ArticleHepatology (Baltimore, Md.)2009
Nuclear factor erythroid 2-related factor 2 is a positive regulator of human bile salt export pump expression.
Article in Hepatology (Baltimore, Md.), 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 73 citations in OpenAlex.
- Advances and Challenges in Modeling Cannabidiol Pharmacokinetics and Hepatotoxicity.Drug metabolism and disposition: the biological fate of chemicals · 2024Review
- Role and Regulation of Hepatobiliary ATP-Binding Cassette Transporters during Chemical-Induced Liver Injury.Drug metabolism and disposition: the biological fate of chemicals · 2022Review
- Farnesoid X receptor contributes to oleanolic acid-induced cholestatic liver injury in mice.Journal of applied toxicology : JAT · 2022Article
- Oltipraz ameliorates the progression of steatohepatitis in Nrf2-null mice fed a high-fat diet.Journal of clinical biochemistry and nutrition · 2022Article
- The Bile Salt Export Pump: Molecular Structure, Study Models and Small-Molecule Drugs for the Treatment of Inherited BSEP Deficiencies.International journal of molecular sciences · 2021Review
- Effects of ablation and activation of Nrf2 on bile acid homeostasis in male mice.Toxicology and applied pharmacology · 2020Article
- The effect of ursodeoxycholic acid on the relative expression of the lipid metabolism genes in mouse cholesterol gallstone models.Lipids in health and disease · 2020Article
- Cholestatic liver disease results increased production of reactive aldehydes and an atypical periportal hepatic antioxidant response.Free radical biology & medicine · 2019Article
- A Change in Bile Flow: Looking Beyond Transporter Inhibition in the Development of Drug-induced Cholestasis.Current drug metabolism · 2019Review
- Mechanistic insights into geniposide regulation of bile salt export pump (BSEP) expression.RSC advances · 2018Article
- Role of NRF2 in protection of the gastrointestinal tract against oxidative stress.Journal of clinical biochemistry and nutrition · 2018Review
- Protection by the Total Flavonoids fromFoods (Basel, Switzerland) · 2018Article
- Post-hepatectomy liver regeneration in the context of bile acid homeostasis and the gut-liver signaling axis.Journal of clinical and translational research · 2018Article
- ABCMdb reloaded: updates on mutations in ATP binding cassette proteins.Database : the journal of biological databases and curation · 2017Article
- Cell-specific overactivation of nuclear erythroid 2 p45-related factor 2-mediated gene expression in myeloid cells decreases hepatic ischemia/reperfusion injury.Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society · 2016Article
- Estrogen and Estrogen Receptor-α-Mediated Transrepression of Bile Salt Export Pump.Molecular endocrinology (Baltimore, Md.) · 2015Article
- Transcriptional dynamics of bile salt export pump during pregnancy: mechanisms and implications in intrahepatic cholestasis of pregnancy.Hepatology (Baltimore, Md.) · 2014Article
- Clinical application of transcriptional activators of bile salt transporters.Molecular aspects of medicine · 2014Review
- Biosynthesis and trafficking of the bile salt export pump, BSEP: therapeutic implications of BSEP mutations.Molecular aspects of medicine · 2014Review
- The role of bile salt export pump gene repression in drug-induced cholestatic liver toxicity.Drug metabolism and disposition: the biological fate of chemicals · 2014Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
unlabelledThe 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.
conclusionNrf2 is a positive transcriptional regulator of human BSEP expression. Pharmacological activation of Nrf2 may be beneficial for cholestatic liver injury.
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