Nrf1 Deficient Mice as a Model for Liver Cancer and Non-Alcoholic Steatohepatitis
Background: Antioxidant and xenobiotic metabolizing enzymes are critical in the protection against chemically induced oxidative/electrophilic stress in cells that cause damage, DNA mutation, apoptosis, and cancer. Transcription of these cytoprotective genes and xenobiotic metabolizing genes is regulated through cis-active sequences known as antioxidant response elements (ARE). Coordinated induction of these genes mediated through the ARE is regulated by a signal transduction system that is still in the process of being fully characterized. Regulation of ARE function is mediated by various basic leucine zipper transcription factors including members of the 'cap n collar' (CNC-bZIP)
Nrf1 is a CNC-bZIP protein that regulates the expression of ARE. Previous attempts at developing viable Nrf1 deficient mice were unsuccessful since the Nrf1 gene is necessary for embryonic development.
Technology: University of California-Irvine researchers have developed a Cre-lox mouse model that has a conditional mutation of the Nrf1 gene. Researchers have found that deficiency of the Nrf1 gene in liver results hepatic cell death, proliferation, fat accumulation, oxidative stress, and inflammation, followed by the appearance of dysplastic cells and ultimately cancer. The changes observed closely mimics the features of non-alcoholic steatohepatitis (NASH). NASH is recognized as one of the risk factors for liver cancer and a precise understanding of the pathogenesis of NASH is lacking. Application: This Nrf1 deficient mouse model may be used to further delineate the molecular and cellular mechanisms of liver carcinogenesis and NASH. These mice may also be used to screen for liver cancer therapeutics.
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