The Farnesoid X Receptor Regulates Transcription Of 3 Beta-Hydroxysteroid Dehydrogenase Type 2 In Human Adrenal Cells

Recent studies have shown that the adrenal cortex expresses high levels of farnesoid X receptor (FXR), but its function remains unknown. Herein, using microarray technology, we tried to identify candidate FXR targeting genes in the adrenal glands. and showed that FXR regulated 3 beta-hydroxysteroid dehydrogenase type 2 (HSD3B2) expression in human adrenocortical cells. We further demonstrated that FXR stimulated HSD3B2 promoter activity and have defined the cis-element responsible for FXR regulation of HSD3B2 transcription. Transfection of H295R adrenocortical cells with FXR expression vector effectively increased FXR expression levels and additional treatment with chenodeoxycholic acid (COCA) caused a 25-fold increase in the mRNA for organic solute transporter alpha (OST alpha), a known FXR target gene. HSD3B2 mRNA levels also increased following CDCA treatment in a concentration-dependent manner. Cells transfected with a HSD3B2 promoter construct and FXR expression vector responded to CDCA with a 20-fold increase in reporter activity compared to control. Analysis of constructs containing sequential deletions of the HSD3B2 promoter suggested a putative regulatory element between -166 and -101. Mutation of an inverted repeat between -137 and -124 completely blocked CDCA/FXR induced reporter activity. Chromatin immuno precipitation assays further confirmed the presence of a FXR response element in the HSD3B2 promoter. In view of the emerging role of FXR agonists as therapeutic treatment of diabetes and certain liver diseases, the effects of such agonists on other FXR expressing tissues should be considered. Our findings suggest that in human adrenal cells, FXR increases transcription and expression of HSD3B2. Alterations in this enzyme would influence the capacity of the adrenal gland to produce corticosteroids. (c) 2008 Elsevier Ireland Ltd. All rights reserved.