Identification of intermediates in the bile acid synthetic pathway as ligands for the farnesoid X receptor
| Autor: | Tomofumi Fujino, Norimasa Tamehiro, Tomoko Nishimaki-Mogami, Koichi Shudo, Mizuho Une, Yosuke Kawahara, Kazuhide Inoue, Yoji Sato |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
medicine.drug_class
bile alcohol Receptors Cytoplasmic and Nuclear QD415-436 Biology bile acid export pump Cholesterol 7 alpha-hydroxylase Ligands Biochemistry Bile Acids and Salts chemistry.chemical_compound small heterodimer partner Endocrinology Chenodeoxycholic acid CYP27A1 Fluorescence Polarization Immunoassay medicine Humans cholesterol 7α-hydroxylase Bile acid Cell Biology Surface Plasmon Resonance Bile Salt Export Pump G protein-coupled bile acid receptor DNA-Binding Proteins chemistry Farnesoid X receptor CYP8B1 liver X receptor Transcription Factors |
| Zdroj: | Journal of Lipid Research, Vol 45, Iss 8, Pp 1538-1545 (2004) |
| ISSN: | 0022-2275 |
| Popis: | Bile acid synthesis from cholesterol is tightly regulated via a feedback mechanism mediated by the farnesoid X receptor (FXR), a nuclear receptor activated by bile acids. Synthesis via the classic pathway is initiated by a series of cholesterol ring modifications and followed by the side chain cleavage. Several intermediates accumulate or are excreted as end products of the pathway in diseases involving defective bile acid biosynthesis. In this study, we investigated the ability of these intermediates to activate human FXR. In a cell-based reporter assay and coactivator recruitment assays in vitro, early intermediates possessing an intact cholesterol side chain were inactive, whereas 26- or 25-hydroxylated bile alcohols and C27 bile acids were highly efficacious ligands for FXR at a level comparable to that of the most potent physiological ligand, chenodeoxycholic acid. Treatment of HepG2 cells with these precursors repressed the rate-limiting cholesterol 7alpha-hydroxylase mRNA level and induced the small heterodimer partner and the bile salt export pump mRNA, indicating the ability to regulate bile acid synthesis and excretion. Because 26-hydroxylated bile alcohols and C27 bile acids are known to be evolutionary precursors of bile acids in mammals, our findings suggest that human FXR may have retained affinity to these precursors during evolution. |
| Databáze: | OpenAIRE |
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