Vitamin D Receptor As an Intestinal Bile Acid Sensor
Makoto Makishima(Howard Hughes Medical Institute), Timothy T. Lu(Howard Hughes Medical Institute), Wen Xie(Salk Institute for Biological Studies), G. Kerr Whitfield(University of Arizona), Hideharu Domoto(Howard Hughes Medical Institute), Ronald M. Evans(Salk Institute for Biological Studies), Mark R. Haussler(University of Arizona), David J. Mangelsdorf(Howard Hughes Medical Institute)
Cited by 1,154
Abstract
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.
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