Please use this identifier to cite or link to this item: http://hdl.handle.net/10216/86226
Author(s): Tiago L. Duarte
Carolina Caldas
Ana G. Santos
Sandro Silva-Gomes
Andreia Santos-Gonçalves
Maria João Martins
Graça Porto
José Manuel Lopes
Title: Genetic disruption of NRF2 promotes the development of necroinflammation and liver fibrosis in a mouse model of HFE-hereditary hemochromatosis
Publisher: Elsevier
Issue Date: 2016-12
Abstract: 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 HFEhemochromatosis). 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.
Subject: Iron
Hepatocyte
Macrophage
Sideronecrosis
Oxidative stress
URI: http://hdl.handle.net/10216/86226
Series: Redox Biology; Vol. 11 p. 157-169
Document Type: Artigo em Revista Científica Internacional
Rights: openAccess
Appears in Collections:I3S - Artigo em Revista Científica Internacional



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