Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice.
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.
Gao
Junwei
J
Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, OR, USA.
Chen
Juxing
J
De Domenico
Ivana
I
Koeller
David M
DM
Harding
Cary O
CO
Fleming
Robert E
RE
Koeberl
Dwight D
DD
Enns
Caroline A
CA
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D000071020:Hemochromatosis Protein; D022781:Hepatocytes / Q000378:metabolism*; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism; D015151:Immunoblotting; D007501:Iron / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics* / Q000378:metabolism
D023181:Antimicrobial Cationic Peptides; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; C534796:TRF2 protein, mouse; D035341:Telomeric Repeat Binding Protein 2; D007501:Iron