Induction of the Fatty Acid Transport Protein 1 and Acyl-CoA Synthase Genes by Dimer-selective Rexinoids Suggests That the Peroxisome Proliferator-activated Receptor-Retinoid X Receptor Heterodimer Is Their Molecular Target

Geneviève Martin (1) , Hélène Poirier (2) , Nathalie Hennuyer (3) , Diane Crombie (3) , Jean Charles Fruchart (4) , Richard Heyman (3, 4) , Philippe Besnard (2) , Johan Auwerx (4)

1 Département d'Athérosclérose, INSERM U325
2 Laboratoire de Physiologie de la Nutrition
3 Ligand Pharmaceuticals
4 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire

The intracellular fatty acid content of insulin-sensitive target tissues determines in part their insulin sensitivity. Uptake of fatty acids into cells is a controlled process determined in part by a regulated import/export system that is controlled at least by two key groups of proteins, i.e. the fatty acid transport protein (FATP) and acyl-CoA synthetase (ACS), which facilitate, respectively, the transport of fatty acids across the cell membrane and catalyze their esterification to prevent their efflux. Previously it was shown that the expression of theFATP-1 and ACS genes was controlled by insulin and by peroxisome proliferator-activated receptor (PPAR) agonists in liver or in adipose tissue. The aim of this investigation was to determine the effects of retinoic acid derivatives on the expression ofFATP-1 and ACS. In several cultured cell lines, it was shown that the expression of both the FATP-1 andACS mRNAs was specifically induced at the transcriptional level by selective retinoid X receptor (RXR) but not by retinoic acid receptor (RAR) ligands. This effect was most pronounced in hepatoma cell lines. A similar induction of FATP-1 andACS mRNA levels was also observed in vivoin Zucker diabetic fatty rats treated with the RXR agonist, LGD1069 (4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]benzoic acid). Through the use of heterodimer-selective compounds, it was demonstrated that the modulatory effect of these rexinoids onFATP-1 and ACS gene expression was mediated through activation of RXR in the context of the PPAR-RXR heterodimer. The observation that both RXR and PPAR agonists can stimulate the transcription of genes implicated in lipid metabolism, suggest that rexinoids may also act as lipid-modifying agents and support a role of the permissive PPAR-RXR heterodimer in the control of insulin sensitivity.

Domaines: Génomique, Transcriptomique et Protéomique [q-bio.GN]; Alimentation et Nutrition; Endocrinologie et métabolisme

Geneviève Martin, Hélène Poirier, Nathalie Hennuyer, Diane Crombie, Jean Charles Fruchart, et al.. Induction of the Fatty Acid Transport Protein 1 and Acyl-CoA Synthase Genes by Dimer-selective Rexinoids Suggests That the Peroxisome Proliferator-activated Receptor-Retinoid X Receptor Heterodimer Is Their Molecular Target. Journal of Biological Chemistry, 2000, 275 (17), pp.12612 - 12618. ⟨10.1074/jbc.275.17.12612⟩. ⟨hal-01917236⟩