title: Hepcidin suppression and defective iron recycling account for dysregulation of iron homeostasis in heme oxygenase-1 deficiency.
abstract: Heme oxygenase-1 (HO-1) contribution to iron homeostasis has been postulated, because it facilitates iron recycling by liberating iron mostly from heme catabolism. This enzyme also appears to be responsible for the resolution of inflammatory conditions. In a patient with HO-1 deficiency, inflammation and dysregulation of body iron homeostasis, including anemia and liver and kidney hemosiderosis, are evidenced. Here we postulated that HO-1 is critical in the regulation of ferroportin, the major cellular iron exporter, and hepcidin, the key regulator of iron homeostasis central in the pathogenesis of anemia of inflammation. Our current experiments in human THP-1 monocytic cells indicate a HO-1-induced iron-mediated surface-ferroportin expression, consistent with the role of HO-1 in iron recycling. Surprisingly, we observed low hepcidin levels in the HO-1-deficient patient, despite the presence of inflammation and hemosiderosis, both inducers of hepcidin. Instead, we observed highly increased soluble transferrin receptor levels. This suggests that the decreased hepcidin levels in HO-1 deficiency reflect the increased need for iron in the bone marrow due to the anaemia. Using human hepatoma cells, we demonstrate that HO-activity did not have a direct modulating effect on expression of HAMP, the gene that encodes for hepcidin. Therefore, we argue that the decreased iron recycling may, in part, have contributed to the low hepcidin levels. These findings indicate that dysregulation of iron homeostasis in HO-1 deficiency is the result of both defective iron recycling and erythroid activity-associated inhibition of hepcidin expression. This study therefore shows a crucial role for HO-1 in maintaining body iron balance.
authors.affiliation: Department of Clinical Chemistry, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Apriliana E R
authors.initials: AE
authors.lastname: Kartikasari
authors.forename: Frank A D T G
authors.initials: FA
authors.lastname: Wagener
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yachie
authors.forename: Erwin T G
authors.initials: ET
authors.lastname: Wiegerinck
authors.forename: Erwin H J M
authors.initials: EH
authors.lastname: Kemna
authors.forename: Dorine W
authors.initials: DW
authors.lastname: Swinkels
authors.forename: Dorine W
authors.initials: DW
authors.lastname: Winkels
mesh_terms: D000740:Anemia / Q000473:pathology; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism; D002470:Cell Survival; D005452:Fluoresceins / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000172:deficiency*; D064451:Hepcidins; D006801:Humans; D007249:Inflammation; D007501:Iron / Q000737:chemistry / Q000378:metabolism*; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000378:metabolism*; D000098742:Ferroportin
chemical_list: D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; D005452:Fluoresceins; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D000098742:Ferroportin; D007501:Iron; D051547:Heme Oxygenase-1; C007740:fluorexon
references.citation: J Clin Invest. 2007 Jul;117(7):1926-32
references.pmid: 17557118
references.citation: Blood. 2006 Dec 1;108(12):3730-5
references.pmid: 16882706
references.citation: Blood. 2007 Jan 1;109(1):353-8
references.pmid: 16946298
references.citation: Haematologica. 2006 Oct;91(10):1336-42
references.pmid: 17018382
references.citation: J Cell Biochem. 2004 Oct 15;93(3):552-62
references.pmid: 15378604
references.citation: Blood. 2007 May 1;109(9):4038-44
references.pmid: 17218383
references.citation: Mol Nutr Food Res. 2005 Nov;49(11):1030-43
references.pmid: 16208635
references.citation: Clin Chim Acta. 2003 Mar;329(1-2):9-22
references.pmid: 12589962
