Pharmacological analysis of wild-type α, γ and δ subtypes of the human peroxisome proliferator-activated receptor

Abstract.

Three distinct peroxisome proliferator-activated receptor (PPAR) cDNAs were isolated from human brain RNA. Whereas the PPARδ subtype perfectly matched the amino acid sequences reported in the Genbank database, several differences were found for the PPARα (Lys¹²³Met, Ala²⁶⁸Val, Gly²⁹⁶Ala and Val⁴⁴⁴Ala) and PPARγ2 (Met⁸Ile, Pro⁹Ala, Met¹⁸⁶Ile, Pro¹⁸⁷Ala and the deletion of a Gln²¹³ residue) subtypes. A pharmacological analysis was undertaken by co-expressing each PPAR subtype with a reporter plasmid containing a luciferase gene under the transcriptional control of a synthetic, triplicated PPAR response element in either HepG2 or Cos-7 cells. Whereas fenofibrate unselectively activated the PPARα and PPARδ subtypes, the related BM-17.0744 compound was more potent and selective for PPARα. The thiazolidine dione derivatives rosiglitazone and pioglitazone were potent and selective PPARγ2 agonists. L-165041, reported as a selective and potent PPARδ ligand, displayed in this specified transactivation system, apart from its highly efficacious PPARδ agonist activity, partial and full agonism at, respectively, PPARα and PPARγ2 subtypes. In conclusion, transcriptional control of a luciferase gene by wild-type PPAR subtypes provides powerful recombinant assays to evaluate ligand's efficacy at these nuclear receptors.