Journal of Biological Chemistry
Volume 270, Issue 33, 18 August 1995, Pages 19269-19276
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Nucleic Acids, Protein Synthesis, and Molecular Genetics
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 (∗)

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The long-chain acyl-coenzyme A synthetase (ACS) gene gives rise to three transcripts containing different first exons preceded by specific regulatory regions A, B, and C. Exon-specific oligonucleotide hybridization indicated that only A-ACS mRNA is expressed in rat liver. Fibrate administration induced liver C-ACS strongly and A-ACS mRNA to a lesser extent. B-ACS mRNA remained undetectable. In primary rat hepatocytes and Fa-32 hepatoma cells C-ACS mRNA increased after treatment with fenofibric acid, α-bromopalmitate, tetradecylthioacetic acid, or α-linolenic acid. Nuclear run-on experiments indicated that fenofibric acid and α-bromopalmitate act at the transcriptional level. Transient transfections showed a 3.4-, 2.3-, and 2.2-fold induction of C-ACS promoter activity after fenofibric acid, α-bromopalmitate, and tetradecylthioacetic acid, respectively. Unilateral deletion and site-directed mutagenesis identified a peroxisome proliferator activator receptor (PPAR)-responsive element (PPRE) mediating the responsiveness to fibrates and fatty acids. This ACS PPRE contains three imperfect half sites spaced by 1 and 3 oligonucleotides and binds PPAR•retinoid X receptor heterodimers in gel retardation assays. In conclusion, the regulation of C-ACS mRNA expression by fibrates and fatty acids is mediated 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.

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This research was sponsored by grants from INSERM, National Fonds voor Wetenschapelijk Guderzoek “levenslijn” 7.0022.91, Fondation pour la Recherche Médicale, Association pour la Recherche sur le Cancer (ARC), ARCOL, the Swiss National Science Foundation, and the Bioavenir program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

Supported by fellowships of the Association pour la Recherche sur le Cancer (ARC) and Institut Francais de Nutrition (IFN).

Supported by a BIOMED-1 fellowship.

∗∗

Research associate of CNRS.