Hepcidin suppression and defective iron recycling account for dysregulation of iron homeostasis in heme oxygenase-1 deficiency.
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.
Kartikasari
Apriliana E R
AE
Department of Clinical Chemistry, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Wagener
Frank A D T G
FA
Yachie
Akihiro
A
Wiegerinck
Erwin T G
ET
Kemna
Erwin H J M
EH
Swinkels
Dorine W
DW
Winkels
Dorine W
DW
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
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
J Clin Invest. 2007 Jul;117(7):1926-32
17557118
Blood. 2006 Dec 1;108(12):3730-5
16882706
Blood. 2007 Jan 1;109(1):353-8
16946298
Haematologica. 2006 Oct;91(10):1336-42
17018382
J Cell Biochem. 2004 Oct 15;93(3):552-62
15378604
Blood. 2007 May 1;109(9):4038-44
17218383
Mol Nutr Food Res. 2005 Nov;49(11):1030-43
16208635
Clin Chim Acta. 2003 Mar;329(1-2):9-22
12589962
Science. 2004 Dec 17;306(5704):2090-3
15514116
Blood. 2003 Apr 1;101(7):2461-3
12433676
J Hepatol. 2006 Jul;45(1):72-80
16510205
Pediatr Int. 2007 Apr;49(2):125-32
17445026
Proc Natl Acad Sci U S A. 1987 Apr;84(8):2464-8
3470805
Gut. 2004 Oct;53(10):1509-15
15361505
Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10925-30
9380736
J Clin Invest. 1980 May;65(5):1135-40
7364941
Neurosci Lett. 2004 Jun 10;363(2):182-6
15172111
Blood. 2005 Sep 1;106(5):1864-6
15886319
Clin Chem. 2000 Mar;46(3):313-8
10702516
Hum Pathol. 2002 Jan;33(1):125-30
11823983
Am J Med Sci. 1999 Oct;318(4):241-56
10522552
FASEB J. 2006 Feb;20(2):353-5
16368718
Blood. 2007 Jun 15;109(12):5525-6
17554070
J Clin Invest. 1999 Jan;103(1):129-35
9884342
Anal Biochem. 1997 May 15;248(1):31-40
9177722
Nat Med. 2007 Sep;13(9):1096-101
17721544
Blood. 2001 Sep 15;98(6):1802-11
11535514
Blood. 2006 Nov 1;108(9):3204-9
16835372
Nat Genet. 2004 Jan;36(1):77-82
14647275
FASEB J. 2006 Dec;20(14):2651-3
17065227
Am J Pathol. 2000 May;156(5):1527-35
10793064
Circulation. 2000 Dec 12;102(24):3015-22
11113055
Physiol Res. 2006;55(6):667-74
16497104
Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10919-24
9380735
J Am Soc Nephrol. 2003 Nov;14(11):2741-9
14569083
Clin Chem. 2006 Jun;52(6):950-68
16627556
Blood. 2008 Jan 15;111(2):924-31
17938254
Nat Cell Biol. 1999 Jul;1(3):152-7
10559901
Blood. 2005 May 15;105(10):4103-5
15671438
Haematologica. 2006 Jun;91(6):809-12
16769583
Nucleic Acids Res. 2001 May 1;29(9):e45
11328886
Cell Metab. 2005 Mar;1(3):191-200
16054062
Mol Cell. 2000 Feb;5(2):299-309
10882071
Hepatology. 1998 Mar;27(3):829-38
9500714
Blood. 2007 Sep 15;110(6):2182-9
17540841
J Biol Chem. 2000 May 19;275(20):15166-73
10809751
Nat Med. 1996 Jan;2(1):87-90
8564848
Pharmacol Rev. 2003 Sep;55(3):551-71
12869663
Pediatrics. 1995 Apr;95(4):468-74
7700742
J Cell Mol Med. 2009 Apr;13(4):712-25
18410527
Blood. 2003 Jul 1;102(1):371-6
12637325
Biochim Biophys Acta. 2006 Jul;1763(7):690-9
16790283
Clin Chem. 2007 Apr;53(4):620-8
17272487
J Biol Chem. 1993 Apr 5;268(10):7365-71
8463269
J Clin Invest. 2004 May;113(9):1271-6
15124018