Haptoglobin is degraded by iron in C57BL/6 mice: a possible link with endoplasmic reticulum stress.
BACKGROUND
Haptoglobin is a glycoprotein produced mainly by the liver and secreted into the circulation. Haptoglobin, by virtue of its high affinity for hemoglobin, protects the tissues against hemoglobin-induced oxidative damage and allows heme iron recycling. Haptoglobin synthesis is controlled by various effectors, however, little is known concerning its regulation by iron. Haptoglobin regulation in C57BL/6 and 129sv mice fed on an iron-rich diet for 3 weeks was thus undertaken.


RESULTS
Iron induced a dramatic post-transcriptional decrease of liver and serum haptoglobin in C57BL/6 mice. In contrast, no alteration of haptoglobin expression was detected in 129sv mice. We assumed that the oxidative stress induced by iron in C57BL/6 mice altered the endoplasmic reticulum (ER) environment, leading to the incorrect folding of haptoglobin and its subsequent degradation. To test this hypothesis, the levels of the RE chaperone GRP78 were measured. This chaperone is known to assist protein folding in the RE during pathophysiological conditions. Interestingly, we found that the mRNA and protein levels of GRP78 were decreased in iron-fed C57BL/6 mice, while they were unchanged in iron-fed 129sv mice. These results suggest that the correct processing of haptoglobin (glycosylation, disulfide linkage, folding, and assembly) might be sensitive to ER stress and that, in the absence of GRP78-mediated assistance, Hp is degraded.


CONCLUSIONS
Our data demonstrate that iron regulates haptoglobin synthesis in C57BL/6 mice and suggest a possible link with iron-induced ER stress.
Faye
Audrey
A
Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
Ramey
Guillemette
G
Foretz
Marc
M
Vaulont
Sophie
S
D000818:Animals; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006031:Glycosylation; D006242:Haptoglobins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007501:Iron / Q000008:administration & dosage / Q000378:metabolism*; D019190:Iron Overload / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational; D014415:Tunicamycin / Q000494:pharmacology
D000091342:Endoplasmic Reticulum Chaperone BiP; D006242:Haptoglobins; D006360:Heat-Shock Proteins; D006454:Hemoglobins; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; D014415:Tunicamycin; D007501:Iron