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. 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.

Key Words::

• acute-phase response
• hepcidin
• interleukin-6
• iron-regulatory genes
• liver regeneration
• partial hepatectomy

Acknowledgements

We are grateful to Ms. Ulla-Britta Torndal for expert technical assistance. This study was supported by grants from the Swedish Society of Medicine (Bengt Ihre´s fund) and from the Karolinska Institutet.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.