INDUCTION OF THE ACYL-COENZYME-A SYNTHETASE GENE BY FIBRATES AND FATTY-ACIDS IS MEDIATED BY A PEROXISOME PROLIFERATOR RESPONSE ELEMENT IN THE C-PROMOTER

The long-chain acyl coenzyme A synthetase (ACS) gene gives rise to thr ee transcripts containing different first exons preceded by specific r egulatory regions A, B, and C. Exon-specific oligonucleotide hybridiza tion indicated that only A-ACS mRNA is expressed in rat liver. Fibrate administration induced liver C-ACS strongly and A-ACS mRNA to a lesse r extent. B-ACS mRNA remained undetectable. In primary rat hepatocytes and Fa-32 hepatoma cells C-ACS mRNA increased after treatment with fe nofibric acid, alpha-bromopalmitate, tetradecylthioacetic acid, or alp ha-linolenic acid. Nuclear run-on experiments indicated that fenofibri c acid and alpha-bromopalmitate act at the transcriptional level. Tran sient transfections showed a 3.4-, 2.3-, and 2.2-fold induction of C-A CS promoter activity after fenofibric acid, alpha-bromopalmitate, and tetradecylthioacetic acid, respectively. Unilateral deletion and site- directed mutagenesis identified a peroxisome proliferator activator re ceptor (PPAR)-responsive element (PPRE) mediating the responsiveness t o fibrates and fatty acids. This ACS PPRE contains three imperfect hal f sites spaced by 1 and 3 oligonucleotides and binds PPAR retinoid X r eceptor heterodimers in gel retardation assays. In conclusion, the reg ulation of C-ACS mRNA expression by fibrates and fatty acids is mediat ed by PPAR retinoid X receptor heterodimers interacting through a PPRE in the C-ACS promoter. PPAR therefore occupies a key position in the transcriptional control of a pivotal enzyme controlling the channeling of fatty acids into various metabolic pathways.