Catabolites of cholesterol synthesis pathways and forskolin as activators of the farnesoid X-activated nuclear receptor

The nuclear receptors are a family of transcriptional mediators that, upon activation, bind DNA and regulate gene transcription. Among these receptors , the farnesoid X-activated receptor (FXR) has recently been identified as one activated by bile acids and farnesol. To investigate the potential of o ther sterols to activate FXR, as well as to examine relevant relationships among identified activators of FXR, the current study used a mammalian cell transcription assay to quantify and compare activation potential. In addit ion to the classical bile acids deoxycholate (DCA) and chenodeoxycholate (C DCA), FXR was shown to be transcriptionally active in the presence of the a ndrogen catabolites 5 alpha-androstan-3 alpha-ol-17-one (androsterone) and 5 beta-androstan-3 alpha-ol-17-one (etiocholanolone), as well as the sterol bronchodilatory drug forskolin. Conversely, cholesterol and several other key precursors to the androgens and bile acids were either not active or on ly slightly active. Furthermore, it was observed that the bile acid ursodeo xycholate (UDCA) could inhibit DCA and CDCA activation of FXR in a manner p arallel to its ability to antagonize DCA and CDCA induction of apoptosis. B y far, the most efficacious activator of FXR was forskolin. Interestingly, although it is classically viewed as an initiator of the adenylate cyclase/ protein kinase A (PKA) pathway, PKA inhibition did not inhibit forskolin's activation of FXR nor was cyclic AMP (cAMP) able to stimulate FXR-mediated transcription. These data would suggest that forskolin acts as a ligand for FXR rather than as a secondary activator of FXR and could have important i mplications with respect to its potential toxicity and pharmacological use, (C) 2000 Academic Press.