Hypoxia-Inducible Factors Link Iron Homeostasis and Erythropoiesis

Shah, Yatrik M.; Xie, Liwei

doi:10.1053/j.gastro.2013.12.031

Cited by 150 publications

(120 citation statements)

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“…Iron absorptive genes increase during pregnancy to maintain maternal iron homeostasis (16,44). Intestinal HIF-2α plays a key role in the adaptive increase in iron absorption during high iron demands (2,3). However, mice with disruption of intestinal HIF-2α exhibited only moderate anemia during the perinatal period.…”

Section: Discussionmentioning

confidence: 99%

“…However, hepcidin levels are restored after parturition or early lactation period during which the maternal iron requirement is still at its peak (15, 16). This suggests alternative mechanisms exist during late pregnancy and lactation that allow efficient intestinal iron absorption independent of hepcidin levels.In addition to hepcidin, the intestinal oxygen-sensing pathway is important in iron homeostasis through cell-autonomous regulation of iron absorptive genes in the intestine (2,3,17,18). The oxygen-sensitive transcription factor hypoxia inducible factor (HIF)-2α has been well characterized as a key transcription factor that promotes intestinal iron absorption by regulating the expression of ferric reductase (DcytB), divalent metal transporter 1 (DMT-1) and FPN in the intestine (17-21).…”

mentioning

confidence: 99%

“…Under normal circumstances, dietary iron provides 1-3% of the systemic iron requirement, due to an efficient recycling of iron from senesced red blood cells (1). During conditions of high iron demand, iron homeostasis relies on intestinal iron absorption (2,3). A major systemic regulator of intestinal iron absorption is the liver-derived peptide hormone hepcidin.…”

mentioning

confidence: 99%

“…In addition to hepcidin, the intestinal oxygen-sensing pathway is important in iron homeostasis through cell-autonomous regulation of iron absorptive genes in the intestine (2,3,17,18). The oxygen-sensitive transcription factor hypoxia inducible factor (HIF)-2α has been well characterized as a key transcription factor that promotes intestinal iron absorption by regulating the expression of ferric reductase (DcytB), divalent metal transporter 1 (DMT-1) and FPN in the intestine (17)(18)(19)(20)(21).…”

mentioning

confidence: 99%

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Maternal intestinal HIF-2α is necessary for sensing iron demands of lactation in mice

Ramakrishnan

Anderson

Martin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The mechanisms that are essential for the maintenance of nutrient status in breast milk are unclear. Our data demonstrate that the intestine via hypoxia-inducible factor (HIF)-2α is an essential regulatory mechanism for maintaining the quality of breast milk. During lactation, intestinal HIF-2α is highly increased, leading to an adaptive induction of apical and basolateral iron transport genes. Disruption of intestinal HIF-2α (but not HIF-1α) or the downstream target gene divalent metal transporter (DMT)-1 in lactating mothers did not alter systemic iron homeostasis in the mothers, but led to anemia, decreased growth, and truncal alopecia in pups which was restored following weaning. Moreover, pups born from mothers with a disruption of intestinal HIF-2α led to long-term cognitive defects. Cross-fostering experiments and micronutrient profiling of breast milk demonstrated that the defects observed were due to decreased maternal iron delivery via milk. Increasing intestinal iron absorption by activation of HIF-2α or parenteral administration of iron-dextran in HIF-2α knockout mothers ameliorated anemia and restored neonatal development and adult cognitive functions. The present work details the importance of breast milk iron in neonatal development and uncovers an unexpected molecular mechanism for the regulation of nutritional status of breast milk through intestinal HIF-2α.iron homeostasis | anemia | HIF-2α | pregnancy | lactation I ron is the most abundant trace element involved in numerous biological processes such as oxygen delivery, mitochondrial respiration, and metabolism. Under normal circumstances, dietary iron provides 1-3% of the systemic iron requirement, due to an efficient recycling of iron from senesced red blood cells (1). During conditions of high iron demand, iron homeostasis relies on intestinal iron absorption (2, 3). A major systemic regulator of intestinal iron absorption is the liver-derived peptide hormone hepcidin. Hepcidin expression is regulated by systemic iron levels and in turn can regulate the only known iron exporter ferroportin (FPN) (4). This adaptive mechanism is essential for systemic iron homeostasis as evidenced in patients with iron-related disorders exhibiting decreased hepcidin expression or function (5). Moreover, mouse models with disruption of hepcidin expression, intestine specific disruption of FPN, or mice with a specific mutation of FPN with decreased hepcidin binding results in robust iron-related disorders, detailing the importance of the hepcidin-FPN axis in iron homeostasis (6-8).During pregnancy, the systemic iron requirement increase by 10-fold to support placental and fetal growth (9). Fetal and neonatal iron deficiency results in decreased growth, immunological dysfunction, anemia, and irreversible cognitive defects (10). Iron supplementation is highly recommended to prevent iron deficiency anemia during pregnancy (11). The increase in iron demand during pregnancy is met by an adaptive decrease in maternal hepcidin levels leading to enhanced iron absorption...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Maternal intestinal HIF-2α is necessary for sensing iron demands of lactation in mice

