Iron-regulatory gene expression during liver regeneration

• Published in: Scandinavian journal of gastroenterology Vol. 47; no. 5; pp. 591 - 600
• Main Authors: Mollbrink, Annelie, Holmström, Petra, Sjöström, Mattias, Hultcrantz, Rolf, Eriksson, Lennart C, Stål, Per
• Format: Journal Article
• Language: English
• Published: Colchester Informa Healthcare 01-05-2012; Taylor & Francis; Informa
• Subjects: acute-phase response; Animals; Antimicrobial Cationic Peptides - genetics; Antimicrobial Cationic Peptides - metabolism; Biological and medical sciences; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Ceruloplasmin - genetics; Ceruloplasmin - metabolism; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression; GPI-Linked Proteins; Hemochromatosis Protein; Hepatectomy; hepcidin; Hepcidins; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - metabolism; interleukin-6; Interleukin-6 - blood; Iron - blood; iron-regulatory genes; Liver - anatomy & histology; Liver - physiology; liver regeneration; Liver Regeneration - genetics; Liver, biliary tract, pancreas, portal circulation, spleen; Male; Medical sciences; Medicin och hälsovetenskap; Membrane Proteins - genetics; Membrane Proteins - metabolism; Organ Size; partial hepatectomy; Rats; Rats, Inbred F344; Receptors, Transferrin - genetics; Receptors, Transferrin - metabolism; RNA, Messenger - metabolism; Signal Transduction - genetics; Smad4 Protein - genetics; Smad4 Protein - metabolism; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the digestive system; partial hepatectomy; hepcidin; iron-regulatory genes; Acute; acute-phase response; Iron; Gene expression; interleukin-6; Hepatectomy; Interleukin 6; Treatment; Partial; Surgery; Gastroenterology; Liver regeneration
• ISSN: 0036-5521; 1502-7708; 1502-7708
• DOI: 10.3109/00365521.2012.661761

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.
Aim.
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.