| Autor: |
Tiago L. Duarte, Carolina Caldas, Ana G. Santos, Sandro Silva-Gomes, Andreia Santos-Gonçalves, Maria João Martins, Graça Porto, José Manuel Lopes |
| Jazyk: |
angličtina |
| Rok vydání: |
2017 |
| Předmět: |
|
| Zdroj: |
Redox Biology, Vol 11, Iss , Pp 157-169 (2017) |
| Druh dokumentu: |
article |
| ISSN: |
2213-2317 |
| DOI: |
10.1016/j.redox.2016.11.013 |
| Popis: |
Background and Aims: In hereditary hemochromatosis, iron deposition in the liver parenchyma may lead to fibrosis, cirrhosis and hepatocellular carcinoma. Most cases are ascribed to a common mutation in the HFE gene, but the extent of clinical expression is greatly influenced by the combined action of yet unidentified genetic and/or environmental modifying factors. In mice, transcription factor NRF2 is a critical determinant of hepatocyte viability during exposure to acute dietary iron overload. We evaluated if the genetic disruption of Nrf2 would prompt the development of liver damage in Hfe-/- mice (an established model of human HFE-hemochromatosis). Methods: Wild-type, Nrf2-/-, Hfe-/- and double knockout (Hfe/Nrf2-/-) female mice on C57BL/6 genetic background were sacrificed at the age of 6 (young), 12–18 (middle-aged) or 24 months (old) for evaluation of liver pathology. Results: Despite the parenchymal iron accumulation, Hfe-/- mice presented no liver injury. The combination of iron overload (Hfe-/-) and defective antioxidant defences (Nrf2-/-) increased the number of iron-related necroinflammatory lesions (sideronecrosis), possibly due to the accumulation of toxic oxidation products such as 4-hydroxy-2-nonenal-protein adducts. The engulfment of dead hepatocytes led to a gradual accumulation of iron within macrophages, featuring large aggregates. Myofibroblasts recruited towards the injury areas produced substantial amounts of collagen fibers involving the liver parenchyma of double-knockout animals with increased hepatic fibrosis in an age-dependent manner. Conclusions: The genetic disruption of Nrf2 promotes the transition from iron accumulation (siderosis) to liver injury in Hfe-/- mice, representing the first demonstration of spontaneous hepatic fibrosis in the long term in a mouse model of hereditary hemochromatosis displaying mildly elevated liver iron. Keywords: Iron, Hepatocyte, Macrophage, Sideronecrosis, Oxidative stress |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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