Ramakrishnan

Anderson

Martin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…This indicates that HIF-3α also possesses transcriptional activity. All the hHIF-3α variants were demonstrated to be able to bind to HIF-β and overexpression of certain HIF-3α variants, together with HIF-β, induces the mRNA expression levels of several HIF-1 and HIF-2 target genes, including EPO (56,57), ANGPTL4 (58,59) and GLUT1 (60,61). However, the overexpression of HIF-3α variants reveals no significant stimulation of the expression of HRE-driven reporter genes (62), suggesting that the target genes induced by HIF-3α variants may contain specific response elements, which are not canonical HREs (31,62).…”

Section: Biological Functions Of Hif-3mentioning

confidence: 99%

Progress on hypoxia-inducible factor-3: Its structure, gene regulation and biological function (Review)

Yang

Xiong

et al. 2015

Molecular Medicine Reports

110

103

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Abstract. Hypoxia inducible factors (HIFs) are transcription factors, which are commonly expressed in mammals, including humans. The HIFs consist of hypoxia-regulated α and oxygen-insensitive β subunits, and are key regulators of gene expression during hypoxia in normal and solid tumor tissues. Three members of the HIF family, HIF-1α, HIF-2α, and HIF-3α, are currently known. HIF-3α differs from HIF-1α and HIF-2α in protein structure and regulation of gene expression. For a long time, HIF-3α was considered as a negative mediator of HIF-regulated genes. HIF-3 has a transcriptional regulatory function, which negatively affects gene expression by competing with HIF-1α and HIF-2α in binding to transcriptional elements in target genes during hypoxia. Previously, certain target genes of HIF-3α have been identified, confirming the role of HIF-3α as a transcription factor. In this review, the protein structure, gene regulation and biological function of HIF-3 are discussed based on the literature.

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Activation of Intestinal HIF2α Ameliorates Iron‐Refractory Anemia

Yu,

Su,

Yang

et al. 2024

Advanced Science

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In clinics, hepcidin levels are elevated in various anemia‐related conditions, particularly in iron‐refractory anemia and in high inflammatory states that suppress iron absorption, which remains an urgent unmet medical need. To identify effective treatment options for various types of iron‐refractory anemia, the potential effect of hypoxia and pharmacologically‐mimetic drug FG‐4592 (Roxadustat) are evaluated, a hypoxia‐inducible factor (HIF)‐prolyl hydroxylase (PHD) inhibitor, on mouse models of iron‐refractory iron‐deficiency anemia (IRIDA), anemia of inflammation and 5‐fluorouracil‐induced chemotherapy‐related anemia. The potent protective effects of both hypoxia and FG‐4592 on IRIDA as well as other 2 tested mouse cohorts are found. Mechanistically, it is demonstrated that hypoxia or FG‐4592 could stabilize duodenal Hif2α, leading to the activation of Fpn transcription regardless of hepcidin levels, which in turn results in increased intestinal iron absorption and the amelioration of hepcidin‐activated anemias. Moreover, duodenal Hif2α overexpression fully rescues phenotypes of Tmprss6 knockout mice, and Hif2α knockout in the gut significantly delays the recovery from 5‐fluorouracil‐induced anemia, which can not be rescued by FG‐4592 treatment. Taken together, the findings of this study provide compelling evidence that targeting intestinal hypoxia‐related pathways can serve as a potential therapeutic strategy for treating a broad spectrum of anemia, especially iron refractory anemia.

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Hypoxia-Inducible Factors Link Iron Homeostasis and Erythropoiesis

Cited by 150 publications

References 140 publications

Maternal intestinal HIF-2α is necessary for sensing iron demands of lactation in mice

Maternal intestinal HIF-2α is necessary for sensing iron demands of lactation in mice

Progress on hypoxia-inducible factor-3: Its structure, gene regulation and biological function (Review)

Activation of Intestinal HIF2α Ameliorates Iron‐Refractory Anemia

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