references.citation: Science. 2004 Dec 17;306(5704):2090-3
references.pmid: 15514116
references.citation: Blood. 2003 Apr 1;101(7):2461-3
references.pmid: 12433676
references.citation: J Hepatol. 2006 Jul;45(1):72-80
references.pmid: 16510205
references.citation: Pediatr Int. 2007 Apr;49(2):125-32
references.pmid: 17445026
references.citation: Proc Natl Acad Sci U S A. 1987 Apr;84(8):2464-8
references.pmid: 3470805
references.citation: Gut. 2004 Oct;53(10):1509-15
references.pmid: 15361505
references.citation: Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10925-30
references.pmid: 9380736
references.citation: J Clin Invest. 1980 May;65(5):1135-40
references.pmid: 7364941
references.citation: Neurosci Lett. 2004 Jun 10;363(2):182-6
references.pmid: 15172111
references.citation: Blood. 2005 Sep 1;106(5):1864-6
references.pmid: 15886319
references.citation: Clin Chem. 2000 Mar;46(3):313-8
references.pmid: 10702516
references.citation: Hum Pathol. 2002 Jan;33(1):125-30
references.pmid: 11823983
references.citation: Am J Med Sci. 1999 Oct;318(4):241-56
references.pmid: 10522552
references.citation: FASEB J. 2006 Feb;20(2):353-5
references.pmid: 16368718
references.citation: Blood. 2007 Jun 15;109(12):5525-6
references.pmid: 17554070
references.citation: J Clin Invest. 1999 Jan;103(1):129-35
references.pmid: 9884342
references.citation: Anal Biochem. 1997 May 15;248(1):31-40
references.pmid: 9177722
references.citation: Nat Med. 2007 Sep;13(9):1096-101
references.pmid: 17721544
references.citation: Blood. 2001 Sep 15;98(6):1802-11
references.pmid: 11535514
references.citation: Blood. 2006 Nov 1;108(9):3204-9
references.pmid: 16835372
references.citation: Nat Genet. 2004 Jan;36(1):77-82
references.pmid: 14647275
references.citation: FASEB J. 2006 Dec;20(14):2651-3
references.pmid: 17065227
references.citation: Am J Pathol. 2000 May;156(5):1527-35
references.pmid: 10793064
references.citation: Circulation. 2000 Dec 12;102(24):3015-22
references.pmid: 11113055
references.citation: Physiol Res. 2006;55(6):667-74
references.pmid: 16497104
references.citation: Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10919-24
references.pmid: 9380735
references.citation: J Am Soc Nephrol. 2003 Nov;14(11):2741-9
references.pmid: 14569083
references.citation: Clin Chem. 2006 Jun;52(6):950-68
references.pmid: 16627556
references.citation: Blood. 2008 Jan 15;111(2):924-31
references.pmid: 17938254
references.citation: Nat Cell Biol. 1999 Jul;1(3):152-7
references.pmid: 10559901
references.citation: Blood. 2005 May 15;105(10):4103-5
references.pmid: 15671438
references.citation: Haematologica. 2006 Jun;91(6):809-12
references.pmid: 16769583
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Cell Metab. 2005 Mar;1(3):191-200
references.pmid: 16054062
references.citation: Mol Cell. 2000 Feb;5(2):299-309
references.pmid: 10882071
references.citation: Hepatology. 1998 Mar;27(3):829-38
references.pmid: 9500714
references.citation: Blood. 2007 Sep 15;110(6):2182-9
references.pmid: 17540841
references.citation: J Biol Chem. 2000 May 19;275(20):15166-73
references.pmid: 10809751
references.citation: Nat Med. 1996 Jan;2(1):87-90
references.pmid: 8564848
references.citation: Pharmacol Rev. 2003 Sep;55(3):551-71
references.pmid: 12869663
references.citation: Pediatrics. 1995 Apr;95(4):468-74
references.pmid: 7700742
references.citation: J Cell Mol Med. 2009 Apr;13(4):712-25
references.pmid: 18410527
references.citation: Blood. 2003 Jul 1;102(1):371-6
references.pmid: 12637325
references.citation: Biochim Biophys Acta. 2006 Jul;1763(7):690-9
references.pmid: 16790283
references.citation: Clin Chem. 2007 Apr;53(4):620-8
references.pmid: 17272487
references.citation: J Biol Chem. 1993 Apr 5;268(10):7365-71
references.pmid: 8463269
references.citation: J Clin Invest. 2004 May;113(9):1271-6
references.pmid: 15124018