The short heterodimer partner receptor differentially modulates peroxisome proliferator-activated receptor α-mediated transcription from the peroxisome proliferator-response elements of the genes encoding the peroxisomal β-oxidation enzymes acyl-CoA oxidase and hydratase-dehydrogenase

The promoter regions of the genes encoding the first two enzymes of the peroxisomal P-oxidation pathway, acyl-CoA oxidase (AOx) and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (HD), contain transcriptional regulatory sequences termed peroxisome proliferator-response elements (PPRE) that are bound by the peroxisome proliferator-activated receptor alpha (PPAR alpha) and 9-cis-retinoic acid receptor (RXR alpha) heterodimeric complex, In this study, the role of the short heterodimer partner (SHP) receptor in modulating PPAR alpha -mediated gene transcription from the PPREs of the genes encoding AOx and I-ID was investigated both in vitro and in vivo. In vitro binding assays using glutathione-S-transferase-tagged chimeric receptors for PPAR alpha and SHP were used to verify the interaction between PPAR alpha and SHP. This interaction was unaffected by the presence of the peroxisome proliferator, Wy-14,643. SHP has been proposed to act as a negative regulator of nuclear hormone receptor activity, and SHP inhibited transcription by PPAR alpha /RXR alpha heterodimers From the AOx-PPRE. Surprisingly, SHP potentiated transcription by PPAR alpha /RXR alpha. heterodimers from the HD-PPRE. This is the first demonstration of positive transcriptional activity attributable to SHP. Together, these results suggest that SHP can modulate PPAR alpha /RXR alpha -mediated transcription in a response element-specific manner, (C) 2001 Elsevier Science Ireland Ltd, All rights reserved.