Dehydroepiandrosterone sulfotransferase gene induction by bile acid activated farnesoid X receptor.
Dehydroepiandrosterone sulfotransferase (STD) is a hydroxysteroid sulfo-conjugating enzyme with preferential substrate specificity for C-19 androgenic steroids and C-24 bile acids. STD is primarily expressed in the liver, intestine and adrenal cortex. Earlier studies have shown that androgens inhibit 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. Chem. 273, 21856-21866). Here we report that the primary bile acid chenodeoxycholic acid (CDCA) also acts as an important regulator of the Std gene promoter. 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 recently characterized member of the nuclear receptor superfamily. The ligand-activated FXR acts as a heterodimer with the 9-cis-retinoic acid receptor (RXR) and regulates the Std gene by binding to an upstream region at base pair positions -169 to -193. This specific binding region was initially identified 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 protein-DNA interaction using in vitro footprinting and electrophoretic mobility shift analyses. Unlike all other previously characterized FXR target genes, which contain an inverted repeat (IR) of the consensus hexanucleotide half-site (A/G)G(G/T)TCA with a single nucleotide spacer (IR-1), the bile acid response element of the Std promoter does not contain any spacer between the two hexanucleotide repeats (IR-0). A promoter-reporter construct carrying 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 in transfected Caco-2 cells upon CDCA treatment. Autoregulation of the STD gene by its bile acid substrate may provide an important contributing role in the enterohepatic bile acid metabolism and cholesterol homeostasis.
Song
C S
CS
Department of Cellular and Structural Biology, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, Texas 78229, USA.
Echchgadda
I
I
Baek
B S
BS
Ahn
S C
SC
Oh
T
T
Roy
A K
AK
Chatterjee
B
B
D001647:Bile Acids and Salts / Q000494:pharmacology*; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000502:physiology*; D019281:Dimerization; D015971:Gene Expression Regulation, Enzymologic; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000502:physiology; D047488:Retinoid X Receptors; D015238:Sulfotransferases / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D015238:Sulfotransferases; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C019998:dehydroepiandrosterone sulfotransferase