共 50 条
Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice
被引:62
作者:
Gao, Junwei
[1
]
Chen, Juxing
[1
]
De Domenico, Ivana
[2
]
Koeller, David M.
[3
]
Harding, Cary O.
[3
]
Fleming, Robert E.
[4
]
Koeberl, Dwight D.
[5
]
Enns, Caroline A.
[1
]
机构:
[1] Oregon Hlth & Sci Univ, Dept Cell & Dev Biol, Portland, OR 97239 USA
[2] Univ Utah, Dept Med, Salt Lake City, UT 84112 USA
[3] Oregon Hlth & Sci Univ, Dept Pediat, Portland, OR 97239 USA
[4] St Louis Univ, Sch Med, Dept Pediat, St Louis, MO 63103 USA
[5] Duke Univ, Med Ctr, Dept Pediat, Div Med Genet, Durham, NC 27710 USA
来源:
基金:
美国国家卫生研究院;
关键词:
HEREDITARY HEMOCHROMATOSIS PROTEIN;
TRANSFERRIN RECEPTOR 2;
AUTOSOMAL-DOMINANT HEMOCHROMATOSIS;
ANTIMICROBIAL PEPTIDE HEPCIDIN;
IRON OVERLOAD;
JUVENILE HEMOCHROMATOSIS;
DEPENDENT REGULATION;
CRYSTAL-STRUCTURE;
KNOCKOUT MOUSE;
GENE;
D O I:
10.1182/blood-2009-09-245209
中图分类号:
R5 [内科学];
学科分类号:
1002 ;
100201 ;
摘要:
Hereditary hemochromatosis is caused by mutations in the hereditary hemochromatosis protein (HFE), transferrin-receptor 2 (TfR2), hemojuvelin, hepcidin, or ferroportin genes. Hepcidin is a key iron regulator, which is secreted by the liver, and decreases serum iron levels by causing the down-regulation of the iron transporter, ferroportin. Mutations in either HFE or TfR2 lower hepcidin levels, implying that both HFE and TfR2 are necessary for regulation of hepcidin expression. In this study, we used a recombinant adeno-associated virus, AAV2/8, for hepatocyte-specific expression of either Hfe or Tfr2 in mice. Expression of Hfe in Hfe-null mice both increased Hfe and hepcidin mRNA and lowered hepatic iron and Tf saturation. Expression of Tfr2 in Tfr2-deficient mice had a similar effect, whereas expression of Hfe in Tfr2-deficient mice or of Tfr2 in Hfe-null mice had no effect on liver or serum iron levels. Expression of Hfe in wild-type mice increased hepcidin mRNA and lowered iron levels. In contrast, expression of Tfr2 had no effect on wild-type mice. These findings suggest that Hfe is limiting in formation of the Hfe/Tfr2 complex that regulates hepcidin expression. In addition, these studies show that the use of recombinant AAV vector to deliver genes is a promising approach for studying physiologic consequences of protein complexes. (Blood. 2010; 115(16): 3374-3381)
引用
收藏
页码:3374 / 3381
页数:8
相关论文