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LIVER AND BILIARY TRACT

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

¹Department of Gastroenterology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba; ²Graduate School of Comprehensive Human Sciences, Center for Tsukuba Advanced Research Alliance and Japan Science and Technology Agency Exploratory Research for Advanced Technology Environmental Response Project, University of Tsukuba, Tsukuba; ³Research Division, Mitsubishi Tanabe Pharma, Yokohama, Japan; ⁴Department of Strategic Surveillance for Functional Food and Comprehensive Traditional Medicine, Wakayama Medical University, Wakayama; ⁵Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya; ⁶Department of Molecular and Cellular Physiology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba; and ⁷Department of Anesthesiology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan

Submitted 2 May 2008 ; accepted in final form 6 August 2008

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.

multidrug resistance-associated proteins; Keap1 gene-knockdown mouse; Nrf2 gene-knockout mouse; transcription factor; bile acid

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