Alternative splicing of human peroxisome proliferator-activated receptor delta (PPARdelta):effects on translation efficiency and trans-activation ability

BACKGROUND: Peroxisome proliferator-activated receptor delta (PPARδ) is a member of the nuclear receptor superfamily. Numerous studies have aimed at unravelling the physiological role of PPARδ as a transcriptional regulator whereas the regulation of PPARδ gene expression has been less studied. RESULTS: The principal transcription start site in the human PPARδ gene identified here is positioned upstream of exon 1, although four alternative 5'-ends related to downstream exons were identified. The demonstration of multiple 5'-UTR splice variants of PPARδ mRNA, with an impact on translation efficiency, suggests a translational regulation of human PPARδ expression. Five untranslated exons identified in this study contribute to the variability among the 5'-UTRs of human PPARδ mRNAs. Moreover, in vitro studies of a 3'-splice transcript encoding a truncated variant of PPARδ (designated PPARδ2) show that this isoform constitutes a potential dominant negative form of the receptor. CONCLUSION: We propose that alternative splicing of human PPARδ constitutes an intrinsic role for the regulation of PPARδ expression and thus activity, and highlight the significance of alternative splicing of this nuclear receptor in physiology and disease.