PMID- 16675527
OWN - NLM
STAT- MEDLINE
DCOM- 20060921
LR  - 20181201
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 147
IP  - 9
DP  - 2006 Sep
TI  - The nuclear hormone receptor farnesoid X receptor (FXR) is activated by 
      androsterone.
PG  - 4025-33
AB  - 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 small heterodimer partner (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. Nuclear magnetic resonance 
      spectroscopy demonstrated the direct binding of androsterone to purified human 
      FXR (hFXR) ligand-binding domain (LBD) protein, resulting in the recruitment of 
      steroid receptor coactivator protein-1 (SRC-1) coactivator peptide. In HEK293 
      cells, androsterone activated gal4-mouse FXR-LBD and gal4-hFXR-LBD fusion 
      proteins, although in contrast to CDCA, androsterone activation was significantly 
      greater for the mouse FXR-LBD than for the hFXR-LBD. Site-directed mutagenesis of 
      the hFXR-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.
FAU - Wang, Shuguang
AU  - Wang S
AD  - Cardiovascular and Metabolic Disease Research, Wyeth Research, 500 Arcola Road, 
      Collegeville, Pennsylvania 19426, USA.
FAU - Lai, KehDih
AU  - Lai K
FAU - Moy, Franklin J
AU  - Moy FJ
FAU - Bhat, Anitha
AU  - Bhat A
FAU - Hartman, Helen B
AU  - Hartman HB
FAU - Evans, Mark J
AU  - Evans MJ
LA  - eng
PT  - Journal Article
DEP - 20060504
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (GAL4 protein, S cerevisiae)
RN  - 0 (Ligands)
RN  - 0 (Pregnenediones)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Saccharomyces cerevisiae Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (nuclear receptor subfamily 0, group B, member 2)
RN  - 0C5V0MRU6P (farnesoid X-activated receptor)
RN  - 0GEI24LG0J (Chenodeoxycholic Acid)
RN  - 3XMK78S47O (Testosterone)
RN  - A4PW148END (pregna-4,17-diene-3,16-dione)
RN  - C24W7J5D5R (Androsterone)
RN  - EC 2.3.1.48 (Histone Acetyltransferases)
RN  - EC 2.3.1.48 (NCOA1 protein, human)
RN  - EC 2.3.1.48 (Ncoa1 protein, mouse)
RN  - EC 2.3.1.48 (Nuclear Receptor Coactivator 1)
SB  - IM
CIN - Endocrinology. 2006 Sep;147(9):4022-4. PMID: 16912235
MH  - Amino Acid Sequence
MH  - Androsterone/metabolism/*pharmacology
MH  - Animals
MH  - Cell Line
MH  - Chenodeoxycholic Acid/pharmacology
MH  - Crystallization
MH  - DNA-Binding Proteins/chemistry/genetics/*physiology
MH  - Embryo, Mammalian
MH  - Gene Expression/drug effects
MH  - Hepatocytes/drug effects/metabolism
MH  - Histone Acetyltransferases
MH  - Humans
MH  - Kidney
MH  - Ligands
MH  - Magnetic Resonance Spectroscopy
MH  - Male
MH  - Mice
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - Nuclear Receptor Coactivator 1
MH  - Orchiectomy
MH  - Pregnenediones/pharmacology
MH  - Receptors, Cytoplasmic and Nuclear/genetics
MH  - Recombinant Fusion Proteins
MH  - Saccharomyces cerevisiae Proteins/genetics
MH  - Structure-Activity Relationship
MH  - Testosterone/metabolism
MH  - Transcription Factors/chemistry/genetics/metabolism/*physiology
EDAT- 2006/05/06 09:00
MHDA- 2006/09/22 09:00
CRDT- 2006/05/06 09:00
PHST- 2006/05/06 09:00 [pubmed]
PHST- 2006/09/22 09:00 [medline]
PHST- 2006/05/06 09:00 [entrez]
AID - en.2005-1485 [pii]
AID - 10.1210/en.2005-1485 [doi]
PST - ppublish
SO  - Endocrinology. 2006 Sep;147(9):4025-33. doi: 10.1210/en.2005-1485. Epub 2006 May 
      4.