Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
Liver Int. 2010 May;30(5):683-92. doi: 10.1111/j.1478-3231.2010.02210.x. Epub 2010 Mar 1.
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.
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.
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-2alpha (p-eIF2alpha), 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-eIF2alpha, and CHOP.
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.
背景/目的：肝铁过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着关键作用。然而，这两种病理生理特征如何相互影响尚不清楚。本研究旨在探讨在存在 HCV 蛋白的情况下，肝铁过载如何促进肝脂肪变性的发展。
雄性 C57BL/6 转基因小鼠表达 HCV 多蛋白和非转基因同窝仔鼠，给予高铁饮食或对照饮食。每组小鼠评估负责肝脏脂肪堆积的分子。
所有小鼠的肝铁水平与肝内甘油三酯浓度呈正相关。与给予对照饮食的非转基因鼠的肝脏相比，给予高铁饮食的转基因鼠的肝脏中肉碱棕榈酰转移酶 I 的表达降低，固醇调节元件结合蛋白 1 和脂肪酸合成酶的表达升高，未剪接和剪接 X 盒 DNA 结合蛋白 1（XBP-1）、磷酸化真核起始因子-2α（p-eIF2α）、CCAAT/增强子结合蛋白同源蛋白（CHOP）的表达升高， unfolded protein response（未折叠蛋白反应）激活，同时伴随着活性氧的产生增加。用抗氧化剂 N-乙酰半胱氨酸治疗 6 个月可显著降低转基因鼠肝铁过载饮食引起的肝脂肪变性，其机制可能与未剪接和剪接 XBP-1、p-eIF2α 和 CHOP 的表达降低有关。
铁诱导的未折叠蛋白反应可能是表达 HCV 多蛋白的转基因鼠肝脏脂肪堆积的机制之一。
