Identification of a peroxisome proliferator-responsive element upstream of the human peroxisomal fatty acyl coenzyme A oxidase gene

Usha Varanasi, Ruiyin Chu, Qin Huang, Raquel Castellon, Anjana V. Yeldandi, Janardan K. Reddy*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

150 Scopus citations

Abstract

Peroxisome proliferators cause a rapid and coordinated transcriptional activation of genes encoding the enzymes of the peroxisomal β-oxidation pathway in rats and mice. Cis-acting peroxisome proliferator responsive elements (PPREs) have been identified in the 5'-flanking region of H2O2- producing rat acyl-CoA oxidase (ACOX) gene and in other genes inducible by peroxisome proliferators. To gain more insight into the purported nonresponsiveness of human liver cells to peroxisome proliferator-induced increases in peroxisome volume density and in the activity of the β- oxidation enzyme system, we have previously cloned the human ACOX gene, the first and rate-limiting enzyme of the peroxisomal β-oxidation system. We now present information on a regulatory element for the peroxisome proliferator- activated receptor (PPAR)/retinoid X receptor (RXR) heterodimers. The PPRE, consists of AGGTCA C TGGTCA, which is a direct repeat of hexamer half-sites interspaced by a single nucleotide (DR1 motif). It is located at -1918 to - 1906 base pairs upstream of the transcription initiation site of this human ACOX gene. This PPRE specifically binds to baculovirus-expressed recombinant rat PPARα/RXRα heterodimers. In transient transfection experiments, the maximum induction of luciferase expression by ciprofibrate and/or 9-cis- retinoic acid is dependent upon cotransfection of expression plasmids for PPARα and RXRα. The functionality of this human ACOX promoter was further demonstrated by linking it to a β-galactosidase reporter gene or to a rat urate oxidase cDNA and establishing stably transfected African green monkey kidney (CV1) cell lines expressing reporter protein. The human ACOX promoter has been found to be responsive to peroxisome proliferators in CV1 cells stably expressing PPARα, whereas only a basal level of promoter activity is detected in stably transfected cells lacking PPARα. The presence of a PPRE in the promoter of this human peroxisomal ACOX gene and its responsiveness to peroxisome proliferators suggests that factors other than the PPRE in the 5'- flanking sequence of the human ACOX gene may account for differences, if any, in the pleiotropic responses of humans to peroxisome proliferators.

Original languageEnglish (US)
Pages (from-to)2147-2155
Number of pages9
JournalJournal of Biological Chemistry
Volume271
Issue number4
DOIs
StatePublished - Jan 26 1996

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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