title: Deletion of HIF-2α in the enterocytes decreases the severity of tissue iron loading in hepcidin knockout mice.
abstract: Hereditary hemochromatosis (HH) is a highly prevalent genetic disorder characterized by excessive parenchymal iron accumulation leading to liver cirrhosis, diabetes, and in some cases hepatocellular carcinoma. HH is caused by mutations in the genes encoding upstream regulators of hepcidin or more rarely in the hepcidin gene itself. A deficit in hepcidin results in intestinal iron hyperabsorption; however, the local effectors mediating the up-regulation of iron absorption genes are unknown. We hypothesized that HIF-2 could mediate high iron absorption rates in HH. We generated Hepc(-/-) mice (a murine model of hemochromatosis) lacking HIF-2 in the intestine and showed that duodenal HIF-2 was essential for the up-regulation of genes involved in intestinal iron import and the consequent iron accumulation in the liver and pancreas. This study highlights a role of HIF-2 in the dysregulation of iron absorption and chronic iron accumulation, as observed in patients with hemochromatosis.
authors: Inserm U, Institut Cochin, Paris, France.
authors: Maria
authors: M
authors: Mastrogiannaki
authors: Pavle
authors: P
authors: Matak
authors: Stéphanie
authors: S
authors: Delga
authors: Jean-Christophe
authors: JC
authors: Deschemin
authors: Sophie
authors: S
authors: Vaulont
authors: Carole
authors: C
authors: Peyssonnaux
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D015153:Blotting, Western; D004386:Duodenum / Q000378:metabolism / Q000473:pathology; D020895:Enterocytes / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006432:Hemochromatosis / Q000209:etiology; D064451:Hepcidins; D007124:Immunoenzyme Techniques; D019426:Integrases / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000473:pathology; D019190:Iron Overload / Q000209:etiology / Q000517:prevention & control*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D023181:Antimicrobial Cationic Peptides; D051792:Basic Helix-Loop-Helix Proteins; D064451:Hepcidins; D019426:Integrases; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1; C579599:Hamp protein, mouse; C045073:Cre recombinase