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Submitted on November 22, 2005
Accepted on April 24, 2006
Cardiovascular and Metabolic Disease Research (S.W., K.L., A.B., H.B.B., M.J.E.), Wyeth Research, Collegeville, PA 19426; Chemical and Screening Sciences (F.J.M.), Wyeth Research, Cambridge, MA, 02140
* To whom correspondence should be addressed. E-mail: Evansm{at}wyeth.com.
Farnesoid X receptor (FXR) uses bile acids as endogenous ligands. Here, we demonstrate that androsterone, a metabolic product of testosterone, is also an FXR ligand. Treatment of castrated male mice with androsterone induced expression of the FXR target gene SHP. In mouse AML-12 hepatocytes, chenodeoxycholic acid (CDCA) or androsterone induced SHP expression with a similar kinetic pattern. The FXR antagonist guggulsterone blocked the induction of SHP by androsterone in AML-12 cells. NMR spectroscopy demonstrated the direct binding of androsterone to purified human FXR ligand binding domain (LBD) protein, resulting in the recruitment of SRC-1 coactivator peptide. In 293 cells, androsterone activated gal4-mouse FXR-LBD and gal4-human FXR-LBD fusion proteins, although in contrast to CDCA, androsterone activation was significantly greater for the mouse FXR-LBD than for the human FXR-LBD. Site-directed mutagenesis of the human FXR-LBD defined amino acids Asn354 and Ser345 as critical for differential species sensitivity to CDCA and androsterone, respectively. Crystal structure studies suggest that the orientation of the steroid nucleus of bile acids within the binding pocket of FXR is reversed from all other nuclear hormone receptors. In support of this model, we show here that mutations M265I or R331H, residues predicted by crystal structure to interact with the carboxylic acid tail of CDCA but not with androsterone, altered CDCA activation but had no effect on androsterone activation. Activation of FXR by androsterone may provide an additional means for physiological or pharmacological modulation of FXR.
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