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

@article{citeulike:3392094, 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. 10.1152/ajpgi.90321.2008}, author = {Okada, Kosuke and Shoda, Junichi and Taguchi, Keiko and Maher, Jonathan M. and Ishizaki, Kaoru and Inoue, Yoshimi and Ohtsuki, Makio and Goto, Nobuharu and Takeda, Koichi and Utsunomiya, Hirotoshi and Oda, Koji and Warabi, Eiji and Ishii, Tetsuro and Osaka, Keiko and Hyodo, Ichinosuke and Yamamoto, Masayuki}, citeulike-article-id = {3392094}, citeulike-linkout-0 = {http://dx.doi.org/10.1152/ajpgi.90321.2008}, citeulike-linkout-1 = {http://ajpgi.physiology.org/cgi/content/abstract/295/4/G735}, day = {1}, doi = {10.1152/ajpgi.90321.2008}, journal = {Am J Physiol Gastrointest Liver Physiol}, keywords = {acid, antioxidatative\_stress, bile, detoxification, efflux, keap1nrf2, transcription\_factor, transporters}, month = {October}, number = {4}, pages = {G735--747}, posted-at = {2008-10-10 02:24:37}, priority = {3}, title = {Ursodeoxycholic acid stimulates Nrf2-mediated hepatocellular transport, detoxification, and antioxidative stress systems in mice}, url = {http://dx.doi.org/10.1152/ajpgi.90321.2008}, volume = {295}, year = {2008} }

TY - JOUR ID - citeulike:3392094 L3 - citeulike-article-id:3392094 N2 - 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. 10.1152/ajpgi.90321.2008 IS - 4 JF - Am J Physiol Gastrointest Liver Physiol EP - 747 TI - Ursodeoxycholic acid stimulates Nrf2-mediated hepatocellular transport, detoxification, and antioxidative stress systems in mice VL - 295 SP - G735 KW - acid KW - antioxidatative_stress KW - bile KW - detoxification KW - efflux KW - keap1nrf2 KW - transcription_factor KW - transporters AU - Okada, Kosuke AU - Shoda, Junichi AU - Taguchi, Keiko AU - Maher, Jonathan AU - Ishizaki, Kaoru AU - Inoue, Yoshimi AU - Ohtsuki, Makio AU - Goto, Nobuharu AU - Takeda, Koichi AU - Utsunomiya, Hirotoshi AU - Oda, Koji AU - Warabi, Eiji AU - Ishii, Tetsuro AU - Osaka, Keiko AU - Hyodo, Ichinosuke AU - Yamamoto, Masayuki PY - 2008/10/01/ UR - http://dx.doi.org/10.1152/ajpgi.90321.2008 ER -