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Identification of human genes of iron homeostasis

人类铁稳态基因的鉴定

基本信息

批准号：
10919440
负责人：
Caroline Philpott
金额：
$ 210.49万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10919440
关键词：
Age Antioxidants Binding Binding Proteins Biochemical Biological Cells Clinical Cytosol Development Diet Enzymes Exhibits Ferritin Fibrosis Friedreich Ataxia Genes Genetic Genetic Diseases Genetic Models Heme Hereditary hemochromatosis Homeostasis Hormones Human Ions Iron Iron Overload Liver Liver diseases Mammalian Cell Mammals Mediating Messenger RNA Metals Methods Molecular Chaperones Mouth Diseases Mus Nutrient Oral Organism Oxidation-Reduction Oxidative Stress Plasma Poly C Process Proteins Regulation Role SLC11A2 gene Sulfur Supplementation System TFRC gene Tissues Tocopherols Toxin Vitamin E biological adaptation to stress cofactor comparison control dietary hepcidin human disease iron metabolism lipophilicity male metal transporting protein 1 non-alcoholic fatty liver disease novel strategies nuclear factor-erythroid 2 oxidative damage protein transport trafficking transcription factor uptake virtual

项目摘要

1)Background: Vitamin E is an essential nutrient that functions as a lipophilic antioxidant and is used clinically to treat non-alcoholic fatty liver disease, where it suppresses oxidative damage and impedes progression of steatosis and fibrosis. Mice lacking a critical liver iron-trafficking protein also manifest steatosis because of iron-mediated oxidative damage and are protected from liver disease by oral vitamin E supplements. Objective: To examine the role of dietary vitamin E supplementation in modulating iron-sensing regulatory systems and non-heme iron levels in mouse liver. Methods: C57Bl/6 male mice, 6 wk of age, were fed purified diets containing normal amounts of iron and either control (45 mg/kg) or elevated (450 mg/kg) levels of 2R--tocopherol (Vit E) for 18 days. Mouse plasma and liver were analyzed for non-heme iron, levels and activity of iron homeostatic proteins, and markers of oxidative stress. We compared means SD for iron and oxidative stress parameters between mice fed control and Vit E diets. Results: Vit E-fed mice exhibited lower levels of liver non-heme iron (38% reduction, p<0.0001) and ferritin (74% reduction, p<0.01) compared to control-fed mice. Levels of liver mRNA for transferrin receptor 1 and divalent metal transporter 1 were reduced to 42% and 57% of control. mRNA levels for targets of nuclear factor erythroid 2-related factor (Nrf2), a major regulator of the oxidative stress response and iron-responsive genes, were also suppressed in Vit E livers. Hepcidin, an iron regulatory hormone, exhibited lower plasma levels (p<0.05) and ferroportin, the iron exporter regulated by hepcidin, was expressed at higher levels in liver (p<0.05). Conclusions: Oral Vit E supplementation in mice can lead to depletion of liver iron stores by suppressing the iron- and redox-sensing transcription factor Nrf2, leading to enhanced iron efflux through liver ferroportin. Iron depletion may indirectly enhance the antioxidative effects of Vit E. 2)Cells express hundreds of iron-dependent enzymes that rely on the iron cofactors heme, iron-sulfur clusters, and mono-or di-nuclear iron centers for activity. Cells require systems for both the assembly and the distribution of iron cofactors to their cognate enzymes. Proteins involved in the binding and trafficking of iron ions in the cytosol, called cytosolic iron chaperones, have been identified and characterized in mammalian cells. The first identified iron chaperone, poly C-binding protein 1 (PCBP1), has also been studied in mice using genetic models of conditional deletion in tissues specialized for iron handling. Studies of iron trafficking in mouse tissues have necessitated the development of new approaches, which have revealed new roles for PCBP1 in the management of cytosolic iron. These approaches can be applied to investigate use of other nutrient metals in mammals.

1）背景：维生素E是一种必需的营养素，作为亲脂性抗氧化剂，在临床上用于治疗非酒精性脂肪肝，它抑制氧化损伤并阻止脂肪变性和纤维化的进展。由于铁介导的氧化损伤，缺乏关键肝脏铁运输蛋白的小鼠也表现出脂肪变性，并通过口服维生素E补充剂保护其免受肝脏疾病的影响。目的：研究膳食维生素E补充剂在调节小鼠肝脏铁敏感调节系统和非血红素铁水平中的作用。研究方法：用6周龄的C57 B1/6雄性小鼠饲喂含有正常量的铁和对照（45 mg/kg）或升高（450 mg/kg）水平的2 R--生育酚（维生素E）的纯化饮食18天。分析小鼠血浆和肝脏的非血红素铁、铁稳态蛋白的水平和活性以及氧化应激的标志物。我们比较了喂养对照和维生素E饮食的小鼠之间的铁和氧化应激参数的平均值SD。结果如下：维生素E喂养的小鼠与对照喂养的小鼠相比表现出较低水平的肝脏非血红素铁（减少38%，p<0.0001）和铁蛋白（减少74%，p<0.01）。肝脏转铁蛋白受体1和二价金属转运蛋白1的mRNA水平分别降低至对照组的42%和57%。核因子红细胞2相关因子（Nrf 2），氧化应激反应和铁反应基因的主要调节因子的靶基因的mRNA水平也在维生素E肝脏中受到抑制。铁调素，一种铁调节激素，显示出较低的血浆水平（p<0.05），而铁转运蛋白，铁调素调节的铁输出蛋白，在肝脏中以较高的水平表达（p<0.05）。结论：小鼠口服维生素E补充剂可通过抑制铁和氧化还原敏感转录因子Nrf 2导致肝脏铁储存耗竭，从而增强通过肝脏铁转运蛋白的铁流出。铁缺乏可间接增强维生素E的抗氧化作用。 2)细胞表达数百种依赖铁的酶，这些酶依赖于铁辅因子血红素、铁硫簇和单核或双核铁中心的活性。细胞需要用于铁辅因子向其同源酶的组装和分布的系统。在哺乳动物细胞中，参与铁离子在胞质中结合和运输的蛋白质，称为胞质铁分子伴侣，已经被鉴定和表征。第一个确定的铁分子伴侣，聚C结合蛋白1（PCBP 1），也已经在小鼠中研究了专门用于铁处理的组织中的条件性缺失的遗传模型。铁在小鼠组织中的运输的研究已经有必要开发新的方法，这揭示了PCBP 1在细胞溶质铁的管理中的新作用。这些方法可以应用于研究其他营养金属在哺乳动物中的使用。