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Glucocorticoid Causes Iron Accumulation in Liver by Up-Regulating Expression of Iron Regulatory Protein 1 Gene Through GR and STAT5

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Abstract

Iron regulatory protein-1 (IRP-1) is a central factor in the regulation of iron metabolism. Stress causes elevated glucocorticoid secretion and is also associated with iron accumulation in liver; however, the relation between these two processes is not known. Whether glucocorticoids alter the expression of liver IRP-1 and if this contributes to the iron accumulation is presently investigated. Administration (i.v.) of corticosterone daily to rats for 7 days resulted in the upregulation of IRP-1 and transferrin receptor-1 and accumulation of iron in liver. However, expression of ferritin was decreased. The effects of corticosterone were reduced by the prior administration of glucocorticoid antagonist, RU486 to the rats. Similarly, in vitro studies using HL7702 liver cells showed that hydrocortisone increases the expression of IRP-1 while decreasing ferritin. It is also observed that Stat-5 phosphorylation is enhanced in HL7702 cells by hydrocortisone. The electrophoretic mobility shift assays revealed that the binding of glucocorticoid receptor and phospho-STAT5 to the promoter region of IRP-1 gene was enhanced in rats of stress group. Combination of both RU486 and STAT5 inhibitor, PIAS resulted in a stronger reduction of IRP-1 expression than when these inhibitors were used separately. These results strongly implicate glucocorticoid receptor and STAT5 in stress-induced up-regulation of IRP-1, which subsequently enhances transferrin receptor-1 expression and down-regulates ferritin, causing iron accumulation in the liver.

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Acknowledgments

This work was supported by National Natural Science Foundation of China (Grant No. 30872120). There is no potential conflict of interest for any of the authors. The authors wish to thank all the people contributing time and energy to carefully read the manuscript and for suggestions to improve the English language.

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Authors and Affiliations

  1. Department of Naval Medicine, Second Military Medical University, Shanghai, 200433, China

    Fang He, Long Ma, Heyang Wang, Zhilei Shen & Min Li

  2. Beijing Military General Hospital Affiliated Bayi Children’s Hospital, Beijing, 100700, China

    Fang He

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Correspondence to Min Li.

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He, F., Ma, L., Wang, H. et al. Glucocorticoid Causes Iron Accumulation in Liver by Up-Regulating Expression of Iron Regulatory Protein 1 Gene Through GR and STAT5. Cell Biochem Biophys 61, 65–71 (2011). https://doi.org/10.1007/s12013-011-9162-z

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