Inhibition of LXRα signaling by vitamin D receptor: Possible role of VDR in bile acid synthesis

The expression of cholesterol 7α-hydroxylase (CYP7α), the rate-limiting enzyme in the catabolism of cholesterol to bile acid, is stimulated by oxysterol receptor, liver X receptor α (LXRα) and negatively regulated by a bile acid receptor, farnesoid X receptor. In the current study, we demonstrated that 1,25-(OH)2D3 blunted the LXRα-mediated induction of CYP7α mRNA in H4IIE rat hepatoma cells. In co-transfection experiments in HepG2 cells, VDR repressed the activity of rat CYP7α promoter in a ligand-dependent manner through inhibition of LXRα signaling. We also confirmed the ability of VDR to repress LXRα transcriptional activation using a synthetic LXRα 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)2D3, the crosstalk between LXRα 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.