Retinoids Increase Human Apolipoprotein A-II Expression through Activation of the Retinoid X Receptor but Not the Retinoic Acid Receptor

Abstract

Considering the link between plasma high-density lipoprotein (HDL) cholesterol levels and a protective effect against coronary artery disease as well as the suggested beneficial effects of retinoids on the production of the major HDL apolipoprotein (apo), apo A-I, the goal of this study was to analyze the influence of retinoids on the expression of apo A-II, the other major HDL protein. Retinoic acid (RA) derivatives have a direct effect on hepatic apo A-II production, since all-trans (at) RA induces apo A-II mRNA levels and apo A-II secretion in primary cultures of human hepatocytes. In the HepG2 human hepatoblastoma cell line, both at-RA and 9-cis RA as well as the retinoid X receptor (RXR)-specific agonist LGD 1069, but not the RA receptor (RAR) agonist ethyl-p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-l-pro penyl]-benzoic acid (TTNPB), induce apo A-II mRNA levels. Transient-transfection experiments with a reporter construct driven by the human apo A-II gene promoter indicated that 9-cis RA and at-RA, as well as the RXR agonists LGD 1069 and LG 100268, induced apo A-II gene expression at the transcriptional level. Only minimal effects of the RAR agonist TTNPB were observed on the apo A-II promoter reporter construct. Unilateral deletions and site-directed mutagenesis identified the J site of the apo A-II promoter mediating the responsiveness to RA. This element contains two imperfect half-sites spaced by 1 oligonucleotide. Cotransfection assays in combination with the use of RXR or RAR agonists showed that RXR but not RAR transactivates the apo A-II promoter through this element. By contrast, RAR inhibits the inductive effects of RXR on the apo A-II J site in a dose-dependent fashion. Gel retardation assays demonstrated that RXR homodimers bind, although with a lower affinity than RAR-RXR heterodimers, to the AH-RXR response element. In conclusion, retinoids induce hepatic apo A-II production at the transcriptional level via the interaction of RXR with an element in the J site containing two imperfect half-sites spaced by 1 oligonucleotide, thereby demonstrating an important role of RXR in controlling human lipoprotein metabolism. Since the J site also confers responsiveness of the apo A-II gene to fibrates and fatty acids via the activation of peroxisome proliferator-activated receptor-RXR heterodimers, this site can be considered a plurimetabolic response element.

Metabolism to a response pathway selective retinoid ligand during axial pattern formation

“…2A). 9-Cis-RA activated this response pathway as reported (33)(34)(35). Similar results were obtained with RXR␤ and RXR␥, the latter being moderately and similarly responsive to RA and 9-cis-4-oxo-RA, and much more responsive to 9-cis-RA (data not shown).…”

Retinoids increase human apo C-III expression at the transcriptional level via the retinoid X receptor. Contribution to the hypertriglyceridemic action of retinoids.

“…These data indicate that the induction of apo C-III expression is mediated via activation of RXR, but not RAR. The observation that TTNPB may repress apo C-III expression is congruent with this and previous data showing a negative transcriptional activity of RAR on RXR DR-1 response elements (30,31).…”

9-cis-Retinoic Acid (9cRA), a Retinoid X Receptor (RXR) Ligand, Exerts Immunosuppressive Effects on Dendritic Cells by RXR-Dependent Activation: Inhibition of Peroxisome Proliferator-Activated Receptor γ Blocks Some of the 9cRA Activities, and Precludes Them to Mature Phenotype Development

“…As additive or synergistic effects on glucose, lipid metabolism and gene activation have been described for RXR and PPAR␥ ligands (67)(68)(69)(70)(71)(72)(73), experiments of coincubation of 9cRA with ROSI were performed (Fig. 4).…”