Retinoids increase human apo C-III expression at the transcriptional level via the retinoid X receptor : Contribution to the hypertriglyceridemic action of retinoids
article
Hypertriglyceridemia is a metabolic complication of retinoid therapy. In this study, we analyzed whether retinoids increase the expression of apo C- III, an antagonist of plasma triglyceride catabolism. In men, isotretinoin treatment (80 mg/d; 5 d) resulted in elevated plasma apo C-III, but not apo E concentrations. In human hepatoma HepG2 cells, retinoids increased apo C-III mRNA and protein production. Transient transfection experiments indicated that retinoids increase apo C-III expression at the transcriptional level. This increased apo C-III transcription is mediated by the retinoid X receptor (RXR), since LG1069 (4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2- naphtalenyl)ethenyl]benzoic acid), a RXR-specific agonist, but not TTNPB ((E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphtalenyl)propenyl]benzoic acid), a retinoic acid receptor (RAR)-specific agonist, induced apo C-III mRNA in HepG2 cells and primary human hepatocytes. Mutagenesis experiments localized the retinoid responsiveness to a cis- element consisting of two imperfect AGGTCA sequences spaced by one oligonucleotide (DR-1), within the previously identified C3P footprint site. Cotransfection assays showed that RXR, but not RAR, activates apo C-III transcription through this element either as a homo- or as a heterodimer with the peroxisome proliferator-activated receptor. Thus, apo C-III is a target gene for retinoids acting via RXR. Increased apo C-III expression may contribute to the hypertriglyceridemia and atherogenic lipoprotein profile observed after retinoid therapy.
Topics
Gene regulationHyperlipidemiaNuclear receptorsRetinoidsTriglyceridesAdultApolipoprotein C-IIIApolipoproteins CBenzoatesCarcinoma, HepatocellularCells, CulturedDimerizationDouble-Blind MethodGene Expression RegulationHela CellsHumansHypertriglyceridemiaIsotretinoinLiverLiver NeoplasmsMaleMutagenesis, Site-DirectedPromoter Regions (Genetics)Receptors, Cytoplasmic and NuclearReceptors, Retinoic AcidRecombinant Fusion ProteinsRegulatory Sequences, Nucleic AcidRetinoid X ReceptorsRetinoidsTetrahydronaphthalenesTranscription FactorsTranscription, GeneticTransfectionTumor Cells, Cultured
TNO Identifier
234555
ISSN
00219738
Source
Journal of Clinical Investigation, 102(3), pp. 625-632.
Pages
625-632