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Protective role of calreticulin in HFE hemochromatosis
Author(s) -
Pinto Jorge P,
Ramos Pedro,
Almeida Sérgio,
Oliveira Susana,
Breda Laura,
Michalak Marek,
Porto Graça,
Rivella Stefano,
Sousa Maria
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.758.37
Subject(s) - calreticulin , hepcidin , hemochromatosis , hereditary hemochromatosis , oxidative stress , transferrin receptor , gene expression , ferroportin , biology , immunology , gene , endoplasmic reticulum , transferrin , microbiology and biotechnology , endocrinology , genetics , inflammation
Background/Aims: HFE mutations are associated with over 80% of cases of Hereditary Hemochromatosis (HH), an iron‐overload disease in which the liver is the most frequently affected organ. Research on HFE has traditionally focused on its interaction with the transferrin receptor. Recent studies suggested a more complex function for this non‐classical MHC‐I protein. The aim of this study was to examine how HFE and its two most common mutations affect the expression of selected genes in a hepatocyte‐like cell line. Methods: Gene expression was analyzed in HepG2 cells over‐expressing wild‐type and mutant HFE. The effect of HFE in iron import and oxidative stress levels was assessed. Unfolded protein response (UPR)‐activated gene expression was analyzed in peripheral blood mononuclear cells from HH patients. Results: C282Y‐HFE down‐regulated hepcidin and enhanced calreticulin mRNA expression. Calreticulin levels correlated with intracellular iron increase and were associated with protection from oxidative stress. In C282Y +/+ patients calreticulin mRNA levels correlated with the expression of the UPR marker BiP and showed a negative association with the number of HH clinical manifestations. Conclusions: The data show that expression of C282Y‐HFE triggers a stress‐protective response and suggest a role for calreticulin as a modifier of the clinical expression of HH.