Gastroenterology
Volume 134, Issue 1 , Pages 348-351, January 2008

HCV, Iron, and Oxidative Stress: The New Choreography of Hepcidin

  • Debbie Trinder

      Affiliations

    • School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia
    • ,
  • Oyekoya T. Ayonrinde

      Affiliations

    • Department of Gastroenterology, Fremantle Hospital, Fremantle, Western Australia
    • ,
  • John K. Olynyk

      Affiliations

    • The Western Australian Institute of Medical Research, Perth, Western Australia
    • Corresponding Author InformationAddress requests for reprints to: John K. Olynyk, MD, School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital Campus, Fremantle, Western Australia.

Article Outline

 

See “Hepatitis C virus–induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription” by Nishina S, Hino K, Korenaga M, et al, on page 226; and “Liver iron, HFE gene mutations, and hepatocellular carcinoma occurrence in patients with cirrhosis” by Nahon P, Sutton A, Rufat P, et al, on page 102.

The burden of liver disease secondary to chronic infection with the hepatitis C virus (HCV) has been increasing progressively. Fundamental to reducing the impact of this disease is the elucidation of new approaches to eradicate HCV and modulate other possible cofactors affecting progression of HCV-related liver disease. For example, chronic excessive alcohol consumption is a well known accelerant of hepatic fibrosis in patients with chronic hepatitis C.1 A putative role for iron in the progression of chronic hepatitis C has also been proposed. Patients with chronic HCV infection frequently have elevated serum ferritin and hepatic iron levels.2 A number of observational studies and clinical trials have demonstrated that iron levels in the liver influence hepatic injury and the response of chronic hepatitis C to therapy.3, 4, 5, 6, 7, 8, 9, 10, 11

The reason underlying the presence of mild iron loading in the livers of individuals with chronic hepatitis C has remained unclear. The study by Nishina et al12 in the current issue of Gastroenterology uses a transgenic mouse model of HCV infection to provide insights into the modifications of iron metabolism that may contribute to increased hepatic iron levels. These investigators used a FL-N/35 transgenic mouse model expressing HCV polyprotein under the control of an albumin liver specific promoter and demonstrated a mild elevation of hepatic iron concentration at 8 and 14 months of age compared with nontransgenic mice. The iron was present predominately in hepatocytes, but also in the sinusoidal lining cells, probably the Kupffer cells. Serum iron and transferrin saturation were elevated, whereas the splenic iron concentration was reduced compared with nontransgenic mice. Accumulation of iron in the liver was associated with a reduction in hepatic hepcidin mRNA expression and accompanied by reduced serum prohepcidin protein levels. Hepcidin is a peptide synthesized in the liver; synthesis is up-regulated by iron and inflammation and down-regulated by oxidative stress.13, 14 Hepcidin is secreted into the blood where it binds to its receptor, ferroportin, which is a cellular iron exporter predominately expressed in duodenal enterocytes, macrophages. and to a lesser degree in hepatocytes.15, 16 Hepcidin induces internalization and degradation of ferroportin, thereby leading to a subsequent reduction in iron export by the cell.17 In the FL-N/35 transgenic mice, reduced hepcidin expression resulted in increased levels of ferroportin protein in the duodenum, spleen, and liver, suggesting it was associated with increased iron absorption and recycling of iron from macrophages, leading to an increase in hepatic iron levels.

Hepcidin is up-regulated in chronic inflammation via an interleukin (IL)-6– and IL-1–mediated STAT3 signaling transduction pathway.18, 19 Inflammation was not present in the current mouse model of HCV; as expected, there were no changes in proinflammatory cytokines or inflammatory-mediated up-regulation of hepcidin. Nishina et al12 performed reporter gene experiments to identify the region of the hepcidin promoter that was affected by HCV protein and showed that the reduced hepcidin transcriptional activity in the FL-N/35 transgenic mouse was due to a decreased DNA binding activity of the transcription factor CCAAT/enhancer-binding protein α (C/EBP-α), which has been shown previously to regulate hepcidin transcription.20 This was also associated with an increase in the nuclear protein C/EBP homology protein (CHOP), an inhibitor of C/EBP DNA binding activity. The up-regulation of CHOP levels was probably caused by the increased levels of reactive oxygen species (ROS) levels in the FL-N/35 transgenic mice.21

The current observations have led the authors to propose a model for HCV-induced iron loading, where HCV protein increases ROS production, up-regulating CHOP which prevents C/EBP-α binding to the hepcidin promoter and reduces hepcidin expression. This, in turn, up-regulates ferroportin expression, increasing iron export from the duodenum and macrophages, raising serum iron levels and transferrin saturation, and resulting in elevated hepatic iron levels. Although this model fits together nicely in an animal model of HCV where there is no inflammation, how well does it fit with clinical observations?

In individuals with chronic hepatitis C, hepcidin mRNA expression has been shown to be positively correlated with hepatic iron concentration, but was not related to markers of inflammation as found in other inflammatory diseases.22, 23 In chronic hepatitis C, hepcidin mRNA expression was relatively low compared with hepatic iron content22 and serum prohepcidin protein levels were reduced compared with healthy controls.24 ROS levels in humans have been shown to be positively correlated with hepatic hepcidin mRNA levels, as well as hepatic iron concentration and the level of inflammation.25 These results suggest that in humans hepcidin maybe up-regulated in response to iron and perhaps inflammation and ROS rather than down-regulated by ROS as was observed in the FL-N/35 transgenic mice. However, iron and inflammation are also known to drive ROS production, so the interaction of these factors that regulate hepcidin synthesis is complex and it is likely to be a balance of all these factors that regulates the final level of hepcidin synthesis. Therefore, it is possible that oxidative stress may attenuate the iron and inflammation-induced up-regulation of hepcidin, which would lead to a relative lowering of hepcidin.

