| Nuclear factor-E2-related factor 2 is a major determinant of bile acid homeostasis in the liver and intestine. | |
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MedLine Citation:
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PMID: 22345550 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The transcription factor nuclear factor-E2-related factor 2 (Nrf2) is a key regulator for induction of hepatic detoxification and antioxidant mechanisms, as well as for certain hepatobiliary transporters. To examine the role of Nrf2 in bile acid homeostasis and cholestasis, we assessed the determinants of bile secretion and bile acid synthesis and transport before and after bile duct ligation (BDL) in Nrf2(-/-) mice. Our findings indicate reduced rates of biliary bile acid and GSH excretion, higher levels of intrahepatic bile acids, and decreased expression of regulators of bile acid synthesis, Cyp7a1 and Cyp8b1, in Nrf2(-/-) compared with wild-type control mice. The mRNA expression of the bile acid transporters bile salt export pump (Bsep) and organic solute transporter (Ostα) were increased in the face of impaired expression of the multidrug resistance-associated proteins Mrp3 and Mrp4. Deletion of Nrf2 also decreased ileal apical sodium-dependent bile acid transporter (Asbt) expression, leading to reduced bile acid reabsorption and increased loss of bile acid in feces. Finally, when cholestasis is induced by BDL, liver injury was not different from that in wild-type BDL mice. These Nrf2(-/-) mice also had increased pregnane X receptor (Pxr) and Cyp3a11 mRNA expression in association with enhanced hepatic bile acid hydroxylation. In conclusion, this study finds that Nrf2 plays a major role in the regulation of bile acid homeostasis in the liver and intestine. Deletion of Nrf2 results in a cholestatic phenotype but does not augment liver injury following BDL. |
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Authors:
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Jittima Weerachayaphorn; Albert Mennone; Carol J Soroka; Kathy Harry; Lee R Hagey; Thomas W Kensler; James L Boyer |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2012-02-16 |
Journal Detail:
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Title: American journal of physiology. Gastrointestinal and liver physiology Volume: 302 ISSN: 1522-1547 ISO Abbreviation: Am. J. Physiol. Gastrointest. Liver Physiol. Publication Date: 2012 May |
Date Detail:
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Created Date: 2012-05-02 Completed Date: 2012-06-25 Revised Date: 2013-05-02 |
Medline Journal Info:
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Nlm Unique ID: 100901227 Medline TA: Am J Physiol Gastrointest Liver Physiol Country: United States |
Other Details:
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Languages: eng Pagination: G925-36 Citation Subset: IM |
Affiliation:
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Department of Internal Medicine, Liver Center, Yale University, School of Medicine, New Haven, Connecticut 06519-8019, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bile Acids and Salts / secretion* Cholestasis / metabolism* Homeostasis* Intestines / metabolism* Liver / metabolism* Male Mice Mice, Inbred C57BL Mice, Knockout NF-E2-Related Factor 2 / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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P30 DK-34989/DK/NIDDK NIH HHS; R01 CA094076/CA/NCI NIH HHS; R37 DK-25636/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Bile Acids and Salts; 0/NF-E2-Related Factor 2 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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