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

• Type: Article in International Scientific Journal
• Date: 2017-12-06

Authors

Lopes, JM (Author) FMUP

Journal

Title: Redox Biology

Vol. 11

Pages: 157-169

ISSN: 2213-2317

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 35 Citations

Scopus - 37 Citations

Other information

Authenticus ID: P-00M-8FF

DOI: 10.1016/j.redox.2016.11.013

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13