Clinical studies in individuals with chronic hepatitis C have also reported changes in the expression of other liver iron transporters and regulatory molecules, with levels of transferrin receptors 1 and 2, ferroportin, and ferritin all being increased while hepatic divalent metal transporter 1 (DMT1) levels were reduced.26, 27 These observations are consistent with an iron-loaded, inflammatory disease state where hepatic transferrin receptor 2 protein levels are up-regulated by increased levels of diferric transferrin28 and hepatic ferritin, DMT1 and ferroportin levels are posttranscriptionally regulated by increased cellular iron levels.29 Thus, hepatic TFR1 expression, which is usually down-regulated by increased hepatic iron levels, can also be up-regulated by elevated hepatic levels of the proinflammatory cytokines IL-1, IL-6, and tumor necrosis factor-α, which are present in chronic hepatitis C.

Alcoholic liver disease, like chronic hepatitis C, may also cause elevated serum ferritin and transferrin saturation and hepatic iron loading, which may contribute to liver injury. Interestingly, recent advances in the understanding of the molecular mechanisms responsible for iron loading in alcoholic liver disease indicate that it has many features in common with hepatitis C. Alcohol administration increases ROS and reduces both C/EBP-α expression and DNA binding activity reducing hepcidin mRNA expression in humans and animal models.14, 30, 31 This is also accompanied by elevated expression of the duodenal iron transporters ferroportin and DMT1,14, 32 suggesting that iron absorption would also be elevated. In addition, alcohol impairs the iron and IL-6–induced up-regulation of hepcidin,30, 32 suggesting that alcohol-induced oxidative stress can attenuate the usual iron- and inflammation-mediated up-regulation of hepcidin. Similarly, oxidative stress, which is induced in chronic hepatitis C, may also have a negative effect on the iron- and inflammation-mediated up-regulation of hepcidin synthesis, causing liver iron loading and possible liver injury.

It is worth noting that the pattern of iron loading in the FL-N/35 transgenic mice is similar to that observed in animal models and humans with hereditary hemochromatosis, with elevated hepatic iron and reduced spleen iron levels.33, 34 In both situations, changes in iron metabolism are due to the impairment of hepcidin synthesis, which increases iron absorption and the recycling of iron by macrophages, particularly in the spleen, to increase serum iron and deposition of iron in the hepatocytes of the liver. This further illustrates the central role of hepcidin in the regulation of iron homeostasis and how alterations in iron metabolism associated with chronic hepatitis C or alcohol-related liver disease are mediated via complex interactions between iron stores, oxidative stress, and inflammation and the resultant effects that these have on hepcidin synthesis (Figure 1).

  • View full-size image.
  • Figure 1. 

    Balance of factors such as HCV protein and alcohol induced ROS production, hemochromatosis mutations, iron and inflammation that influence hepcidin expression and regulate iron absorption, macrophage recycling of iron and the level of iron in the liver.

It is clear that although iron may be a cofactor contributing to development of tissue injury, it is not a potent inducer of liver cirrhosis or hepatocellular carcinoma (HCC), as exemplified by the relatively small proportion of individuals with HFE hereditary hemochromatosis who develop HCC.35 This is illustrated in another study in the current edition of Gastroenterology by Nahon et al,36 which highlights the higher rate of development of HCC in patients with cirrhosis owing to chronic hepatitis C when compared with alcoholic cirrhosis, despite higher hepatic iron concentrations in the latter group. The orchestration of other factors, including oxidative stress, in influencing the oncogenic potential of HCV needs to be further clarified.

The study by Nishina et al12 provides an elegant insight into the modifications of iron metabolism that lead to increased hepatic iron levels in chronic hepatitis C infection. The influence of ROS and hepcidin on iron homeostasis and disease progression in chronic hepatitis C may have implications for the role of iron in other liver disorders; however, the complex interactions presently limit the translation of these findings to humans.

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PII: S0016-5085(07)02125-7

doi:10.1053/j.gastro.2007.11.048

Refers to article:

  • Hepatitis C Virus–Induced Reactive Oxygen Species Raise Hepatic Iron Level in Mice by Reducing Hepcidin Transcription , 11 October 2007

    Sohji Nishina, Keisuke Hino, Masaaki Korenaga, Chiara Vecchi, Antonello Pietrangelo, Yoichi Mizukami, Takakazu Furutani, Aya Sakai, Michiari Okuda, Isao Hidaka, Kiwamu Okita, Isao Sakaida
    Gastroenterology January 2008 (Vol. 134, Issue 1, Pages 226-238)

  • Liver Iron, HFE Gene Mutations, and Hepatocellular Carcinoma Occurrence in Patients With Cirrhosis , 29 October 2007

    Pierre Nahon, Angela Sutton, Pierre Rufat, Marianne Ziol, Gabriel Thabut, Pierre–Olivier Schischmanoff, Dominique Vidaud, Nathalie Charnaux, Philippe Couvert, Nathalie Ganne–Carrie, Jean–Claude Trinchet, Liliane Gattegno, Michel Beaugrand
    Gastroenterology January 2008 (Vol. 134, Issue 1, Pages 102-110)

Gastroenterology
Volume 134, Issue 1 , Pages 348-351, January 2008

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