Ursodeoxycholic acid stimulates Nrf2-mediated hepatocellular transport, detoxification, and antioxidative stress systems in mice

Kosuke Okada, Junichi Shoda, Keiko Taguchi, Jonathan M. Maher, Kaoru Ishizaki, Yoshimi Inoue, Makio Ohtsuki, Nobuharu Goto, Koichi Takeda, Hirotoshi Utsunomiya, Koji Oda, Eiji Warabi, Tetsuro Ishii, Keiko Osaka, Ichinosuke Hyodo, Masayuki Yamamoto

Research output: Contribution to journalArticlepeer-review

99 Citations (Scopus)

Abstract

The protective action of ursodeoxycholic acid (UDCA) in cholestatic liver diseases may be mediated by choleresis, detoxification, and cytoprotection against oxidative stress. Nrf2, one transcription factor, serves as a cellular stress sensor and is a key regulator for hepatic induction of detoxifying enzymes, antioxidative stress genes, and numerous Mrp family members. We aimed to investigate whether UDCA induces hepatic Mrp expression along with that of detoxifying enzymes and antioxidative stress genes via the Nrf2 transcriptional pathway. The protein level, subcellular localization, and mRNA level of Mrp family members were assessed in livers of Keap1 gene-knockdown (Keap1-kd) mice and those of UDCA-fed wild-type (WT) and Nrf2 gene-null (Nrf2-null) mice. Nuclear levels of Nrf2 in livers of Keap1-kd mice markedly increased, resulting in constitutive activation of Nrf2. Keap1-kd mice have high-level expression of hepatic Mrp2, Mrp3, and Mrp4 relative to WT mice. UDCA potently increased nuclear Nrf2 expression level in livers of WT mice, and the treatment showed maximal hepatic induction of Mrp2, Mrp3, and Mrp4 in association with enhanced membranous localizations in an Nrf2-dependent manner. UDCA similarly increased nuclear Nrf2 expression level in rat hepatocytes. Chromatin immunoprecipitation assays using mouse hepatocytes revealed the binding of Nrf2 to antioxidant response elements in the promoter regions of Mrp2, Mrp3, and Mrp4. These findings demonstrate an important role of Nrf2 in the induction of Mrp family members in livers and suggest that a therapeutic mechanism of UDCA action is, via Nrf2 activation, a stimulation of detoxification and antioxidative stress systems, along with Mrp-mediated efflux transport.

Original languageEnglish
Pages (from-to)G735-G747
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume295
Issue number4
DOIs
Publication statusPublished - 2008 Oct 1
Externally publishedYes

Keywords

  • Bile acid
  • Keap1 gene-knockdown mouse
  • Multidrug resistance-associated proteins
  • Nrf2 gene-knockout mouse
  • Transcription factor

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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