Proteomic analysis of Nrf2 deficient transgenic mice reveals cellular defence and lipid metabolism as primary Nrf2-dependent pathways in the liver

Neil R. Kitteringham, Azman Abdullah, Joanne Walsh, Laura Randle, Rosalind E. Jenkins, Rowena Sison, Christopher E. P. Goldring, Helen Powell, Christopher Sanderson, Samantha Williams, Larry Higgins, Masayuki Yamamoto, John Hayes, B. Kevin Park

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    Abstract

    The transcription factor Nrf2 regulates expression of multiple cellular defence proteins through the antioxidant response element (ARE). Nrf2-deficient mice (Nrf2(-/-)) are highly susceptible to xenobiotic-mediated toxicity, but the precise molecular basis of enhanced toxicity is unknown. Oligonucleotide array studies suggest that a wide range of gene products is altered constitutively, however no equivalent proteomics analyses have been conducted. To define the range of Nrf2-regulated proteins at the constitutive level, protein expression profiling of livers from Nrf2(-/-) and wild type mice was conducted using both stable isotope labelling (iTRAQ) and gel electrophoresis methods. To establish a robust reproducible list of Nrf2-dependent proteins, three independent groups of mice were analysed. Correlative network analysis (MetaCore) identified two predominant groups of Nrf2-regulated proteins. As expected, one group comprised proteins involved in phase II drug metabolism, which were down-regulated in the absence of Nrf2. Surprisingly, the most profound changes were observed amongst proteins involved in the synthesis and metabolism of fatty acids and other lipids. Importantly, we show here for the first time, that the enzyme ATP-citrate lyase, responsible for acetyl-CoA production, is negatively regulated by Nrf2. This latter finding suggests that Nrf2 is a major regulator of cellular lipid disposition in the liver. (C) 2010 Elsevier B.V. All rights reserved.

    Original languageEnglish
    Pages (from-to)1612-1631
    Number of pages20
    JournalJournal of Proteomics
    Volume73
    Issue number8
    DOIs
    Publication statusPublished - 16 Jun 2010

    Keywords

    • Nrf2
    • Transgenic
    • Liver
    • Protein expression
    • iTRAQ
    • Lipid metabolism
    • GAMMA-GLUTAMYLCYSTEINE SYNTHETASE
    • ANTIOXIDANT RESPONSIVE ELEMENT
    • TRANSCRIPTION FACTOR NRF2
    • CONTROLLING INDUCIBLE EXPRESSION
    • SUBUNIT GENE-EXPRESSION
    • HEME OXYGENASE-1 GENE
    • HIGH-FAT DIET
    • OXIDATIVE STRESS
    • MOUSE-LIVER
    • OLIGONUCLEOTIDE MICROARRAY

    Cite this

    Kitteringham, N. R., Abdullah, A., Walsh, J., Randle, L., Jenkins, R. E., Sison, R., Goldring, C. E. P., Powell, H., Sanderson, C., Williams, S., Higgins, L., Yamamoto, M., Hayes, J., & Park, B. K. (2010). Proteomic analysis of Nrf2 deficient transgenic mice reveals cellular defence and lipid metabolism as primary Nrf2-dependent pathways in the liver. Journal of Proteomics, 73(8), 1612-1631. https://doi.org/10.1016/j.jprot.2010.03.018