Vitamin D receptor as an intestinal bile acid sensor.
The vitamin D receptor (VDR) mediates the effects of the calcemic hormone 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3]. We show that VDR also functions as a receptor for the secondary bile acid lithocholic acid (LCA), which is hepatotoxic and a potential enteric carcinogen. VDR is an order of magnitude more sensitive to LCA and its metabolites than are other nuclear receptors. Activation of VDR by LCA or vitamin D induced expression in vivo of CYP3A, a cytochrome P450 enzyme that detoxifies LCA in the liver and intestine. These studies offer a mechanism that may explain the proposed protective effects of vitamin D and its receptor against colon cancer.
Makishima
Makoto
M
Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9050, USA.
Lu
Timothy T
TT
Xie
Wen
W
Whitfield
G Kerr
GK
Domoto
Hideharu
H
Evans
Ronald M
RM
Haussler
Mark R
MR
Mangelsdorf
David J
DJ
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001667:Binding, Competitive; D019556:COS Cells; D002460:Cell Line; D003110:Colonic Neoplasms / Q000517:prevention & control; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D015971:Gene Expression Regulation, Enzymologic; D051548:Histone Acetyltransferases; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism*; D008024:Ligands; D008095:Lithocholic Acid / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D056920:Nuclear Receptor Coactivator 1; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic; D051381:Rats; D018167:Receptors, Calcitriol / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D000099150:Receptor, Farnesoid X-Activated
D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D008024:Ligands; D008095:Lithocholic Acid; D056920:Nuclear Receptor Coactivator 1; D010089:Oxidoreductases, N-Demethylating; D000077297:Pregnane X Receptor; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C455860:3-ketolithocholic acid; C538859:NCOA1 protein, human; C538861:Ncoa1 protein, mouse