Nuclear factor-E2-related factor 2 expression in liver is critical for induction of NAD(P)H:quinone oxidoreductase 1 during cholestasis

Lauren M. Aleksunes, Angela L. Slitt, Jonathan M. Maher, Matthew Z. Dieter, Tamara R. Knight, Michael Goedken, Nathan J. Cherrington, Jefferson Y. Chan, Curtis D. Klaassen, José E. Manautou

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Bile duct ligation (BDL) causes hepatocellular oxidative stress and injury. The transcription factor nuclear factor-E2-related factor (Nrf2) induces expression of numerous genes including NAD(P)H:quinone oxidoreductase 1 (Nqo1) during periods of oxidative stress. Therefore, we hypothesized that BDL increases liver expression of mouse antioxidant genes in an Nrf2-dependent manner. BDL or sham surgeries were performed on male C57BL/6, Nrf2-null, and wild-type mice. Livers were collected at 1, 3, and 7 days after surgery for analysis of messenger ribonucleic acid (mRNA) levels of Nrf2-responsive genes as well as Nqo1 protein and activity. BDL increased mRNA expression of multiple Nrf2 genes in mouse liver, compared to sham-operated controls. Follow-up studies investigating protein expression, enzyme activity, and Nrf2 dependency were limited to Nqo1. Nqo1 protein expression and activity in mouse livers was increased 2- to 3-, and 4- to 5-fold at 3 and 7 days after BDL, respectively. Studies also showed that BDL increases Nqo1 mRNA, protein expression, and enzyme activity in livers from wild-type mice, but not in Nrf2-null mice. In conclusion, expression of Nrf2-dependent genes is increased during cholestasis. These studies also demonstrate that Nqo1 expression and activity in mouse liver are induced via an Nrf2-dependent mechanism.

Original languageEnglish (US)
Pages (from-to)356-363
Number of pages8
JournalCell Stress and Chaperones
Volume11
Issue number4
DOIs
StatePublished - Dec 1 2006

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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    Aleksunes, L. M., Slitt, A. L., Maher, J. M., Dieter, M. Z., Knight, T. R., Goedken, M., Cherrington, N. J., Chan, J. Y., Klaassen, C. D., & Manautou, J. E. (2006). Nuclear factor-E2-related factor 2 expression in liver is critical for induction of NAD(P)H:quinone oxidoreductase 1 during cholestasis. Cell Stress and Chaperones, 11(4), 356-363. https://doi.org/10.1379/CSC-217.1