A glycyrrhizin-containing preparation reduces hepatic steatosis induced by hepatitis C virus protein and iron in mice
A glycyrrhizin-containing preparation reduces hepatic steatosis induced by hepatitis C virus protein and iron in mice
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DOI：
10.1111/j.1478-3231.2011.02469.x
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发表时间：
2011-04-01
影响因子：
6.7
通讯作者：
Hino, Keisuke
中科院分区：
文献类型：
--
作者：
Korenaga, Masaaki;Hidaka, Isao;Hino, Keisuke
背景/目的：一项欧洲随机试验显示，在慢性丙型肝炎患者中，用含有胡萝卜素的制剂Stronger Neo-Minophagen C（TM）（SNMC）治疗6个月可产生生化效应，但其潜在机制仍不清楚。我们以前报道，SNMC表现出抗氧化作用的丙型肝炎病毒（HCV）转基因小鼠，发展显着的肝脂肪变性与线粒体损伤下铁超载。肝脂肪变性和铁超负荷是慢性丙型肝炎氧化应激相关的病理生理学特征。本研究的目的是调查是否长期治疗SNMC可以防止铁超载的HCV转基因小鼠肝脂肪变性的发展。研究方法：表达HCV多聚蛋白的C57BL/6转基因小鼠喂食过量铁饮食，同时腹膜内注射生理盐水、SNMC或7倍浓缩的SNMC，每周三次，持续6个月。结果如下：更强的Neo-Minophagen C（TM）以剂量依赖性方式抑制肝脂肪变性的发展，而不影响肝铁含量，减弱肝线粒体的超微结构改变，激活线粒体β-氧化，增加肉毒碱棕榈酰转移酶I的表达，并减少铁超载转基因小鼠肝中活性氧的产生。然而，SNMC几乎没有影响未折叠蛋白质的反应，转录后激活固醇调节元件结合蛋白1，参与脂质合成的转录因子，即使我们以前报道的激活未折叠蛋白质的反应在相同的铁超载转基因小鼠。结论：这些结果表明，SNMC可能通过保护线粒体免受HCV蛋白和铁过载诱导的氧化应激而预防肝脂肪变性。
Background/Aim: A European randomized trial showed biochemical effects of 6-month treatment with Stronger Neo-Minophagen C (TM) (SNMC), a glycyrrhizin-containing preparation, in patients with chronic hepatitis C, but its underlying mechanisms remain elusive. We reported previously that SNMC exhibits an anti-oxidative effect in hepatitis C virus (HCV) transgenic mice that develop marked hepatic steatosis with mitochondrial injury under iron overloading. Hepatic steatosis and iron overload are oxidative stress-associated pathophysiological features in chronic hepatitis C. The aim of this study was to investigate whether long-term treatment with SNMC could prevent the development of hepatic steatosis in iron-overloaded HCV transgenic mice. Methods: C57BL/6 transgenic mice expressing the HCV polyprotein were fed an excess iron diet concomitantly with intraperitoneal injection of saline, SNMC, or seven-fold-concentrated SNMC thrice weekly for 6 months. Results: Stronger Neo-Minophagen C (TM) inhibited the development of hepatic steatosis in a dose-dependent manner without affecting hepatic iron content, attenuated ultrastructural alterations of mitochondria of the liver, activated mitochondrial beta-oxidation with increased expression of carnitine palmitoyl transferase I and decreased the production of reactive oxygen species in the liver in iron-overloaded transgenic mice. However, SNMC hardly affected the unfolded protein response, which post-transcriptionally activates sterol regulatory element-binding protein 1, a transcription factor involved in lipid synthesis, even though we reported previously the activation of the unfolded protein response in the same iron-overloaded transgenic mice. Conclusions: These results suggest that SNMC prevents hepatic steatosis possibly by protecting mitochondria against oxidative stress induced by HCV proteins and iron overload.