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

Research output: Contribution to journalArticle

100 Citations (Scopus)

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.

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

Fingerprint

Lipid Metabolism
Liver
Proteomics
Transgenic Mice
Proteins
Metabolism
Toxicity
ATP Citrate (pro-S)-Lyase
Antioxidant Response Elements
Isotope Labeling
Lipids
Acetyl Coenzyme A
Xenobiotics
Electric network analysis
Oligonucleotide Array Sequence Analysis
Electrophoresis
Oligonucleotides
Isotopes
Labeling
Transcription Factors

Keywords

  • iTRAQ
  • Lipid metabolism
  • Liver
  • Nrf2
  • Protein expression
  • Transgenic

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics

Cite this

Proteomic analysis of Nrf2 deficient transgenic mice reveals cellular defence and lipid metabolism as primary Nrf2-dependent pathways in the liver. / Kitteringham, Neil R.; Abdullah, Azman; Walsh, Joanne; Randle, Laura; Jenkins, Rosalind E.; Sison, Rowena; Goldring, Christopher E P; Powell, Helen; Sanderson, Christopher; Williams, Samantha; Higgins, Larry; Yamamoto, Masayuki; Hayes, John; Park, B. Kevin.

In: Journal of Proteomics, Vol. 73, No. 8, 16.06.2010, p. 1612-1631.

Research output: Contribution to journalArticle

Kitteringham, NR, Abdullah, A, Walsh, J, Randle, L, Jenkins, RE, Sison, R, Goldring, CEP, Powell, H, Sanderson, C, Williams, S, Higgins, L, Yamamoto, M, Hayes, J & Park, BK 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, vol. 73, no. 8, pp. 1612-1631. https://doi.org/10.1016/j.jprot.2010.03.018
Kitteringham, Neil R. ; Abdullah, Azman ; Walsh, Joanne ; Randle, Laura ; Jenkins, Rosalind E. ; Sison, Rowena ; Goldring, Christopher E P ; Powell, Helen ; Sanderson, Christopher ; Williams, Samantha ; Higgins, Larry ; Yamamoto, Masayuki ; Hayes, John ; Park, B. Kevin. / Proteomic analysis of Nrf2 deficient transgenic mice reveals cellular defence and lipid metabolism as primary Nrf2-dependent pathways in the liver. In: Journal of Proteomics. 2010 ; Vol. 73, No. 8. pp. 1612-1631.
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