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

The promoter regions of the genes encoding the first two enzymes of the per oxisomal P-oxidation pathway, acyl-CoA oxidase (AOx) and enoyl-CoA hydratas e/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 modulat ing PPAR alpha -mediated gene transcription from the PPREs of the genes enc oding AOx and I-ID was investigated both in vitro and in vivo. In vitro bin ding assays using glutathione-S-transferase-tagged chimeric receptors for P PAR alpha and SHP were used to verify the interaction between PPAR alpha an d SHP. This interaction was unaffected by the presence of the peroxisome pr oliferator, Wy-14,643. SHP has been proposed to act as a negative regulator of nuclear hormone receptor activity, and SHP inhibited transcription by P PAR alpha /RXR alpha heterodimers From the AOx-PPRE. Surprisingly, SHP pote ntiated transcription by PPAR alpha /RXR alpha. heterodimers from the HD-PP RE. This is the first demonstration of positive transcriptional activity at tributable to SHP. Together, these results suggest that SHP can modulate PP AR alpha /RXR alpha -mediated transcription in a response element-specific manner, (C) 2001 Elsevier Science Ireland Ltd, All rights reserved.