title: Increased duodenal iron absorption through up-regulation of divalent metal transporter 1 from enhancement of iron regulatory protein 1 activity in patients with nonalcoholic steatohepatitis.
abstract: Increased hepatic iron accumulation is thought to be involved in the pathogenesis of nonalcoholic steatohepatitis (NASH). Hepatic iron accumulation, as well as oxidative DNA damage, is significantly increased in NASH livers. However, the precise mechanism of iron accumulation in the NASH liver remains unclear. In this study, 40 cases with a diagnosis of NASH (n = 25) or simple steatosis (SS; n = 15) by liver biopsy were enrolled. An oral iron absorption test (OIAT) was used, in which 100 mg of sodium ferrous citrate was administered to each individual. The OIAT showed that absorption of iron from the gastrointestinal (GI) tract was increased significantly in NASH patients, compared to SS and control subjects. Iron reduction therapy was effective in patients with NASH, who exhibited iron deposition in the liver and no alanine aminotransferase improvement after other therapies (n = 9). Serum hepcidin concentration and messenger RNA (mRNA) levels of divalent metal transporter 1 (DMT1) also were significantly elevated in patients with NASH. OIAT results were correlated with grade of liver iron accumulation and DMT1 mRNA levels. Then, we demonstrated that DMT1 mRNA levels increased significantly in Caco-2/TC7 cell monolayers cultured in transwells with serum from NASH patients. An electrophoresis mobility shift assay showed activation of iron regulatory protein (IRP) in those cells, and IRP1 small interfering RNA clearly inhibited the increase of DMT1 mRNA levels.
  
  
  CONCLUSIONS
  In spite of elevation of serum hepcidin, iron absorption from the GI tract increased through up-regulation of DMT1 by IRP1 activation by humoral factor(s) in sera of patients with NASH.
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hoki
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Miyanishi
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan.
authors.forename: Kohichi
authors.initials: K
authors.lastname: Takada
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawano
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Sakurada
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Sato
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kubo
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan.
authors.forename: Rishu
authors.initials: R
authors.lastname: Takimoto
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kobune
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University, School of Medicine, Sapporo, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Kato
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001707:Biopsy, Needle; D018938:Caco-2 Cells; D016022:Case-Control Studies; D002478:Cells, Cultured; D004386:Duodenum / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012016:Reference Values; D012189:Retrospective Studies; D018709:Statistics, Nonparametric; D015533:Transcriptional Activation; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D007501:Iron; D035941:Iron Regulatory Protein 1