Shpyleva Svitlana, Pogribna Marta, Cozart Christy, Bryant Matthew S, Muskhelishvili Levan, Tryndyak Volodymyr P, Ross Sharon A, Beland Frederick A, Pogribny Igor P
Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, AR 72079.
Toxicologic Pathology Associates, National Center for Toxicological Research, FDA, Jefferson, AR 72079.
J Nutr Biochem. 2014 Dec;25(12):1235-42. doi: 10.1016/j.jnutbio.2014.06.012. Epub 2014 Aug 19.
Nonalcoholic fatty liver disease (NAFLD) is a major health problem worldwide. Currently, there is a lack of conclusive information to clarify the molecular events and mechanisms responsible for the progression of NAFLD to fibrosis and cirrhosis and, more importantly, for differences in interindividual disease severity. The aim of this study was to investigate a role of interindividual differences in iron metabolism among inbred mouse strains in the pathogenesis and severity of fibrosis in a model of NAFLD. Feeding male A/J, 129S1/SvImJ and WSB/EiJ mice a choline- and folate-deficient diet caused NAFLD-associated liver injury and iron metabolism abnormalities, especially in WSB/EiJ mice. NAFLD-associated fibrogenesis was correlated with a marked strain- and injury-dependent increase in the expression of iron metabolism genes, especially transferrin receptor (Tfrc), ferritin heavy chain (Fth1), and solute carrier family 40 (iron-regulated transporter), member 1 (Slc40a1, Fpn1) and their related proteins, and pronounced down-regulation of the iron regulatory protein 1 (IRP1), with the magnitude being A/J<129S1/SvImJ<WSB/EiJ. Mechanistically, down-regulation of IRP1 was linked to an increased expression of microRNAs miR-200a and miR-223, which was negatively correlated with IRP1. The results of this study demonstrate that the interstrain variability in the extent of fibrogenesis was associated with a strain-dependent deregulation of hepatic iron homeostasis.
非酒精性脂肪性肝病（NAFLD）是全球范围内的一个主要健康问题。目前，缺乏确凿信息来阐明导致NAFLD进展为纤维化和肝硬化的分子事件及机制，更重要的是，缺乏有关个体间疾病严重程度差异的信息。本研究的目的是探讨近交系小鼠品系间铁代谢差异在NAFLD模型中纤维化发病机制和严重程度中的作用。给雄性A/J、129S1/SvImJ和WSB/EiJ小鼠喂食胆碱和叶酸缺乏的饮食会导致NAFLD相关的肝损伤和铁代谢异常，尤其是在WSB/EiJ小鼠中。NAFLD相关的纤维生成与铁代谢基因表达的显著品系和损伤依赖性增加相关，特别是转铁蛋白受体（Tfrc）、铁蛋白重链（Fth1）和溶质载体家族40（铁调节转运蛋白）成员1（Slc40a1，Fpn1）及其相关蛋白，以及铁调节蛋白1（IRP1）的明显下调，其程度为A/J＜129S1/SvImJ＜WSB/EiJ。从机制上讲，IRP1的下调与微小RNA miR-200a和miR-223的表达增加有关，这与IRP1呈负相关。本研究结果表明，纤维生成程度的品系间变异性与肝铁稳态的品系依赖性失调有关。
