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标题：Maternal intestinal HIF-2α is necessary for sensing iron demands of lactation in mice
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作者：Sadeesh K. Ramakrishnan
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：28
页码：E3738-E3747
DOI：10.1073/pnas.1504891112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe benefits of breast milk in neonatal development are well characterized. However, very little is known about the essential nutrient components in breast milk that are critical for neonatal development and how these nutrients are maintained at adequate levels in breast milk. The present work demonstrates that the intestine is an essential sensor of systemic iron demand during lactation. During high iron demand from lactation, hypoxia-inducible factor-2-mediated increase in maternal intestinal iron absorption is essential to maintain milk iron levels. This work demonstrates the significant role of maternal intestinal iron absorption in postnatal iron homeostasis of newborns and provides a therapeutic target to maintain iron homeostasis during pregnancy and lactation in anemic patients who are refractory to iron supplementation. 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)-2 is an essential regulatory mechanism for maintaining the quality of breast milk. During lactation, intestinal HIF-2 is highly increased, leading to an adaptive induction of apical and basolateral iron transport genes. Disruption of intestinal HIF-2 (but not HIF-1) 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-2 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-2 or parenteral administration of iron-dextran in HIF-2 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-2.
关键词：iron homeostasis ; anemia ; HIF-2α ; pregnancy ; lactation