title: Ursodeoxycholic acid stimulates Nrf2-mediated hepatocellular transport, detoxification, and antioxidative stress systems in mice.
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.
authors.affiliation: Dept. of Gastroenterology, Graduate School of Comprehensive Human Sciences, Univ. of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Okada
authors.forename: Junichi
authors.initials: J
authors.lastname: Shoda
authors.forename: Keiko
authors.initials: K
authors.lastname: Taguchi
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Maher
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ishizaki
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Inoue
authors.forename: Makio
authors.initials: M
authors.lastname: Ohtsuki
authors.forename: Nobuharu
authors.initials: N
authors.lastname: Goto
authors.forename: Koichi
authors.initials: K
authors.lastname: Takeda
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Utsunomiya
authors.forename: Koji
authors.initials: K
authors.lastname: Oda
authors.forename: Eiji
authors.initials: E
authors.lastname: Warabi
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ishii
authors.forename: Keiko
authors.initials: K
authors.lastname: Osaka
authors.forename: Ichinosuke
authors.initials: I
authors.lastname: Hyodo
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000502:physiology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000502:physiology; D000072019:Kelch-Like ECH-Associated Protein 1; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D051267:NF-E2-Related Factor 2 / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D003598:Cytoskeletal Proteins; D000072019:Kelch-Like ECH-Associated Protein 1; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051267:NF-E2-Related Factor 2; D014580:Ursodeoxycholic Acid; C490549:Abcb11 protein, mouse; C117301:Keap1 protein, mouse; C495636:Nfe2l2 protein, mouse