Identification of human genes of iron homeostasis

人类铁稳态基因的鉴定

• 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
• 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

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是一种重要的营养物质，具有亲脂性抗氧化剂的功能，临床上用于治疗非酒精性脂肪性肝病，它可以抑制氧化损伤，阻止脂肪变性和纤维化的进展。缺乏关键的肝脏铁转运蛋白的小鼠也会因为铁介导的氧化损伤而表现出脂肪变性，并通过口服维生素E补充剂来保护自己免受肝病的侵袭。 目的：研究补充维生素E对小鼠肝脏铁敏感调节系统和非血红素铁水平的调节作用。 方法：C57BL/6雄性小鼠，6周龄，饲喂含有正常铁的纯净日粮，对照组(45 mg/kg)和高铁水平(450 mg/kg)的2R-生育酚(VitE)。分析小鼠血浆和肝脏中非血红素铁、铁稳态蛋白水平和活性，以及氧化应激标志物。我们比较了喂养对照组和维生素E饮食的小鼠的铁和氧化应激参数的平均值SD。 结果：与对照组相比，饲喂维生素E的小鼠的肝脏非血红素铁(减少38%，p&lt；0.0001)和铁蛋白(减少74%，p&lt；0.01)水平较低。肝脏转铁蛋白受体1和二价金属转运蛋白1的mRNA水平分别降低到对照组的42%和57%。核因子红系2相关因子(Nrf2)是氧化应激反应和铁反应基因的主要调节因子，其靶标的mRNA水平在维生素E肝脏中也受到抑制。铁调节激素海普西丁的血浆水平较低(p&lt；0.05)，而受海普西丁调节的铁出口蛋白在肝脏中的表达水平较高(p&lt；0.05)。 结论：小鼠口服维生素E可通过抑制铁敏感转录因子Nrf2和氧化还原敏感转录因子Nrf2，导致肝脏铁外流增强，从而导致肝脏铁储备耗竭。铁缺乏可能间接增强维生素E的抗氧化作用。 2)细胞表达数百种依赖铁的酶，这些酶依赖于铁辅助因子血红素、铁硫簇和单核或双核铁中心的活性。细胞需要系统来组装和分配铁辅助因子到它们的同源酶。参与胞浆中铁离子结合和运输的蛋白质，称为胞质铁伴侣，已在哺乳动物细胞中被鉴定和鉴定。第一个被发现的铁伴侣，聚C结合蛋白1(PCBP1)，也已经在小鼠身上进行了研究，使用了专门处理铁的组织中条件缺失的遗传模型。对小鼠组织中铁的运输的研究需要开发新的方法，这些方法揭示了PCBP1在细胞内铁管理中的新作用。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。

项目成果

Metabolic remodeling in iron-deficient fungi.

• DOI: 10.1016/j.bbamcr.2012.01.012
• 发表时间: 2012-09
• 期刊: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
• 影响因子: 5.1
• 作者: Philpott, Caroline C.;Leidgens, Sebastien;Frey, Avery G.
• 通讯作者: Frey, Avery G.

Iron-tracking strategies: Chaperones capture iron in the cytosolic labile iron pool.

• DOI: 10.3389/fmolb.2023.1127690
• 发表时间: 2023
• 期刊: Frontiers in molecular biosciences
• 影响因子: 5

Another tool in the toolkit to manage iron overload.

• DOI: 10.1073/pnas.2208868119
• 发表时间: 2022-08-02
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1

Special delivery: distributing iron in the cytosol of mammalian cells.

• DOI: 10.3389/fphar.2014.00173
• 发表时间: 2014
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Philpott CC;Ryu MS
• 通讯作者: Ryu MS

TLR signals posttranscriptionally regulate the cytokine trafficking mediator sortilin.

• DOI: 10.1038/srep26566
• 发表时间: 2016-05-25
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Yabe-Wada T;Matsuba S;Takeda K;Sato T;Suyama M;Ohkawa Y;Takai T;Shi H;Philpott CC;Nakamura A
• 通讯作者: Nakamura A