Identification of human genes of iron homeostasis

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

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.