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

摘要: Background and AimsIn 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).MethodsWild-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.ResultsDespite the parenchymal iron …