title: Iron-regulatory gene expression during liver regeneration.
abstract: BACKGROUND
  In rat, the first 18-24 h after partial hepatectomy (PH) are characterized by an acute-phase reaction, after which liver regeneration predominates. Interleukin-6 (IL-6) induces the iron hormone hepcidin, which blocks iron uptake and may compromise iron uptake in the growing liver. The expressions of hepcidin and the iron-regulatory pathway of hepcidin gene expression during the late phase of liver regeneration are unknown.
  
  
  OBJECTIVE
  To characterize the expression pattern of hepcidin and the iron-sensing pathway of hepcidin regulation during liver regeneration.
  
  
  METHODS
  Rats were subjected to PH or sham operation. Liver weights, number of S-phase nuclei, and serum levels of iron and IL-6 were determined. Messenger-RNA levels of hepcidin, ferritin, hemojuvelin, transferrin receptor 1 and 2, HFE, divalent metal transporter 1, ferroportin, and ceruloplasmin were determined with qPCR at different time points. Protein levels of STAT3 and SMAD4 were determined with western blot.
  
  
  RESULTS
  During the acute-phase response, IL-6 release induced STAT3 protein and hepcidin mRNA, whereas mRNA levels of proteins in the iron-sensing pathway (HFE, hemojuvelin, and transferrin receptor 2) decreased. The mRNA levels of proteins involved in cellular iron uptake were increased and cellular iron export unchanged. During liver regeneration >24 h after PH, gene expressions in the iron-sensing pathway were continuously suppressed and hepcidin mRNA levels declined 3-7 days after surgery.
  
  
  CONCLUSIONS
  Hepcidin gene expression peaks during the acute-phase response, but a sustained down-regulation of the iron-sensing pathway of hepcidin regulation gradually reduces hepcidin gene expression until regeneration is complete, thereby promoting iron mobilization to the regenerating liver.
authors.affiliation: Department of Medicine, Karolinska University Hospital Huddinge, Division of Gastroenterology and Hepatology, Stockholm, Sweden. Annelie.Mollbrink@ki.se
authors.forename: Annelie
authors.initials: A
authors.lastname: Mollbrink
authors.forename: Petra
authors.initials: P
authors.lastname: Holmström
authors.forename: Mattias
authors.initials: M
authors.lastname: Sjöström
authors.forename: Rolf
authors.initials: R
authors.lastname: Hultcrantz
authors.forename: Lennart C
authors.initials: LC
authors.lastname: Eriksson
authors.forename: Per
authors.initials: P
authors.lastname: Stål
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics* / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002570:Ceruloplasmin / Q000235:genetics / Q000378:metabolism; D058851:GPI-Linked Proteins; D015870:Gene Expression; D000071020:Hemochromatosis Protein; D006498:Hepatectomy; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D007501:Iron / Q000097:blood; D008099:Liver / Q000033:anatomy & histology* / Q000502:physiology; D008115:Liver Regeneration / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009929:Organ Size; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; D002570:Ceruloplasmin; D058851:GPI-Linked Proteins; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; D015850:Interleukin-6; D007501:Iron; D008565:Membrane Proteins; D012333:RNA, Messenger; D011990:Receptors, Transferrin; D050796:STAT3 Transcription Factor; D051901:Smad4 Protein; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2; C484232:HFE protein, rat; C578703:Hamp protein, rat; C513726:Hjv protein, rat; C490811:Smad4 protein, rat; C494088:Stat3 protein, rat; C548977:Tfr2 protein, rat; C545564:Tfrc protein, rat