Ursodeoxycholic acid stimulates Nrf2-mediated hepatocellular transport, detoxification, and antioxidative stress systems in mice
- 1 October 2008
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Gastrointestinal and Liver Physiology
- Vol. 295 (4), G735-G747
- https://doi.org/10.1152/ajpgi.90321.2008
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.Keywords
This publication has 41 references indexed in Scilit:
- Induction of Mrp3 and Mrp4 transporters during acetaminophen hepatotoxicity is dependent on Nrf2Toxicology and Applied Pharmacology, 2008
- Bezafibrate induces multidrug‐resistance P‐Glycoprotein 3 expression in cultured human hepatocytes and humanized livers of chimeric miceHepatology Research, 2007
- Inchinkoto, a herbal medicine, and its ingredients dually exert Mrp2/MRP2-mediated choleresis and Nrf2-mediated antioxidative action in rat liversAmerican Journal of Physiology-Gastrointestinal and Liver Physiology, 2007
- Mice lacking Mrp3 (Abcc3) have normal bile salt transport, but altered hepatic transport of endogenous glucuronidesJournal of Hepatology, 2006
- Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicityBiochemical and Biophysical Research Communications, 2006
- Complementary Stimulation of Hepatobiliary Transport and Detoxification Systems by Rifampicin and Ursodeoxycholic Acid in HumansGastroenterology, 2005
- CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in miceJournal of Hepatology, 2005
- Ursodeoxycholic acid protects against secondary biliary cirrhosis in rats by preventing mitochondrial oxidative stressJournal of Hepatology, 2004
- Ursodeoxycholic acid for primary biliary cirrhosis: lessons from the pastissues for the futureJournal of Hepatology, 2000
- Ursodeoxycholic Acid Protects Hepatocytes against Oxidative Injury via Induction of AntioxidantsBiochemical and Biophysical Research Communications, 1999