Dehydroepiandrosterone sulfotransferase gene induction by bile acid activated farnesoid X receptor

Dehydroepiandrosterone sulfotransferase (STD) is a hydroxysteroid sulfo-con jugating enzyme with preferential substrate specificity for C-19 androgenic steroids and C-24 bile acids. STD is primarily expressed in the liver, int estine and adrenal cortex. Earlier studies have shown that androgens inhibi t the rat Std promoter function through a negative androgen response region located between -235 and -310 base pair positions (Song, C. S., Jung, M. H ., Kim, S. C., Hassan, T., Roy, A. K., and Chatterjee, B. (1998) J. Biol Ch em. 273, 21856-21866). Here we report that the primary bile acid chenodeoxy cholic acid (CDCA) also acts as an important regulator of the Std gene prom oter. CDCA is a potent inducer of the Std gene, and its inducing effect is mediated through the bile acid-activated farnesoid X receptor (FXR), a rece ntly characterized member of the nuclear receptor superfamily. The ligand-a ctivated FXR acts as a heterodimer with the 9-cis-retinoic acid receptor (R XR) and regulates the Std gene by binding to an upstream region at base pai r positions -169 to -193. This specific binding region was initially identi fied by bile acid responsiveness of the progressively deleted forms of the Std promoter in transfected HepG2 hepatoma and enterocyte-like Caco-2 cells . Subsequently, the precise RXR/FXR binding position was established by pro tein-DNA interaction using in vitro footprinting and electrophoretic mobili ty shift analyses. Unlike all other previously characterized FXR target gen es, which contain an inverted repeat (IR) of the consensus hexanucleotide h alf-site (A/G)G(G/T)TCA with a single nucleotide spacer (IR-1), the bile ac id response element of the Std promoter does not contain any spacer between the two hexanucleotide repeats (IR-0). A promoter-reporter construct carry ing three tandem copies of the IR-0 containing -169/-193 element, linked to a minimal thymidine kinase promoter, can be stimulated more than 70-fold i n transfected Caco-2 cells upon CDCA treatment. Autoregulation of the STD g ene by its bile acid substrate may provide an important contributing role i n the enterohepatic bile acid metabolism and cholesterol homeostasis.