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Title: Nuclear factor-E2-related factor 2 is a major determinant of bile acid homeostasis in the liver and intestine
Authors: Jittima Weerachayaphorn
Albert Mennone
Carol J. Soroka
Kathy Harry
Lee R. Hagey
Thomas W. Kensler
James L. Boyer
Yale University
Mahidol University
University of California, San Diego, School of Medicine
Johns Hopkins Bloomberg School of Public Health
Keywords: Biochemistry, Genetics and Molecular Biology;Medicine
Issue Date: 1-May-2012
Citation: American Journal of Physiology - Gastrointestinal and Liver Physiology. Vol.302, No.9 (2012)
Abstract: 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 sodiu m-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. © 2012 the American Physiological Society.
ISSN: 15221547
Appears in Collections:Scopus 2011-2015

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