Article first published online: 7 JUL 2009
Copyright © 2009 American Association for the Study of Liver Diseases
Volume 50, Issue 5, pages 1588–1596, November 2009
How to Cite
Weerachayaphorn, J., Cai, S.-Y., Soroka, C. J. and Boyer, J. L. (2009), Nuclear factor erythroid 2–related factor 2 is a positive regulator of human bile salt export pump expression. Hepatology, 50: 1588–1596. doi: 10.1002/hep.23151
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Potential conflict of interest: Nothing to report.
- Issue published online: 29 OCT 2009
- Article first published online: 7 JUL 2009
- Accepted manuscript online: 7 JUL 2009 12:00AM EST
- Manuscript Accepted: 28 JUN 2009
- Manuscript Received: 9 FEB 2009
- National Institutes of Health. Grant Numbers: R37 DK 25636, P30 DK34989
The bile salt export pump (BSEP) is the major determinant of bile salt–dependent bile secretion, and its deficiency leads to cholestatic liver injury. BSEP/Bsep gene expression is regulated by the nuclear farnesoid X receptor. However, BSEP expression, though reduced, is retained in the livers of Fxr−/− mice, indicating that additional transcriptional factors may regulate its expression. Nuclear factor erythroid 2–related factor 2 (Nrf2) plays a major role in response to oxidative stress by binding to antioxidant-responsive elements that regulate many hepatic phase I and II enzymes as well as hepatic efflux transporters. Computer software analysis of human BSEP reveals two musculo-aponeurotic fibrosacroma (Maf) recognition elements (MAREs) from the sequence in the proximal promoter region where Nrf2 may bind. In this study, we assessed whether Nrf2 plays a role in human BSEP expression and if this might be mediated by MAREs. Oltipraz, a potent activator of Nrf2, increased BSEP messenger RNA expression by approximately seven-fold in HepG2 cells and protein by approximately 70% in human hepatocytes. Small interfering RNAs lowered NRF2 expression in HepG2 cells and prevented the up-regulation of BSEP by oltipraz. Human BSEP promoter activity was stimulated by Nrf2 in a dose-dependent manner in luciferase reporter assays. Mutations of the predicted MARE1, but not MARE2, abolished this Nrf2 transcriptional activation. Chromatin immunoprecipitation assays also demonstrated that Nrf2 specifically bound to MARE1, but not MARE2 regions in the BSEP promoter in HepG2 cells. Electrophoretic mobility shift assays further demonstrated direct binding of MARE1 in the BSEP promoter. Conclusion: Nrf2 is a positive transcriptional regulator of human BSEP expression. Pharmacological activation of Nrf2 may be beneficial for cholestatic liver injury. (HEPATOLOGY 2009.)