Rgy production, enzyme activity, oxygen transport, and regulation of gene expression (1). Systemic iron levels are maintained by intestinal absorption, which can be precisely controlled as there’s no active excretory mechanism in mammals. Iron absorption is enhanced throughout iron deprivation as reflected by improved expression of iron transport-related genes like divalent metal transporter 1 (Dmt12; an iron importer), duodenal cytochrome b (Dcytb; a brush-border membrane ferrireductase), and ferroportin 1 (Fpn1; an iron exporter) in duodenal enterocytes (2). Studies also located that the Menkes copper-transporting ATPase (Atp7a), an enterocyte copper exporter, was up-regulated within the rat duodenal epithelium during iron deficiency, constant with noted increases in copper content material from the intestinal mucosa, liver, and serum (2, 3). Comparable perturbations in tissue copper levels have been noted in other mammalian species for the duration of states of iron deficiency (4 ?). It has hence been hypothesized that copper plays a function within the upkeep of iron homeostasis (7). Importantly, two multicopper ferroxidases, 1 expressed in enterocytes with the smaller intestine (hephaestin) and one particular made in liver and secreted into the blood (ceruloplasmin), provide key links between iron and copper homeostasis (8). Depletion of body iron stores results in decreased red blood cell hemoglobin levels causing tissue hypoxia. Low tissue oxygen tension in turn final results in stabilization of trans-acting hypoxia-inducible factors (HIFs). The HIFs function as heterodimers, containing a constitutively expressed subunit along with a hypoxia-responsive subunit (a single of 3 known Hif subunits). The improve in intestinal iron absorption when body iron stores are depleted has in actual fact been shown to be mediated by means of activation of Hif2 . This regulatory mechanism was revealed by two recent research in which the subunits (Hif1 and Hif2 ) on the functional HIF protein complexes were especially inactivated inside the intestinal epithelium of mice (9, ten). Results showed that regulation of iron absorption was defective in* This function was supported, in whole or in portion, by National Institutes of HealthGrant 1R01-DK074867 (to J. F. C.). This article includes supplemental Table S1. 1 To whom correspondence really should be addressed: Food Science and Human Nutrition Dept., University of Florida, 572 Newell Dr., FSN Bldg.5-Formylnicotinic acid web , 441, Gainesville, FL 32611.1205671-72-2 Data Sheet Tel.PMID:33749451 : 352-392-1991 (ext. 289); Fax: 352-392-9467; E-mail: [email protected] abbreviations applied are: Dmt1, divalent metal transporter 1; Ankrd37, ankyrin repeat domain 37; Dcytb, duodenal cytochrome b; Fpn1, ferroportin 1; HRE, hypoxia-responsive element; HIF, hypoxia-inducible issue; Sp, specificity factor; Tfr1, transferrin receptor 1; Atp7a, Menkes copper-transporting ATPase; qRT-PCR, quantitative RT-PCR.AUGUST 16, 2013 ?VOLUME 288 ?NUMBERJOURNAL OF BIOLOGICAL CHEMISTRYSp1 and Hif2 Regulate Atp7a Transcription for the duration of Hypoxiamice lacking intestinal Hif2 , whereas induction of iron absorption through iron deprivation was maintained in mice lacking Hif1 . It was further shown that the Dmt1, Dcytb, and Fpn1 promoters contained functional hypoxia-responsive elements (HREs) that specifically interacted with Hif2 , explaining their induction in the course of iron deficiency (and tissue hypoxia) (9?1). Hif2 is hence critical to keep intestinal iron homeostasis in mice. Interestingly, our prior studies in iron-deficient rats showed that Atp7a was up-regulated inside the duode.