Genetic disruption of NRF2 promotes the development of necroinflammation and liver fibrosis in a mouse model of HFE-hereditary hemochromatosis
Tiago L. Duarte,
Carolina Caldas,
Ana G. Santos,
Sandro Silva-Gomes,
Andreia Santos-Gonçalves,
Maria João Martins,
Graça Porto,
José Manuel Lopes
Affiliations
Tiago L. Duarte
Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Basic & Clinical Research on Iron Biology, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal; Correspondence to: Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
Carolina Caldas
Iron and Innate Immunity Group, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
Ana G. Santos
Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Basic & Clinical Research on Iron Biology, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
Sandro Silva-Gomes
Iron and Innate Immunity Group, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
Andreia Santos-Gonçalves
Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Basic & Clinical Research on Iron Biology, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
Maria João Martins
Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Department of Biomedicine, Unit of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal
Graça Porto
Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Basic & Clinical Research on Iron Biology, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal; Centro Hospitalar do Porto-Hospital Santo António, Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
José Manuel Lopes
Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto, Portugal; Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal; Centro Hospitalar de São João, Porto, Portugal
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
