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

K. Schoonjans, Mitsuhiro Watanabe, H. Suzuki, A. Mahfoudi, G. Krey, W. Wahli, P. Grimaldi, B. Staels, T. Yamamoto, J. Auwerx

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)19269-19276
Number of pages8
JournalJournal of Biological Chemistry
Volume270
Issue number33
DOIs
Publication statusPublished - 1995
Externally publishedYes

Fingerprint

Coenzyme A Ligases
Peroxisome Proliferators
Fibric Acids
Response Elements
Fatty Acids
Genes
Messenger RNA
Peroxisome Proliferator-Activated Receptors
Oligonucleotides
Liver
Rats
Exons
Mutagenesis
alpha-Linolenic Acid
Nucleic Acid Regulatory Sequences
Electrophoretic Mobility Shift Assay
Site-Directed Mutagenesis
Metabolic Networks and Pathways
Transfection
Hepatocytes

ASJC Scopus subject areas

  • Biochemistry

Cite this

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. / Schoonjans, K.; Watanabe, Mitsuhiro; Suzuki, H.; Mahfoudi, A.; Krey, G.; Wahli, W.; Grimaldi, P.; Staels, B.; Yamamoto, T.; Auwerx, J.

In: Journal of Biological Chemistry, Vol. 270, No. 33, 1995, p. 19269-19276.

Research output: Contribution to journalArticle

Schoonjans, K. ; Watanabe, Mitsuhiro ; Suzuki, H. ; Mahfoudi, A. ; Krey, G. ; Wahli, W. ; Grimaldi, P. ; Staels, B. ; Yamamoto, T. ; Auwerx, J. / 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. In: Journal of Biological Chemistry. 1995 ; Vol. 270, No. 33. pp. 19269-19276.
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abstract = "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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T1 - 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

AU - Schoonjans, K.

AU - Watanabe, Mitsuhiro

AU - Suzuki, H.

AU - Mahfoudi, A.

AU - Krey, G.

AU - Wahli, W.

AU - Grimaldi, P.

AU - Staels, B.

AU - Yamamoto, T.

AU - Auwerx, J.

PY - 1995

Y1 - 1995

N2 - 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.

AB - 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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