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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
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Abstract
- 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 the FATP-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 of FATP-1 and ACS. In several cultured cell lines, it was shown that the expression of both the FATP-1 and ACS 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 and ACS mRNA levels was also observed in vivo in 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 on FATP-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.
- Subjects :
- Male
Peroxisome proliferator-activated receptor gamma
Time Factors
Receptors, Retinoic Acid
Retinoic acid
Receptors, Cytoplasmic and Nuclear
Peroxisome proliferator-activated receptor
Tretinoin
Retinoid X receptor
Biology
Fatty Acid-Binding Proteins
Biochemistry
Mice
chemistry.chemical_compound
Coenzyme A Ligases
Tumor Cells, Cultured
Animals
Humans
Tissue Distribution
Molecular Biology
Nucleic Acid Synthesis Inhibitors
Cell Nucleus
chemistry.chemical_classification
Dose-Response Relationship, Drug
Fatty Acids
Membrane Proteins
Fatty acid
Membrane Transport Proteins
Serum Albumin, Bovine
3T3 Cells
Cell Biology
Fatty Acid Transport Proteins
Rats
Rats, Zucker
Retinoic acid receptor
Retinoid X Receptors
chemistry
Dactinomycin
Free fatty acid receptor
RNA
Peroxisome proliferator-activated receptor alpha
Caco-2 Cells
Carrier Proteins
Transcription Factors
Subjects
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....f1a6fe28298a6480712413cec505cad3