Coactivation of the human vitamin D receptor by the peroxisome proliferator-activated receptor γ coactivator-1 α

The vitamin D Receptor (VDR) belongs to the superfamily of steroid/thyroid hormone receptors that is activated by 1 alpha, 25-dihydroxyvitamin D-3. Traditional targets for 1 alpha, 25-dihydroxyvitamin D-3 action include tissues involved in the maintenance of calcium homeostasis and bone development and remodeling. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha), a transcriptional coactivator that plays a role in mitochondrial biogenesis and energy metabolism, is predominantly expressed in kidney, heart, liver, and skeletal muscle. Because VDR and PGC-1 alpha display an overlapping pattern of expression, we investigated the possibility that PGC-1 alpha could serve as a coactivator for VDR. Transient cotransfection assays demonstrate that PGC-1 alpha augments ligand-dependent VDR transcription when either full-length VDR or Gal4 DNA binding domain-VDR-ligand binding domain chimeras were analyzed. Furthermore, mammalian two-hybrid assays, coimmunoprecipitation analyses, and biochemical coactivator recruitment assays demonstrate a ligand-dependent interaction between the two proteins both in cells and in vitro. The coactivation potential of PGC-1 alpha requires an intact AF-2 domain of VDR and the LXXLL motif in PGC-1 alpha. Taken together, these results indicate that PGC-1 alpha serves as a coactivator for VDR.