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

Cell Stress Chaperones. Winter 2006;11(4):356-63. doi: 10.1379/csc-217.1.

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 Nqol 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase / metabolism
  • Animals
  • Bile Acids and Salts / metabolism
  • Bile Ducts / surgery
  • Cholestasis / enzymology*
  • Cholestasis / metabolism
  • Glutathione Transferase / metabolism
  • Heme Oxygenase-1 / metabolism
  • Liver / enzymology
  • Liver / metabolism*
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NAD(P)H Dehydrogenase (Quinone)
  • NADP / metabolism*
  • NADPH Dehydrogenase / metabolism*
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • RNA, Messenger / metabolism

Substances

  • Bile Acids and Salts
  • NF-E2-Related Factor 2
  • RNA, Messenger
  • NADP
  • Heme Oxygenase-1
  • NAD(P)H Dehydrogenase (Quinone)
  • Nqo1 protein, mouse
  • NADPH Dehydrogenase
  • Glutathione Transferase
  • Alanine Transaminase