title: Iron accumulation in alcoholic liver diseases.
abstract: Increased hepatic iron is one of the important key factors which contribute alcohol toxicity of liver due to the production of reactive oxygen species. In patients with alcoholic liver diseases (ALD), liver iron is increased and the resulted lipid metabolite 4-hydroxynonenal-protein adduct was also increased. In general, iron is deposited in both parenchymal cells and and Kupffer cells in ALD. However, in patients with mild ALD, the parenchymal iron deposition is dominant rather than reticuloendothelial iron deposition, while the latter iron deposition is domimant in severe ALD, possibly due to endotoxemia and overproduction of inflammatory cytokines. We speculated that a parenchymal iron deposition in mild ALD is an important factor to trigger hepatocytes injury by ethanol, and the possible cause of parencynal iron deposition may be an increase of cellular iron uptake via serum transferrin in hepatocytes after ethanol exposure. By immuno-histochemical study of biopsied liver samples, the expression of transferrin receptor 1 (TfR1), which mediates cellular iron uptake by serum transferrin was increased. This increase of TfR1 by ethanol is confirmed by in vitro experiment using HepG2 cells and primary rat hepatocytes culture. Fe-labeled transferrin incorporation (but not transferrin non-bound iron (NTBI)) into the cells is also increased, suggesting that the increased TfR1 is functional. The increase of TfR1 expression is partially due to the increased activity of iron regulatory protein (IRP) by oxidative stress of ethanol metabolism. Thus, the post-transcriptional regulation of iron uptake by ethanol is involved in the hepatocyte iron accumulation. Another possibility is an increase of intestinal iron absorption. Our recent finding regarding the increase of pro-hepcidin serum in alcoholic patients with high serum ferritin support this assumption.
authors.affiliation: Third Department of Internal Medicine, Asahikawa Medical College, and Fourth Department of Internal Medicine, Sapporo Medical University, Japan. yk1950@asahikawa-med.ac.jp
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kohgo
authors.forename: Takaaki
authors.initials: T
authors.lastname: Ohtake
authors.forename: Katsuya
authors.initials: K
authors.lastname: Ikuta
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Hosoki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Saito
authors.forename: Junji
authors.initials: J
authors.lastname: Kato
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D064451:Hepcidins; D006801:Humans; D007501:Iron / Q000378:metabolism*; D035925:Iron-Regulatory Proteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008108:Liver Diseases, Alcoholic / Q000378:metabolism*; D018384:Oxidative Stress; D011990:Receptors, Transferrin / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism
chemical_list: D000447:Aldehydes; D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; C578703:Hamp protein, rat; D064451:Hepcidins; D035925:Iron-Regulatory Proteins; D011990:Receptors, Transferrin; D014168:Transferrin; D007501:Iron; C027576:4-hydroxy-2-nonenal