Nrf2 counteracts cholestatic liver injury via stimulation of hepatic defense systems

Kosuke Okada, Junichi Shoda, Keiko Taguchi, Jonathan M. Maher, Kaoru Ishizaki, Yoshimi Inoue, Makio Ohtsuki, Nobuharu Goto, Hirokazu Sugimoto, Hirotoshi Utsunomiy, Koji Oda, Eiji Warabi, Tetsuro Ishii, Masayuki Yamamoto

Research output: Contribution to journalArticlepeer-review

62 Citations (Scopus)

Abstract

The transcription factor Nrf2 is a key regulator for hepatic induction of detoxifying enzymes, antioxidative stress genes and Mrp efflux transporters. We aimed to investigate whether Nrf2 activation counteracts liver injury associated with cholestasis. The role of Nrf2 activation in counteracting cholestatic liver injury was studied using a bile duct-ligation (BDL) model of Keap1 gene-knockdown (Keap1-kd) mice that represent the sustained activation of Nrf2 in the liver. Upon Nrf2 activation, Keap1-kd mice showed large increases in Mrp efflux transporters, detoxifying enzymes and antioxidative stress genes in the livers. After BDL, the number of hepatic parenchymal necrosis and the reactive oxygen species content were significantly smaller in the livers of the Keap1-kd mice than in those of the WT mice. Moreover, the increase in serum bilirubin levels was attenuated in the Keap1-kd mice. In conclusion, the results suggest a hepatoprotective role of sustained Nrf2 activation against liver injury associated with cholestasis.

Original languageEnglish
Pages (from-to)431-436
Number of pages6
JournalBiochemical and biophysical research communications
Volume389
Issue number3
DOIs
Publication statusPublished - 2009 Nov

Keywords

  • Cytoprotection
  • Keap1 gene-knockdown mouse
  • Nrf2
  • Obstructive cholestasis
  • Oxidative stress
  • Transcription factor

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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