Hepatitis C virus protein and iron overload induce hepatic steatosis through the unfolded protein response in mice
Hepatitis C virus protein and iron overload induce hepatic steatosis through the unfolded protein response in mice
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DOI：
10.1111/j.1478-3231.2010.02210.x
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发表时间：
2010-05-01
影响因子：
6.7
通讯作者：
Hino, Keisuke
中科院分区：
文献类型：
--
作者：
Nishina, Sohji;Korenaga, Masaaki;Hino, Keisuke
背景/目的：肝脏铁超载和脂肪变性在丙型肝炎病毒（HCV）相关慢性肝病的进展中起关键作用。然而，这两个病理生理特征如何相互影响仍然未知。本研究的目的是探讨在HCV蛋白存在的情况下，肝脏铁超载如何促进肝脏脂肪变性的发展。方法：雄性C57 BL/6转基因小鼠表达的HCV多聚蛋白和非转基因的同窝出生的人喂养过量铁饮食或对照饮食。对每组小鼠中负责肝脏脂肪积累的分子进行评估。结果：所有小鼠肝脏铁水平与肝脏甘油三酯浓度呈正相关。与喂食对照饮食的非转基因小鼠的肝脏相比，喂食过量铁饮食的转基因小鼠的肝脏显示出肉毒碱棕榈酰转移酶I的较低表达，甾醇调节元件结合蛋白1和脂肪酸合成酶的较高表达，以及由未剪接和剪接的X-box DNA结合蛋白1（XBP-1）的较高表达所指示的活化的未折叠蛋白应答，磷酸化的真核起始因子-2 α（p-eIF 2 α）、CCAAT/增强子结合蛋白同源蛋白（CHOP）和丰富的自噬体伴随活性氧产生的增加。用抗氧化剂N-乙酰半胱氨酸治疗6个月，通过降低未剪接和剪接的XBP-1、p-eIF 2 α和CHOP的表达，显著降低了喂食过量铁饮食的转基因小鼠的肝脏脂肪变性。结论：铁诱导的未折叠蛋白反应似乎是表达HCV多蛋白的转基因小鼠肝脏脂肪蓄积的机制之一。
Background/Aim: Hepatic iron overload and steatosis play critical roles in the progression of hepatitis C virus (HCV)-associated chronic liver disease. However, how these two pathophysiological features affect each other remains unknown. The aim of this study was to investigate how hepatic iron overload contributes to the development of hepatic steatosis in the presence of HCV proteins. Methods: Male C57BL/6 transgenic mice expressing the HCV polyprotein and nontransgenic littermates were fed an excess-iron diet or a control diet. Mice in each group were assessed for the molecules responsible for fat accumulation in the liver. Results: Hepatic iron levels were positively correlated with triglyceride concentrations in the liver for all mice. As compared with the livers of nontransgenic mice fed the control diet, the livers of transgenic mice fed the excess-iron diet showed a lower expression of carnitine palmitoyl transferase I, a higher expression of sterol-regulatory element-binding protein 1 and fatty acid synthetase and an activated unfolded protein response indicated by a higher expression of unspliced and spliced X-box DNA-binding protein 1 (XBP-1), phosphorylated eukaryotic initiation factor-2 alpha (p-eIF2 alpha), CCAAT/enhancer-binding protein homology protein (CHOP) and abundant autophagosomes concomitant with increased production of reactive oxygen species. Six-month treatment with the anti-oxidant N-acetyl cysteine dramatically reduced hepatic steatosis in transgenic mice fed the excess-iron diet through decreased expression of unspliced and spliced XBP-1, p-eIF2 alpha, and CHOP. Conclusions: The iron-induced unfolded protein response appears to be one of the mechanisms responsible for fat accumulation in the liver in transgenic mice expressing the HCV polyprotein.