Effects of alcohol consumption on iron metabolism in mice with hemochromatosis mutations.
BACKGROUND
Alcoholic liver disease is associated with increased hepatic iron accumulation. The liver-derived peptide hepcidin is the central regulator of iron homeostasis and recent animal studies have demonstrated that exposure to alcohol reduces hepcidin expression. This down-regulation of hepcidin in vivo implies that disturbed iron sensing may contribute to the hepatosiderosis seen in alcoholic liver disease. Alcohol intake is also a major factor in expression of the hemochromatosis phenotype in patients homozygous for the C282Y mutation of the HFE gene.


METHODS
To assess the effect of alcohol in mice with iron overload, alcohol was administered to mice with disrupted Hfe and IL-6 genes and Tfr2 mutant mice and their respective 129x1/SvJ, C57BL/6J, and AKR/J wild-type congenic strains. Iron absorption, serum iron levels, and hepcidin expression levels were then measured in these mice compared with water-treated control mice.


RESULTS
Alcohol was shown to have a strain-specific effect in 129x1/SvJ mice, with treated 129x1/SvJ mice showing a significant increase in iron absorption, serum iron levels, and a corresponding decrease in hepcidin expression. C57BL/6J and AKR/J strain mice showed no effect from alcohol treatment. 129x1/SvJ mice heterozygous or homozygous for the Hfe knockout had a diminished response to alcohol. All 3 strains were shown to have high blood alcohol levels.


CONCLUSIONS
The effect of alcohol on iron homeostasis is dependent on the genetic background in mice. In an alcohol-susceptible strain, mutation of the Hfe gene diminished the response of the measured iron indices to alcohol treatment. This indicates that either maximal suppression of hepcidin levels had already occurred as a result of the Hfe mutation or that Hfe was a component of the pathway utilized by EtOH in suppressing hepcidin production and increasing iron absorption.
Flanagan
Jonathan M
JM
Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, USA. jflan@scripps.edu
Peng
HongFan
H
Beutler
Ernest
E
D000428:Alcohol Drinking / Q000378:metabolism*; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis / Q000235:genetics; D006432:Hemochromatosis / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D007408:Intestinal Absorption / Q000502:physiology; D007501:Iron / Q000097:blood / Q000378:metabolism*; D019190:Iron Overload / Q000139:chemically induced; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012313:RNA / Q000096:biosynthesis / Q000235:genetics
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; D012313:RNA; D007501:Iron