Regulation of hepcidin expression at high altitude

Abstract

Enhanced erythropoietic drive and iron deficiency both influence iron homeostasis through the suppression of the iron regulatory hormone hepcidin. Hypoxia also suppresses hepcidin through a mechanism that is unknown. We measured iron indices and plasma hepcidin levels in healthy volunteers during a 7-day sojourn to high altitude (4340 m above sea level), with and without prior intravenous iron loading. Without prior iron loading, a rapid reduction in plasma hepcidin was observed that was almost complete by the second day at altitude. This occurred before any index of iron availability had changed. Prior iron loading delayed the decrease in hepcidin until after the transferrin saturation, but not the ferritin concentration, had normalized. We conclude that hepcidin suppression by the hypoxia of high altitude is not driven by a reduction in iron stores. (Blood. 2012;119(3):857-860) IntroductionDietary iron absorption was shown in the 1950s to be under the dual regulation of body iron stores and the prevailing rate of erythropoiesis, giving rise to the concept of the "store regulator" and the "erythroid regulator" in iron homeostasis. 1,2 The downstream mediator of both regulators was later shown to be the iron-regulatory hormone hepcidin, 3 which opposes iron absorption and recycling by binding and internalizing the cellular iron exporter ferroportin. 4 The molecular mechanisms of hepcidin regulation are not completely understood. Oral iron loading stimulates hepcidin production in healthy humans. 5,6 This may result in part from the binding of serum holotransferrin to transferrin receptor 1 in the liver, releasing the non-classical MHC class 1 molecule hereditary hemochromatosis protein (HFE) to interact with a holotransferrintransferrin receptor 2 (TfR2) complex that up-regulates hepcidin expression. [7][8][9] There is also evidence of a role for the membranebound protein hemojuvelin in the response to iron loading, 5,10 and mutations in HFE, TfR2, or hemojuvelin can all cause hemochromatosis via inadequate hepcidin production. 11 The signal linking erythropoiesis to hepcidin suppression remains unknown. Candidates include erythropoietin (EPO) itself, soluble transferrin receptor (sTfR), and growth differentiation factor-15 (GDF15), which is released by maturing erythroblasts and reduces hepcidin mRNA expression in cultured hepatocytes. 12 Excessive serum GDF15 appears to underlie the paradoxical iron overload seen in patients with ␤-thalassemia. 12 It is now known that hepcidin expression is also suppressed by hypoxia, but the mechanism is controversial. In mice, hypoxiainducible factor was reported to regulate hepcidin expression via direct transcriptional suppression, 13 but this finding has not been replicated in isolated hepatocytes. 14 Hypoxia-inducible factor may, however, contribute to hepcidin suppression indirectly via effects on the breakdown of hemojuvelin. 15,16 In vivo, hypoxia could also suppress hepcidin indirectly through erythropoiesis and enhanced iron use. Recently, a decrease in hepcidin was...

Hepcidin is suppressed by erythropoiesis in hemoglobin E β-thalassemia and β-thalassemia trait

“…When compared by sex, there were no significant differences for any parameter measured except GDF-15 (6676 and 12,033 pg/mL in females and males, respectively) (supplemental Table 2). Hepcidin was suppressed below levels previously reported in healthy male adults, using this assay (mean, 14 ng/mL) 29 in 62 (90%) of 69 patients analyzed (ie, 25/27 males and 37/42 females). The mean hepcidin level was 2.07 ng/mL (Table 1), and hepcidin was below the detection limit in 11 patients.…”

Prevalence, Clinical Profile, Iron Status, and Subject-Specific Traits for Excessive Erythrocytosis in Andean Adults Living Permanently at 3,825 Meters Above Sea Level

“…Acute and prolonged exposure to high altitude in lowlanders may induce a marked suppression of hepcidin allowing increased iron absorption and release of iron from stores despite infl ammatory activation. 7,23 In highlanders exposed to chronic hypoxia, iron regulation may, thus, reach equilibrium at a diff erent level of hemoglobin, but proving this would require additional biomarkers including erythropoietin, hepcidin, and soluble transferrin receptor in EE group and in a representative subgroup of non-EE to better understand the underlying mechanism.…”

“…Moreover, the association between hemoglobin and iron status in normal subjects and EE participants is less well known. 7,8 We sought to characterize the prevalence, clinical profi le, iron status, and subject-specifi c traits for EE in a population living at 3,825 m above sea level. …”

Serum testosterone levels and excessive erythrocytosis during the process of adaptation to high altitudes

“…During exposure to hypoxia at HA, the levels of hepcidin are reduced, and this reduction is not driven by a reduction in iron storage. 84 EPO is the hormone responsible for erythropoiesis and has also been related to improved hypoxic ventilatory response. 85 An increase in EPO levels has been observed after acute exposure to HA.…”