Biochemical and Biophysical Research Communications, Vol.351, No.1, 176-184, 2006
Inhibition of LXR alpha signaling by vitamin D receptor: Possible role of VDR in bile acid synthesis
The expression of cholesterol 7 alpha-hydroxylase (CYP7 alpha), the rate-limiting enzyme in the catabolism of cholesterol to bile acid, is stimulated by oxysterol receptor, liver X receptor alpha (LXR alpha) and negatively regulated by a bile acid receptor, farnesoid X receptor. In the current study, we demonstrated that 1,25-(OH)(2)D3 blunted the LXR alpha-mediated induction of CYP7a mRNA in H4IIE rat hepatoma cells. In co-transfection experiments in HepG2 cells, VDR repressed the activity of rat CYP7a promoter in a ligand-dependent manner through inhibition of LXR alpha signaling. We also confirmed the ability of VDR to repress LXR alpha transcriptional activation using a synthetic LXR alpha responsive reporter. Deletion analyses revealed that the ligand-binding domain of VDR was required for the suppression and the DNA-binding domain was dispensable. Given the fact that VDR can be activated by the secondary bile acid as well as 1,25(OH)(2)D3, the crosstalk between LXR alpha and VDR signaling in regulation of bile acid metabolism provides a possible contribution of VDR to modulate bile acid and cholesterol homeostasis, and highlights a physiological function of VDR beyond calcium metabolism in the body. (c) 2006 Elsevier Inc. All rights reserved.