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NCOA4 is regulated by HIF and mediates mobilization of murine hepatic iron stores after blood loss.

ABSTRACT: The mechanisms by which phlebotomy promotes the mobilization of hepatic iron stores are not well understood. NCOA4 (nuclear receptor coactivator 4) is a widely expressed intracellular protein previously shown to mediate the autophagic degradation of ferritin. Here, we investigate a local requirement for NCOA4 in the regulation of hepatic iron stores and examine mechanisms of NCOA4 regulation. Hepatocyte-targeted Ncoa4 knockdown in nonphlebotomized mice had only modest effects on hepatic ferritin subunit levels and nonheme iron concentration. After phlebotomy, mice with hepatocyte-targeted Ncoa4 knockdown exhibited anemia and hypoferremia similar to control mice with intact Ncoa4 regulation but showed a markedly impaired ability to lower hepatic ferritin subunit levels and hepatic nonheme iron concentration. This impaired hepatic response was observed even when dietary iron was limited. In both human and murine hepatoma cell lines, treatment with chemicals that stabilize hypoxia inducible factor (HIF), including desferrioxamine, cobalt chloride, and dimethyloxalylglycine, raised NCOA4 messenger RNA. This NCOA4 messenger RNA induction occurred within 3 hours, preceded a rise in NCOA4 protein, and was attenuated in the setting of dual HIF-1α and HIF-2α knockdown. In summary, we show for the first time that NCOA4 plays a local role in facilitating iron mobilization from the liver after blood loss and that HIF regulates NCOA4 expression in cells of hepatic origin. Because the prolyl hydroxylases that regulate HIF stability are oxygen- and iron-dependent enzymes, our findings suggest a novel mechanism by which hypoxia and iron deficiency may modulate NCOA4 expression to impact iron homeostasis.

SUBMITTER: Li X

PROVIDER: S-EPMC7735158 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The similarities between swine and humans in physiological and genomic patterns, as well as significant correlation in size and anatomy, make pigs an useful animal model in nutritional studies during pregnancy. In humans and pigs iron needs exponentially increase during the last trimester of pregnancy, mainly due to increased red blood cell mass. Insufficient iron supply during gestation may be responsible for the occurrence of maternal iron deficiency anemia and decreased iron status in neonates. On the other hand, preventive iron supplementation of non-anemic mothers may be of potential risk due to iron toxicity. Several different regimens of iron supplementation have been applied during pregnancy. The majority of oral iron supplementations routinely applied to pregnant sows provide inorganic, non-heme iron compounds, which exhibit low bioavailability and intestinal side effects. The aim of this study was to check, using pig as an animal model, the effect of sucrosomial ferric pyrophosphate (SFP), a new non-heme iron formulation on maternal and neonate iron and hematological status, placental transport and pregnancy outcome; Methods: Fifteen non-anemic pregnant sows were recruited to the experiment at day 80 of pregnancy and randomized into the non-supplemented group (control; n = 5) and two groups receiving oral iron supplementation-sows given sucrosomial ferric pyrophosphate, 60 mg Fe/day (SFP; n = 5) (SiderAL®, Pisa, Italy) and sows given ferrous sulfate 60 mg Fe/day (Gambit, Kutno, Poland) (FeSO4; n = 5) up to delivery (around day 117). Biological samples were collected from maternal and piglet blood, placenta and piglet tissues. In addition, data on pregnancy outcome were recorded.; Results: Results of our study show that both iron supplements do not alter neither systemic iron homeostasis in pregnant sows nor their hematological status at the end of pregnancy. Moreover, we did not detect any changes of iron content in the milk and colostrum of iron supplemented sows in comparison to controls. Neonatal iron status of piglets from iron supplemented sows was not improved compared with the progeny of control females. No statistically significant differences were found in average piglets weight and number of piglets per litter between animals from experimental groups. The placental expression of iron transporters varied depending on the iron supplement.

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NCOA4 is regulated by HIF and mediates mobilization of murine hepatic iron stores after blood loss.

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