Bile acids: natural ligands for an orphan nuclear receptor.
Bile acids regulate the transcription of genes that control cholesterol homeostasis through molecular mechanisms that are poorly understood. Physiological concentrations of free and conjugated chenodeoxycholic acid, lithocholic acid, and deoxycholic acid activated the farnesoid X receptor (FXR; NR1H4), an orphan nuclear receptor. As ligands, these bile acids and their conjugates modulated interaction of FXR with a peptide derived from steroid receptor coactivator 1. These results provide evidence for a nuclear bile acid signaling pathway that may regulate cholesterol homeostasis.
Parks
D J
DJ
Department of Molecular Biochemistry, Glaxo Wellcome Research and Development, Research Triangle Park NC, 27709, USA.
Blanchard
S G
SG
Bledsoe
R K
RK
Chandra
G
G
Consler
T G
TG
Kliewer
S A
SA
Stimmel
J B
JB
Willson
T M
TM
Zavacki
A M
AM
Moore
D D
DD
Lehmann
J M
JM
D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002635:Chenodeoxycholic Acid / Q000378:metabolism* / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003840:Deoxycholic Acid / Q000378:metabolism / Q000494:pharmacology; D051548:Histone Acetyltransferases; D006706:Homeostasis; D006801:Humans; D008024:Ligands; D008095:Lithocholic Acid / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D056920:Nuclear Receptor Coactivator 1; D029363:Organic Anion Transporters, Sodium-Dependent; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D027981:Symporters; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D002352:Carrier Proteins; D002635:Chenodeoxycholic Acid; D002784:Cholesterol; D004268:DNA-Binding Proteins; D003840:Deoxycholic Acid; D051548:Histone Acetyltransferases; D008024:Ligands; D008095:Lithocholic Acid; D056920:Nuclear Receptor Coactivator 1; D029363:Organic Anion Transporters, Sodium-Dependent; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D027981:Symporters; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C071908:sodium-bile acid cotransporter; C538859:NCOA1 protein, human; C538861:Ncoa1 protein, mouse