培养物的体外实验证实了乙醇对TfR 1的这种增加。Fe-59标记的转铁蛋白掺入细胞的量（但转铁蛋白非结合铁（NTBI）不增加）也增加，这表明增加的TfR 1是有功能的。TfR 1表达的增加部分是由于乙醇代谢的氧化应激引起的铁调节蛋白（IRP）活性的增加。因此，乙醇对铁摄取的转录后调节参与肝细胞铁积累。另一种可能性是肠道铁吸收增加。我们最近的发现，关于增加前铁调素血清酒精患者血清高血清铁蛋白支持这一假设。
Increased hepatic iron is one of the important key factors which contribute alcohol toxicity of liver due to the production of reactive oxygen species. In patients with alcoholic liver diseases (ALD), liver iron is increased and the resulted lipid metabolite 4-hydroxynonenal-protein adduct was also increased. In general, iron is deposited in both parenchymal cells and and Kupffer cells in ALD. However, in patients with mild ALD, the parenchymal iron deposition is dominant rather than reticuloendothelial iron deposition, while the latter iron deposition is domimant in severe ALD, possibly due to endotoxemia and overproduction of inflammatory cytokines. We speculated that a parenchymal iron deposition in mild ALD is an important factor to trigger hepatocytes injury by ethanol, and the possible cause of parencynal iron deposition may be an increase of cellular iron uptake via serum transferrin in hepatocytes after ethanol exposure. By immuno-histochemical study of biopsied liver samples, the expression of transferrin receptor 1 (TfR1), which mediates cellular iron uptake by serum transferrin was increased. This increase of TfR1 by ethanol is confirmed by in vitro experiment using HepG2 cells and primary rat hepatocytes culture. Fe-59-labeled transferrin incorporation (but not transferrin nonbound iron (NTBI)) into the cells is also increased, suggesting that the increased TfR1 is functional. The increase of TfR1 expression is partially due to the increased activity of iron regulatory protein (IRP) by oxidative stress of ethanol metabolism. Thus, the post-transcriptional regulation of iron uptake by ethanol is involved in the hepatocyte iron accumulation. Another possibility is an increase of intestinal iron absorption. Our recent finding regarding the increase of pro-hepcidin serum in alcoholic patients with high serum ferritin support this assumption.