title: Intestinal brush-border Na+/H+ exchanger-3 drives H+-coupled iron absorption in the mouse.
abstract: Divalent metal-ion transporter-1 (DMT1), the principal mechanism by which nonheme iron is taken up at the intestinal brush border, is energized by the H(+)-electrochemical potential gradient. The provenance of the H(+) gradient in vivo is unknown, so we have explored a role for brush-border Na(+)/H(+) exchanger (NHE) isoforms by examining iron homeostasis and intestinal iron handling in mice lacking NHE2 or NHE3. We observed modestly depleted liver iron stores in NHE2-null (NHE2(-/-)) mice stressed on a low-iron diet but no change in hematological or blood iron variables or the expression of genes associated with iron metabolism compared with wild-type mice. Ablation of NHE3 strongly depleted liver iron stores, regardless of diet. We observed decreases in blood iron variables but no overt anemia in NHE3-null (NHE3(-/-)) mice on a low-iron diet. Intestinal expression of DMT1, the apical surface ferrireductase cytochrome b reductase-1, and the basolateral iron exporter ferroportin was upregulated in NHE3(-/-) mice, and expression of liver Hamp1 (hepcidin) was suppressed compared with wild-type mice. Absorption of (59)Fe from an oral dose was substantially impaired in NHE3(-/-) compared with wild-type mice. Our data point to an important role for NHE3 in generating the H(+) gradient that drives DMT1-mediated iron uptake at the intestinal brush border.
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio; Systems Biology and Physiology Program, University of Cincinnati College of Medicine, Cincinnati, Ohio; and.
authors.forename: Ali
authors.identifier: 0000-0002-6413-5313
authors.initials: A
authors.lastname: Shawki
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio; Systems Biology and Physiology Program, University of Cincinnati College of Medicine, Cincinnati, Ohio; and.
authors.forename: Melinda A
authors.initials: MA
authors.lastname: Engevik
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio;
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kim
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio;
authors.forename: Patrick B
authors.initials: PB
authors.lastname: Knight
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio;
authors.forename: Rusty A
authors.initials: RA
authors.lastname: Baik
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio;
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Anthony
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio; Systems Biology and Physiology Program, University of Cincinnati College of Medicine, Cincinnati, Ohio; and.
authors.forename: Roger T
authors.initials: RT
authors.lastname: Worrell
authors.affiliation: Systems Biology and Physiology Program, University of Cincinnati College of Medicine, Cincinnati, Ohio; and Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Shull
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio; Systems Biology and Physiology Program, University of Cincinnati College of Medicine, Cincinnati, Ohio; and bryan.mackenzie@uc.edu.
authors.forename: Bryan
authors.identifier: 0000-0002-9661-8838
authors.initials: B
authors.lastname: Mackenzie
mesh_terms: D000818:Animals; D001692:Biological Transport; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008871:Microvilli / Q000502:physiology*; D009865:Oocytes; D012964:Sodium / Q000378:metabolism; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014883:Water-Electrolyte Imbalance; D014981:Xenopus
chemical_list: C110547:DMRT1 protein; C000613385:SLC9A3 protein, human; C513111:Slc9a2 protein, mouse; C000613386:Slc9a3 protein, mouse; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D014157:Transcription Factors; D012964:Sodium; D007501:Iron
keywords: SLC11A2; SLC9A2; SLC9A3; acidic microclimate; hereditary hemochromatosis; iron absorption; iron overload