Date Published: September 6, 2011
Publisher: Hindawi Publishing Corporation
Author(s): Korry J. Hintze, James P. McClung.
Iron status affects cognitive and physical performance in humans. Recent evidence indicates that iron balance is a tightly regulated process affected by a series of factors other than diet, to include hypoxia. Hypoxia has profound effects on iron absorption and results in increased iron acquisition and erythropoiesis when humans move from sea level to altitude. The effects of hypoxia on iron balance have been attributed to hepcidin, a central regulator of iron homeostasis. This paper will focus on the molecular mechanisms by which hypoxia affects hepcidin expression, to include a review of the hypoxia inducible factor (HIF)/hypoxia response element (HRE) system, as well as recent evidence indicating that localized adipose hypoxia due to obesity may affect hepcidin signaling and organismal iron metabolism.
Despite the initial identification of iron as a major component of human blood over two hundred years ago, poor iron status continues to affect billions of people worldwide. Although the prevalence of iron deficiency (diminished iron stores, ID) and iron deficiency anemia (diminished iron stores coupled with reduced hemoglobin, IDA) is greatest in the developing world, poor iron status also affects a significant portion of the population in developed nations. For example, ID and IDA affect up to 12 and 4% of premenopausal women in the United States, respectively . Iron functions biochemically through incorporation into a series of proteins and enzymes. Many of these proteins and enzymes, including myoglobin, cytochrome c, and hemoglobin, are required for optimal cognitive and physical performance in humans [2–4]. Although diminished work capacity due to reduced hemoglobin levels is the best described functional consequence of poor iron status, other outcomes include diminished intellectual performance, altered body temperature regulation, and reduced immunity and resistance to infections .
Hepcidin was first identified as an antimicrobial peptide synthesized by the liver in 2000 [6, 7]. Although hepcidin confers antimicrobial properties in vitro, the estimated concentrations found in biological fluids may not support a major role for this peptide hormone as an antimicrobial agent in vivo . In 2001, the observation that hepcidin was overexpressed in response to dietary iron overload led to the hypothesis that hepcidin may function as a central regulator of iron homeostasis . Subsequently, roles for hepcidin in both the acquisition of iron from the gastrointestinal tract and the efflux of iron from macrophages have been characterized.
The profound effects of hypoxia on organismal iron metabolism have been well described. Early studies demonstrated that hypoxia affected dietary iron absorption [30–32] and increased erythropoiesis when humans were moved from sea level to high altitude . As the partial pressure of O2 decreases through increased elevation, anemia, or localized tissue hypoxia, a battery of genes are induced by the hypoxia inducible factor (HIF)/hypoxia response element (HRE) system. The HIF system senses O2 levels through degradation of HIF transcription factors (HIF-1α and HIF-2α) that are mediated by the partial pressure of O2 and iron-dependent hydroxylases. At normoxic O2 tensions, HIF-1α is hydroxylated by prolyl hydroxylase and then bound by the von Hippel-Lindau (VHL) protein leading ultimately to ubiquitination and proteasome degradation. During hypoxic conditions, the activity of hydroxylases is inhibited allowing HIF-1α to accumulate and bind along with HIF-1β to HRE found in the promoters of target genes. Similar to HIF-1α, HIF-2α stability is mediated by the partial pressure of O2 through prolyl hydroxylase and plays a dominant role in hypoxic signaling of EPO expression .
Reduced expression of hepcidin during hypoxia was first reported in 2002 by Nicolas et al. , who demonstrated a marked reduction in hepcidin mRNA in HepG2 cells cultured at 2 and 0.1% O2 compared to standard 20% O2 culture conditions. Similarly, when mice were placed in atmospheric chambers emulating an altitude of 5,500 m, hepcidin expression was downregulated after 48 hrs of hypoxia. Leung et al.  also reported decreased hepcidin mRNA expression in HepG2 cells cultured at 1% O2 and in liver from rats placed in atmospheric chambers containing 10% O2. However, the molecular mechanisms linking hypoxia and decreased hepcidin expression remained unexplained. Because the HIF signaling system imparts a dominant role in sensing O2 deprivation and subsequent gene expression, including the upregulation of EPO , it is a probable, direct or upstream, mediator of hypoxia-induced, hepcidin gene regulation.
Early studies have demonstrated a link between obesity and poor iron status [56, 57]. Studies have demonstrated this association in children and adolescents [57–60], adult men and women [61–64], and postmenopausal women . Obesity has been suggested as an independent factor contributing to iron deficiency [60, 61, 63, 65], and studies have correlated obesity, BMI, and increased hepcidin in premenopausal women  and children . Chronic inflammation is associated with central obesity and has been implicated in many obesity-related problems such as insulin resistance [68, 69]. Obese mice (ob/ob line) have significantly higher plasma IL-6 levels than their lean counterparts, and this difference is attributed to increased IL-6 expression in adipose tissue, suggesting that adipose tissue contributes to plasma inflammatory cytokine levels .
The recent discovery of hepcidin, which has been described as a central regulator of iron homeostasis, has provided evidence that iron balance is a tightly regulated process affected by a series of factors other than diet, to include hypoxia. Hypoxia has profound effects on iron absorption [30–32] and results in increased erythropoiesis when humans move from sea level to altitude . Several mechanisms or combinations thereof may explain decreased hepcidin expression mediated by hypoxia (Figure 2). There is evidence that the hepcidin promoter may be a target for direct negative regulation by the HIF/HRE system , although not all studies support this assertion . Despite sometimes conflicting results, studies utilizing hypoxia mimetics that stabilize HIF proteins have consistently demonstrated decreased hepcidin expression [38, 40, 42, 55] suggesting that the HIF system is involved in hepcidin regulation either directly or through upstream mediators. Localized adipose hypoxia due to obesity may in part play a role in hepcidin signaling and organismal iron metabolism. The emerging literature concerning obesity, adipocyte hypoxia, and inflammation suggests that the etiology of obesity-related hypoferremia may be mediated in part through increased hepcidin expression through inflammatory pathways originating from adipose tissue. Research in the area of hypoxia and iron metabolism continues to provide novel evidence of the molecular regulation of hepcidin and its effects on iron status. It is likely that recent findings will result in the development of novel interventions affecting hepcidin expression, and, subsequently, iron balance.