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Am J Med Sci. 2018 Feb;355(2):183-190. doi: 10.1016/j.amjms.2017.08.012. Epub 2017 Aug 23.

Iron Enhances Hepatic Fibrogenesis and Activates Transforming Growth Factor-β Signaling in Murine Hepatic Stellate Cells.

Author information

1
Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver Research, London, UK; Faculty of Life Sciences & Medicine, King's College London, London, UK; Department of Biomedical Sciences, University of Westminster, London, UK.
2
Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver Research, London, UK; Faculty of Life Sciences & Medicine, King's College London, London, UK.
3
Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver Research, London, UK; Faculty of Life Sciences & Medicine, King's College London, London, UK; Division of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany.
4
Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver Research, London, UK.
5
Department of Biomedical Sciences, University of Westminster, London, UK.
6
Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver Research, London, UK; Faculty of Life Sciences & Medicine, King's College London, London, UK; Section of Gastroenterology, Ralph H Johnson VAMC, Charleston, South Carolina; Department of Medicine, Medical University of South Carolina, Charleston, South Carolina. Electronic address: synw@musc.edu.

Abstract

BACKGROUND:

Although excess iron induces oxidative stress in the liver, it is unclear whether it directly activates the hepatic stellate cells (HSC).

MATERIALS AND METHODS:

We evaluated the effects of excess iron on fibrogenesis and transforming growth factor beta (TGF-β) signaling in murine HSC. Cells were treated with holotransferrin (0.005-5g/L) for 24 hours, with or without the iron chelator deferoxamine (10µM). Gene expressions (α-SMA, Col1-α1, Serpine-1, TGF-β, Hif1-α, Tfrc and Slc40a1) were analyzed by quantitative real time-polymerase chain reaction, whereas TfR1, ferroportin, ferritin, vimentin, collagen, TGF-β RII and phospho-Smad2 proteins were evaluated by immunofluorescence, Western blot and enzyme-linked immunosorbent assay.

RESULTS:

HSC expressed the iron-uptake protein transferrin receptor 1 (TfR1) and the iron-export protein ferroportin. Holotransferrin upregulated TfR1 expression by 1.8-fold (P < 0.03) and ferritin accumulation (iron storage) by 2-fold (P < 0.01), and activated HSC with 2-fold elevations (P < 0.03) in α-SMA messenger RNA and collagen secretion, and a 1.6-fold increase (P < 0.01) in vimentin protein. Moreover, holotransferrin activated the TGF-β pathway with TGF-β messenger RNA elevated 1.6-fold (P = 0.05), and protein levels of TGF-β RII and phospho-Smad2 increased by 1.8-fold (P < 0.01) and 1.6-fold (P < 0.01), respectively. In contrast, iron chelation decreased ferritin levels by 30% (P < 0.03), inhibited collagen secretion by 60% (P < 0.01), repressed fibrogenic genes α-SMA (0.2-fold; P < 0.05) and TGF-β (0.4-fold; P < 0.01) and reduced levels of TGF-β RII and phospho-Smad2 proteins.

CONCLUSIONS:

HSC express iron-transport proteins. Holotransferrin (iron) activates HSC fibrogenesis and the TGF-β pathway, whereas iron depletion by chelation reverses this, suggesting that this could be a useful adjunct therapy for patients with fibrosis. Further studies in primary human HSC and animal models are necessary to confirm this.

KEYWORDS:

Fibroblasts; Fibrosis; Holotransferrin; Liver

PMID:
29406047
DOI:
10.1016/j.amjms.2017.08.012
[Indexed for MEDLINE]

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