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Hepcidin bound to α2-macroglobulin reduces ferroportin-1 expression and enhances its activity at reducing serum iron levels
ML. Huang, CJ. Austin, MA. Sari, YS. Rahmanto, P. Ponka, D. Vyoral, DR. Richardson,
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
NS10300
MZ0
CEP - Centrální evidence projektů
Digitální knihovna NLK
Plný text - Článek
Zdroj
NLK
Free Medical Journals
od 2008 do Před 1 rokem
Freely Accessible Science Journals
od 1905 do Před 1 rokem
PubMed Central
od 2005
Europe PubMed Central
od 2005 do Před 1 rokem
Open Access Digital Library
od 1905-10-01
Open Access Digital Library
od 1905-10-01
ROAD: Directory of Open Access Scholarly Resources
od 1905
PubMed
23846698
DOI
10.1074/jbc.m113.471573
Knihovny.cz E-zdroje
- MeSH
- alfa-makroglobuliny genetika metabolismus MeSH
- biologické modely * MeSH
- buněčné linie MeSH
- hepcidiny krev genetika MeSH
- LDL-receptory genetika metabolismus MeSH
- lidé MeSH
- multiproteinové komplexy krev genetika MeSH
- myši knockoutované MeSH
- myši MeSH
- nádorové supresorové proteiny genetika metabolismus MeSH
- protein 1 související s LDL-receptory genetika metabolismus MeSH
- proteiny přenášející kationty biosyntéza genetika MeSH
- regulace genové exprese fyziologie MeSH
- železo krev MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Hepcidin regulates iron metabolism by down-regulating ferroportin-1 (Fpn1). We demonstrated that hepcidin is complexed to the blood transport protein, α2-macroglobulin (α2M) (Peslova, G., Petrak, J., Kuzelova, K., Hrdy, I., Halada, P., Kuchel, P. W., Soe-Lin, S., Ponka, P., Sutak, R., Becker, E., Huang, M. L., Suryo Rahmanto, Y., Richardson, D. R., and Vyoral, D. (2009) Blood 113, 6225-6236). However, nothing is known about the mechanism of hepcidin binding to α2M or the effects of the α2M·hepcidin complex in vivo. We show that decreased Fpn1 expression can be mediated by hepcidin bound to native α2M and also, for the first time, hepcidin bound to methylamine-activated α2M (α2M-MA). Passage of high molecular weight α2M·hepcidin or α2M-MA·hepcidin complexes (≈725 kDa) through a Sephadex G-25 size exclusion column retained their ability to decrease Fpn1 expression. Further studies using ultrafiltration indicated that hepcidin binding to α2M and α2M-MA was labile, resulting in some release from the protein, and this may explain its urinary excretion. To determine whether α2M-MA·hepcidin is delivered to cells via the α2M receptor (Lrp1), we assessed α2M uptake and Fpn1 expression in Lrp1(-/-) and Lrp1(+/+) cells. Interestingly, α2M·hepcidin or α2M-MA·hepcidin demonstrated similar activities at decreasing Fpn1 expression in Lrp1(-/-) and Lrp1(+/+) cells, indicating that Lrp1 is not essential for Fpn1 regulation. In vivo, hepcidin bound to α2M or α2M-MA did not affect plasma clearance of α2M/α2M-MA. However, serum iron levels were reduced to a significantly greater extent in mice treated with α2M·hepcidin or α2M-MA·hepcidin relative to unbound hepcidin. This effect could be mediated by the ability of α2M or α2M-MA to retard kidney filtration of bound hepcidin, increasing its half-life. A model is proposed that suggests that unlike proteases, which are irreversibly bound to activated α2M, hepcidin remains labile and available to down-regulate Fpn1.
Citace poskytuje Crossref.org
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