Genetic disruption of NRF2 promotes the development of necroinflammation and liver fibrosis in a mouse model of HFE-hereditary hemochromatosis

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 o...

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Detalles Bibliográficos
Autores principales: Duarte, Tiago L., Caldas, Carolina, Santos, Ana G., Silva-Gomes, Sandro, Santos-Gonçalves, Andreia, Martins, Maria João, Porto, Graça, Lopes, José Manuel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2016
Materias:
Research Paper
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5149069/
https://www.ncbi.nlm.nih.gov/pubmed/27936457
http://dx.doi.org/10.1016/j.redox.2016.11.013
Descripción
Sumario: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.

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