Inhibition of LXRalpha signaling by vitamin D receptor: possible role of VDR in bile acid synthesis.

The expression of cholesterol 7alpha-hydroxylase (CYP7alpha), the rate-limiting enzyme in the catabolism of cholesterol to bile acid, is stimulated by oxysterol receptor, liver X receptor alpha (LXRalpha) 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 LXRalpha-mediated induction of CYP7alpha mRNA in H4IIE rat hepatoma cells. In co-transfection experiments in HepG2 cells, VDR repressed the activity of rat CYP7alpha promoter in a ligand-dependent manner through inhibition of LXRalpha signaling. We also confirmed the ability of VDR to repress LXRalpha transcriptional activation using a synthetic LXRalpha 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 LXRalpha 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.

Inhibition of peroxisome proliferator-activated receptor alpha signaling by vitamin D receptor.

Peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors that have been implicated to play an important role in lipid and glucose homeostasis. PPARalpha potentiates fatty acid catabolism in the liver and is activated by the lipid-lowering fibrates, whereas PPARgamma is essential for adipocyte differentiation. Here we report that nuclear vitamin D(3) receptor (VDR) represses the transcriptional activity of PPARalpha but not PPARgamma in a 1,25(OH)(2)D(3)-dependent manner. The analysis using chimeric receptors revealed that ligand binding domain of PPARalpha and VDR was involved in the molecular basis of this functional interaction and that the DNA binding domain of VDR was not required for the suppression, suggesting a novel mechanism that might involve protein-protein interactions rather than a direct DNA binding. Furthermore, the treatment of rat hepatoma H4IIE cells with 1,25(OH)(2)D(3) diminishes the induction of AOX mRNA by PPARalpha ligands, Wy14,643. VDR signaling might be considered as a factor regulating lipid metabolism via PPARalpha pathway. We report here the novel action of VDR in controlling gene expression through PPARalpha signaling.