Transcriptional activity of iron homeostasis maintaining genes in HCV infection

Background and Objectives: In chronic hepatitis C, hepatic iron content is mildly elevated. An excess of hepatocyte iron is currently discussed as a cofactor for the development of HCC. The mechanisms leading to iron overload are not yet understood and may range simply from an iron shift from serum to tissue as it occurs e.g. in bacterial infections to a dysregulation of the complex iron homeostasis. To address this issue, we quantified the expression of several genes that are involved in iron metabolism both in liver tissue from chronic hepatitis C patients and in human Huh–7 hepatoma cells harbouring HCV replicons. Methods: Total cellular RNA was obtained from liver tissue or from hepatoma cells that had been treated with or without interferon-γ, and was reverse transcribed using random hexamer oligonucleotides. The amounts of transcripts were quantified by real-time RT-PCR using SYBR Green I dye. Data were normalized to two endogenous references, β-actin and GAPDH. Results: Liver tissue as well as hepatoma cells show high expression of hepcidin, ferritin, transferrin, transferrin receptor 2, ferroportin, and hemojuvelin, and less expression of the divalent metal transporter 1 (DMT1), the ferricreductase Dcytb, transferrin receptor 1, and hephaestin. The amount of transcripts, however, was not found to differ significantly when liver tissue from chronic hepatitis C patients (n=26) was compared to tissue obtained from patients with chronic hepatitis B (n=8), from those with liver disorders of non-viral etiology (n=24), or from healthy tissue (n=7). Gene expression in HCV RNA replicating Huh–7 cells was also not significantly different from naïve Huh–7 or from mock-transfected cells. No significant changes in gene expression were observed when cells were treated with IFN-γ, although this cytokine induces IP–10. Hypothesis: HCV infection does not change hepatic expression of the iron-pathway genes neither directly nor indirectly through IFN-γ. However, other mediators of the inflammatory infiltrate may be responsible for increased iron uptake in hepatocytes and in non-parenchymal cells as well.

hepatitis C - iron