Farnesoid X receptor regulation of adrenal cell steroidogenic enzyme expression

Abstract

Farnesoid X receptor (FXR, NR1H4), a member of the nuclear receptor superfamily, is expressed in a number of tissues including the liver, ovary and adrenal. In the liver, FXR regulates cholesterol and glucose homeostasis, but its function in the ovary and adrenal remains unknown. Herein, we tested the hypothesis that FXR regulates expression of the enzymes involved in steroid hormone biosynthesis. Human adrenocortical cells were transfected with FXR expression vectors and treated with the FXR ligand GW4064; followed by microarray analysis. Among the adrenal FXR target genes were the well established liver FXR target, OSTα as well as the steroid‐metabolizing enzyme, 3β‐hydroxysteroid dehydrogenase type II (HSD3B2). HSD3B2 promoter construct studies and quantitative real‐time RTPCR showed that FXR stimulates HSD3B2 transcriptional activity and mRNA levels. Sequential deletions and mutational analysis of the HSD3B2 promoter defined an inverted hormone response element repeat between −137 and −124 that was necessary for FXR‐induced reporter activity. Chromatin immunoprecipitation assay demonstrated the ability of FXR to bind this response element. Since HSD3B2 is critical for the production of both adrenal and ovarian steroid hormones, these results indicate a new and important role of FXR in the regulation of steroidogenesis in the ovary and adrenal.