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Iron, absorption, hepcidin, anemia, inflammation
by hepcidin is consistent with the relative contributions of these pathways to the maintenance of body iron home- ostasis. Also, to our knowledge, this is the first human experimental study showing that SHep does not increase in anemic subjects after a mild acute inflammatory stimu- lus. This suggests that, in IDA, iron homeostasis prioritizes correction of iron deficiency, rather than iron withholding, during mild acute infection/inflammation. Our findings provide new insights into how the relative and opposing stimuli that effect hepcidin expression combine to deter- mine net circulating hepcidin, iron absorption and iron homeostasis in young women, and may be clinically rele-
vant given that young women are a main target group for iron supplements and fortification to reduce iron deficien- cy and anemia.
Acknowledgments
The authors thank all the women who participated in the study, the nursing staff and the other members of the RDC- Nutrition.
Funding
They also thank the International Atomic Energy Agency for funding and technical assistance (MOR6022).
References
1. SangkhaeV,NemethE.RegulationoftheIron Homeostatic Hormone Hepcidin. Adv Nutr. 2017;8(1):126-136.
2. Constante M, Jiang W, Wang D, Raymond VA, Bilodeau M, Santos MM. Distinct require- ments for Hfe in basal and induced hepcidin levels in iron overload and inflammation. Am J Physiol Gastrointest Liver Physiol. 2006;291(2):G229-237.
3. Huang H, Constante M, Layoun A, Santos MM. Contribution of STAT3 and SMAD4 pathways to the regulation of hepcidin by opposing stimuli. Blood. 2009; 113(15):3593- 3599.
4. TheurlI,AignerE,TheurlM,etal.Regulation of iron homeostasis in anemia of chronic dis- ease and iron deficiency anemia: diagnostic
and therapeutic implications. Blood. 2009;113(21):5277-5286.
5. DarshanD,FrazerDM,WilkinsSJ,Anderson GJ. Severe iron deficiency blunts the response of the iron regulatory gene Hamp and pro- inflammatory cytokines to lipopolysaccha- ride. Haematologica. 2010; 95(10):1660-1667.
6. KearneySL,NemethE,NeufeldEJ,ThapaD, Ganz T, Weinstein DA, et al. Urinary hepcidin in congenital chronic anemias. Pediatr Blood Cancer. 2007;48(1):57-63.
7. Gardenghi S, Marongiu MF, Ramos P, et al. Ineffective erythropoiesis in beta-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin. Blood. 2007;109(11):5027-5035.
8. Prentice AM, Doherty CP, Abrams SA, et al. Hepcidin is the major predictor of erythrocyte iron incorporation in anemic African children. Blood. 2012;119(8):1922-1928.
9. Hella J, Cercamondi CI, Mhimbira F, et al. Anemia in tuberculosis cases and household controls from Tanzania: Contribution of dis- ease, coinfections, and the role of hepcidin. PloS One. 2018;13(4):e0195985.
10. Kemna E, Pickkers P, Nemeth E, van der Hoeven H, Swinkels D. Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood. 2005;106(5):1864-1866.
11. Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory
hormone hepcidin. J Clin Invest. 2004;113(9):1271-1276.
12. van der Beek MT, Visser LG, de Maat MPM. Yellow fever vaccination as a model to study the response to stimulation of the inflamma- tion system. Vasc Pharmacol. 2002;39(3):117- 121.
13. Tsai MY, Hanson NQ, Straka RJ, et al. Effect of influenza vaccine on markers of inflammation and lipid profile. J Lab Clin Med. 2005;145 (6):323-327.
14. Hotz K, Krayenbuehl PA, Walczyk T. Mobilization of storage iron is reflected in the iron isotopic composition of blood in humans. J Biol Inorg Chem. 2012;17(2):301-309.
15. Brown E, Hopper J Jr, Hodges JL Jr, Bradley B, Wennesland R, Yamauchi H. Red cell, plasma, and blood volume in the healthy women measured by radiochromium cell-labeling and hematocrit. J Clin Invest. 1962;41:2182-2190.
