Document Detail


Nuclear factor-E2-related factor 2 is a major determinant of bile acid homeostasis in the liver and intestine.
MedLine Citation:
PMID:  22345550     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Jittima Weerachayaphorn; Albert Mennone; Carol J Soroka; Kathy Harry; Lee R Hagey; Thomas W Kensler; James L Boyer
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-02-16
Journal Detail:
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:
Created Date:  2012-05-02     Completed Date:  2012-06-25     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  100901227     Medline TA:  Am J Physiol Gastrointest Liver Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  G925-36     Citation Subset:  IM    
Affiliation:
Department of Internal Medicine, Liver Center, Yale University, School of Medicine, New Haven, Connecticut 06519-8019, USA.
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MeSH Terms
Descriptor/Qualifier:
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:
P30 DK-34989/DK/NIDDK NIH HHS; P30 DK034989/DK/NIDDK NIH HHS; R01 CA094076/CA/NCI NIH HHS; R37 DK-25636/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Bile Acids and Salts; 0/NF-E2-Related Factor 2
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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