| Activation of nuclear factor (erythroid-2 like) factor 2 by toxic bile acids provokes adaptive defense responses to enhance cell survival at the emergence of oxidative stress. | |
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MedLine Citation:
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PMID: 17724089 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Oxidative stress, causing necrotic and apoptotic cell death, is associated with bile acid toxicity. Using liver (HepG2, Hepa1c1c7, and primary human hepatocytes) and intestinal (C2bbe1, a Caco-2 subclone) cells, we demonstrated that toxic bile acids, such as lithocholic acid (LCA) and chenodeoxycholic acid, induced the nuclear factor (erythroid-2 like) factor 2 (Nrf2) target genes, especially the rate-limiting enzyme in glutathione (GSH) biosynthesis [glutamate cysteine ligase modulatory subunit (GCLM) and glutamate cysteine ligase catalytic subunit (GCLC)] and thioredoxin reductase 1. Nrf2 activation and induction of Nrf2 target genes were also evident in vivo in the liver of CD-1 mice treated 7 to 8 h or 4 days with LCA. Silencing of Nrf2 via small-interfering RNA suppressed basal and bile acid-induced mRNA levels of the above-mentioned genes. Consistent with this, overexpression of Nrf2 enhanced, but dominant-negative Nrf2 attenuated, Nrf2 target gene induction by bile acids. The activation of Nrf2-antioxidant responsive element (ARE) transcription machinery by bile acids was confirmed by increased nuclear accumulation of Nrf2, enhanced ARE-reporter activity, and increased Nrf2 binding to ARE. It is noteworthy that Nrf2 silencing increased cell susceptibility to LCA toxicity, as evidenced by reduced cell viability and increased necrosis and apoptosis. Concomitant with GCLC/GCLM induction, cellular GSH was significantly increased in bile acid-treated cells. Cotreatment with N-acetyl-l-cysteine, a GSH precursor, ameliorated LCA toxicity, whereas cotreatment with buthionine sulfoximine, a GSH synthesis blocker, exacerbated it. In summary, this study provides molecular evidence linking bile acid toxicity to oxidative stress. Nrf2 is centrally involved in counteracting such oxidative stress by enhancing adaptive antioxidative response, particularly GSH biosynthesis, and hence cell survival. |
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Authors:
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Kah Poh Tan; Mingdong Yang; Shinya Ito |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2007-08-27 |
Journal Detail:
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Title: Molecular pharmacology Volume: 72 ISSN: 0026-895X ISO Abbreviation: Mol. Pharmacol. Publication Date: 2007 Nov |
Date Detail:
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Created Date: 2007-10-24 Completed Date: 2007-12-13 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0035623 Medline TA: Mol Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 1380-90 Citation Subset: IM |
Affiliation:
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Division of Clinical Pharmacology and Toxicology, Department of Pediatrics, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bile Acids and Salts / toxicity* Cell Line Cell Survival Chenodeoxycholic Acid / toxicity Cytoprotection / genetics Gene Expression Glutamate-Cysteine Ligase / genetics Glutathione / biosynthesis* Humans Lithocholic Acid / toxicity Mice Mice, Mutant Strains NF-E2-Related Factor 2 / genetics, physiology* Oxidative Stress* |
| Chemical | |
Reg. No./Substance:
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0/Bile Acids and Salts; 0/NF-E2-Related Factor 2; 434-13-9/Lithocholic Acid; 474-25-9/Chenodeoxycholic Acid; 70-18-8/Glutathione; EC 6.3.2.2/Glutamate-Cysteine Ligase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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