16. Hosain F, Marsaglia G, Noyes W, Finch CA. The nature of internal iron exchange in man. Trans Assoc Am Physicians. 1962;75:59-63.
17. WHO. Nutritional anaemias: tool for effective prevention and control. 2017. (Available from: https://www.who.int/nutrition/publica- tions/micronutrients/anaemias-tools-preven- tion-control/en/Last accessed 8 April 2019.
18. Prentice S, Jallow MW, Prentice AM, Group MR-IN. The effect of BCG on iron metabo- lism in the early neonatal period: A controlled trial in Gambian neonates. Vaccine. 2015;33(26):2963-2967.
19. Arezes J, Foy N, McHugh K, et al. Erythroferrone inhibits the induction of hep- cidin by BMP6. Blood. 2018; 4;132(14):1473- 1477
20. Muckenthaler MU, Rivella S, Hentze MW, Galy B. A Red Carpet for Iron Metabolism. Cell. 2017;168(3):344-361.
21. Nemeth E, Ganz T. Anemia of inflammation. Hematol Oncol Clin North Am. 2014;28(4):671-681, vi.
22. Guida C, Altamura S, Klein FA, et al. A novel inflammatory pathway mediating rapid hep- cidin-independent hypoferremia. Blood. 2015;125(14):2265-2275.
23. Deschemin JC, Vaulont S. Role of Hepcidin in the Setting of Hypoferremia during Acute Inflammation. Am J Hematol. 2013; 88(5):E132-E133.
24. Harada N, Kanayama M, Maruyama A, et al. Nrf2 regulates ferroportin 1-mediated iron efflux and counteracts lipopolysaccharide- induced ferroportin 1 mRNA suppression in macrophages. Arch Biochem Biophys. 2011;508(1):101-109.
25. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflam- mation. J Clin Invest. 2002; 110(7):1037-1044.
26. Cherian S, Forbes DA, Cook AG, et al. An Insight into the Relationships between Hepcidin, Anemia, Infections and Inflammatory Cytokines in Pediatric Refugees: A Cross-Sectional Study. PloS One. 2008;3(12):e4030.
27. Atkinson SH, Armitage AE, Khandwala S, et al. Combinatorial effects of malaria season, iron deficiency, and inflammation determine plasma hepcidin concentration in African chil- dren. Blood. 2014; 123(21):3221-3229.
28. Moretti D, Goede JS, Zeder C, et al. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood. 2015;126(17):1981-1989.
29. Stoffel NU, Cercamondi CI, Brittenham G, et al. Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials. Lancet Haematol. 2017; 4(11):e524-e533.
30. Knutson MD, Oukka M, Koss LM, Aydemir F, Wessling-Resnick M. Iron release from macrophages after erythrophagocytosis is up- regulated by ferroportin 1 overexpression and down-regulated by hepcidin. Proc Natl Acad Sci U S A. 2005;102(5):1324-1328.
31. Laftah AH, Ramesh B, Simpson RJ, et al. Effect of hepcidin on intestinal iron absorption in mice. Blood. 2004;103(10):3940-3944.
32. Chaston T, Chung B, Mascarenhas M, et al. Evidence for differential effects of hepcidin in macrophages and intestinal epithelial cells. Gut. 2008;57(3):374-382.
33. Drakesmith H, Nemeth E, Ganz T. Ironing out Ferroportin. Cell Metab. 2015; 22(5):777-787.
34. Mena NP, Esparza A, Tapia V, Valdes P, Nunez MT. Hepcidin inhibits apical iron uptake in intestinal cells. Am J Physiol Gastrointest Liver Physiol. 2008; 294(1):G192-198.
35. Galy B, Ferring-Appel D, Becker C, et al. Iron regulatory proteins control a mucosal block to intestinal iron absorption. Cell Rep. 2013;3(3):844-857.
36. Taylor M, Qu AJ, Anderson ER, et al. Hypoxia-Inducible Factor-2 alpha Mediates the Adaptive Increase of Intestinal Ferroportin During Iron Deficiency in Mice. Gastroenterology. 2011;140(7):2044-2055.
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