Protective role of calreticulin in HFE hemochromatosis

Free Radic Biol Med. 2008 Jan 1;44(1):99-108. doi: 10.1016/j.freeradbiomed.2007.09.014. Epub 2007 Oct 4.

Abstract

HFE gene 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. More recent studies have suggested a more complex function for this nonclassical 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. Gene expression was analyzed in HepG2 cells overexpressing 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 characterized HH patients. 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 levels correlated with the expression of the UPR marker BiP and showed a negative association with the number of hereditary hemochromatosis clinical manifestations. The data show that expression of C282Y HFE triggers a stress-protective response in HepG2 cells and suggest a role for calreticulin as a modifier of the clinical expression of HH.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Antimicrobial Cationic Peptides / genetics
  • Antimicrobial Cationic Peptides / metabolism
  • Calreticulin / antagonists & inhibitors
  • Calreticulin / blood*
  • Calreticulin / genetics*
  • Cell Line
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation
  • Hemochromatosis / genetics*
  • Hemochromatosis / physiopathology
  • Hemochromatosis Protein
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Hepcidins
  • Histocompatibility Antigens Class I / genetics*
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism*
  • Mice
  • Middle Aged
  • Monocytes / metabolism
  • Monocytes / pathology
  • Mutation, Missense*
  • Oxidative Stress
  • RNA, Messenger / analysis
  • RNA, Small Interfering / administration & dosage
  • Rats
  • Receptors, Transferrin / biosynthesis
  • Receptors, Transferrin / blood
  • Receptors, Transferrin / genetics
  • Transfection

Substances

  • Antimicrobial Cationic Peptides
  • Calreticulin
  • HAMP protein, human
  • HFE protein, human
  • Hamp protein, mouse
  • Hamp protein, rat
  • Hemochromatosis Protein
  • Hepcidins
  • Histocompatibility Antigens Class I
  • Membrane Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Transferrin