IDENTIFICATION OF FATTY-ACID METHYL-ESTER AS NATURALLY-OCCURRING TRANSCRIPTIONAL REGULATORS OF THE MEMBERS OF THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR FAMILY

The nuclear hormone receptors NUC-1 (PPAR delta) and PPAR alpha are me mbers of the peroxisome proliferator-activated receptor (PPAR) family. The members of this receptor family are activated by agents that stim ulate peroxisome proliferation, free fatty acids, prostaglandin J2 met abolites, and agents considered for the therapy of insulin-independent diabetes mellitus. To identify putative physiological agents that act ivate NUC-1, we tested the ability of acetone extracts of various rat tissues to activate the transcription of an MMTV-luciferase reporter g ene, via a GR/NUC-1 hybrid receptor. GR/NUC-1 contains the ligand bind ing region of the NUC-1 receptor and the DNA binding domain of the glu cocorticoid receptor. Using this assay, we found stimulatory activity in the pancreas, which upon purification and characterization was iden tified as methyl-palmitate, known to be enriched in pancreatic lipids. In addition, we determined that ethyl esters of palmitic and oleic ac ids are also potent activators of this receptor. Thus, fatty acid este r formation may control the cellular concentrations of fatty acids, an d acyl-ester formation may play a role in the control of metabolic pat hways and the activation of the PPAR.