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Chapter 35 Pathophysiology of Iron Homeostasis 477

absorbed dietary nonheme iron. In the enterocyte cytosol, the iron 8. Ruiz JC, Bruick RK: F-box and leucine-rich repeat protein 5 (FBXL5):
can be (1) retained for cellular requirements or stored in cytosolic sensing intracellular iron and oxygen. J Inorg Biochem 133:73–77, 2014.
ferritin and then lost when the enterocyte is exfoliated or (2) exported 9. Montalbetti N, Simonin A, Kovacs G, et al: Mammalian iron transport-
through ferroportin on the enterocyte basolateral membrane. Iron ers: families SLC11 and SLC40. Mol Aspects Med 34:270–287, 2013.
export through ferroportin requires oxidation by membrane-bound 10. Davis M, Clarke S: Influence of microRNA on the maintenance of
hephaestin or circulating ceruloplasmin to the ferric form for binding human iron metabolism. Nutrients 5:2611–2628, 2013.
29
by plasma transferrin. Control of duodenal iron uptake is intricate, 11. Nai A, Lidonnici MR, Rausa M, et al: The second transferrin receptor
depending on both systemic factors (hepcidin control of ferroportin) regulates red blood cell production in mice. Blood 125:1170–1179,
and local modulation of iron absorption through transcriptional 2015.
(HIF-2α) and posttranscriptional (by the iron regulatory protein/ 12. Rouault TA: Mammalian iron-sulphur proteins: novel insights into
29
iron-responsive element system) mechanisms. Expression of FPN1B, biogenesis and function. Nat Rev Mol Cell Biol 16:45–55, 2015.
which lacks the iron-responsive element in its 5′ untranslated region, 13. Leidgens S, Bullough KZ, Shi H, et al: Each member of the poly-r(C)-
allows enterocytes to bypass iron regulatory protein repression of binding protein 1 (PCBP) family exhibits iron chaperone activity toward
ferroportin iron export even when cells throughout the body are ferritin. J Biol Chem 288:17791–17802, 2013.
iron-deficient. 29 14. Wilkinson N, Pantopoulos K: The IRP/IRE system in vivo: insights from
mouse models. Front Pharmacol 5:176, 2014.
15. Chen JJ: Translational control by heme-regulated eIF2alpha kinase
FUTURE DIRECTIONS during erythropoiesis. Curr Opin Hematol 21:172–178, 2014.
16. Korolnek T, Hamza I: Macrophages and iron trafficking at the birth and
Remarkable progress has been made in unraveling the molecular death of red cells. Blood 125:2893–2897, 2015.
mechanisms underlying systemic iron homeostasis, but much remains 17. Nairz M, Schroll A, Demetz E, et al: Ride on the ferrous wheel—the
to be done. Genomic studies are needed to identify additional genes cycle of iron in macrophages in health and disease. Immunobiology
involved in the regulation of iron homeostasis. Little is known about 220:280–294, 2015.
developmental changes in the absorption, use, and storage of iron. 18. Schaer DJ, Vinchi F, Ingoglia G, et al: Haptoglobin, hemopexin, and
Management of iron disposition within the systemic circulation related defense pathways—basic science, clinical perspectives, and drug
needs further clarification, especially with respect to the basis for the development. Front Physiol 5:415, 2014.
dominant role of erythropoietic iron requirements and to the integra- 19. Musci G, Polticelli F, Bonaccorsi di Patti MC: Ceruloplasmin-ferroportin
tion of intracellular and systemic regulatory elements. Control of iron system of iron traffic in vertebrates. World J Biol Chem 5:204–215, 2014.
balance needs more elucidation to determine the genetic basis for 20. Brissot P, Ropert M, Le Lan C, et al: Non-transferrin bound iron:
individual susceptibilities both to iron deficiency and to iron overload. a key role in iron overload and iron toxicity. Biochim Biophys Acta
More insight is needed into organ-specific iron handling and into the 1820:403–410, 2012.
iron biology of specific disease states. A better understanding is 21. Jenkitkasemwong S, Wang CY, Coffey R, et al: SLC39A14 is required
needed of iron homeostasis in the three areas in the body that are for the development of hepatocellular iron overload in murine models
outside systemic control: the central nervous system, the testis, and of hereditary hemochromatosis. Cell Metab 22:138, 2015.
the retina. Nonetheless, a pivotal point has been reached when the 22. Mleczko-Sanecka K, Roche F, da Silva AR, et al: Unbiased RNAi screen
advances already made will begin to yield therapeutic benefits from for hepcidin regulators links hepcidin suppression to proliferative Ras/
new approaches to biologic therapy using agonists and antagonists to RAF and nutrient-dependent mTOR signaling. Blood 123:1574–1585,
the components of the iron regulatory pathways summarized in this 2014.
chapter. Clinical trials of hepcidin antagonists have already begun. 30 23. Zhao N, Zhang AS, Enns CA: Iron regulation by hepcidin. J Clin Invest
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24. Heeney MM, Finberg KE: Iron-refractory iron deficiency anemia
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