Human Bile Salt Export Pump Promoter Is Transactivated by the Farnesoid X Receptor/Bile Acid Receptor*

By M. Ananthanarayanan, N. Balasubramanian, M. Makishima, D. Mangelsdorf, F. Suchy. Journal of Biological Chemistry, 2001

776 citations recorded by the source corpus.

The bile salt excretory pump (BSEP, ABCb11) is critical for ATP-dependent transport of bile acids across the hepatocyte canalicular membrane and for generation of bile acid-dependent bile secretion. Recent studies have demonstrated that the expression of this transporter is sensitive to the flux of bile acids through the hepatocyte, possibly at the level of transcription of the BSEP gene. To determine the mechanisms underlying the regulation of BSEP by bile acids, the promoter of the BSEP gene was cloned. The sequence of the promoter contained an inverted repeat (IR)-1 element (5′-GGGACA T TGATCCT-3′) at base pairs −63/−50 consisting of two nuclear receptor half-sites organized as an inverted repeat and separated by a single nucleotide. This IR-1 element has been shown in several recent studies to serve as a binding site for the farnesoid X receptor (FXR), a nuclear receptor for bile acids. FXR activity requires heterodimerization with RXRα, and when bound by bile acids, the complex effectively regulates the transcription of several genes involved in bile acid homeostasis. Gel mobility shift assays demonstrated specific binding of FXR/RXRα heterodimers to the IR-1 element in the BSEP promoter. In HepG2 cells, co-transfection of FXR and RXRα is required to attain full transactivation of the BSEP promoter by bile acids. Two FXR transactivation-deficient mutants (an AF-2 deletion and a W469A point mutant) failed to transactivate, indicating that the effect of bile acids is FXR-dependent. Further, mutational analysis confirms that the FXR/RXRα heterodimer activates transcription through the IR-1 site in the human BSEP promoter. These results demonstrate a mechanism by which bile acids transcriptionally regulate the activity of the bile salt excretory pump, a critical component involved in the enterohepatic circulation of bile acids.

Subfields: Oncology, Pediatrics, Perinatology and Child Health, Surgery

View Paper: https://www.semanticscholar.org/paper/c7f8f6fc6954d47b67d64dc3fe905c790971e024

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In Oncology

1. C. Klaassen
2. Lauren M. Aleksunes
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1. Bart Staels
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Citations in the corpus

• Liver inflammation and fibrosis. (2017, background): “FXR signaling is also a potential target because it facilitates secretion of bile acids (126), resulting in decreased hepatic storage of triglycerides and fatty acid esters (Figure 1).”
• Bile Formation and Secretion (2013, neutral): “BCRP expression in hepatocytes can be induced by xeno-biotics sites, and aryl hydrocarbon receptor (AHR) and constitutive androstane receptor (CAR) response elements (58).”
• The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. (2002, background): “FXR stimulates the expression of genes involved in bile acid homeostasis, including the intestinal bile acid binding protein and the bile salt export pump (125, 126).”
• Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. (2004, neutral): “Specifically, FXR activation increases BSEP expression (230), FXR, PXR, and CAR activation increase MRP2 expression (231), LXR activation increases ABCG5 and”
• Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease (2011, neutral): “HEK293T cells were co-transfected with a reporter construct containing the responsive element for NF-κB (pGL3-2κB luc) and pcDNA or pcDNA-FXR or pcDNA-FXRW469A (ligand-binding domain mutant)”
• Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation (2010, background): “Inverted repeat response elements are essential for transactivation of the SLCO1B3 and ABCB11 promoters in response to bile acids (Ananthanarayanan et al., 2001; Jung et al., 2002a).”
• Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. (2003, background): “Specifically, FXR induces the expression of ATP-binding cassette (ABC) transporters bile salt export pump (BSEP; ABCB11; Sinal et al. 2000; Ananthanarayanan et al. 2001; Plass et al. 2002), multidrug resistance protein 3 (MDR3, ABCB4; B. Goodwin and S.A. Jones, unpubl.)”