Inhibition of peroxisome proliferator-activated receptor α signaling by vitamin D receptor

Abstract Peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors that have been implicated to play an important role in lipid and glucose homeostasis. PPARα potentiates fatty acid catabolism in the liver and is activated by the lipid-lowering fibrates, whereas PPARγ is essential for adipocyte differentiation. Here we report that nuclear vitamin D 3 receptor (VDR) represses the transcriptional activity of PPARα but not PPARγ in a 1,25(OH) 2 D 3 -dependent manner. The analysis using chimeric receptors revealed that ligand binding domain of PPARα 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 PPARα ligands, Wy14,643. VDR signaling might be considered as a factor regulating lipid metabolism via PPARα pathway. We report here the novel action of VDR in controlling gene expression through PPARα signaling.