Retinoid X receptor agonist elevation of serum triglycerides in rats by potentiation of retinoic acid receptor agonist induction or by action as single agents

Hypertriglyceridemia is a major side-effect of retinoid therapy in humans. We previously reported that agonists for the retinoic acid receptors (RARs) , but not the retinoid X receptors (RXRs), elevate serum triglycerides in m ale Fischer rats, and that, surprisingly, the RAR/RXR pan-agonists 9-cis-re tinoic acid and AGN 191659 {(E)-5-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamet hyl-2-naphthyl)propen-1-yl]-2-thiophenecarboxylic acid} induce 2- to 3-fold higher levels of serum triglycerides than the RAR-selective agonists alone . We have now demonstrated that hypertriglyceridemia induced by an RAR agon ist, AGN 190121 [4-[4-(2',6',6'-trimethylcyclohex-1-enyl)-but-1-yne-3-enyl] benzoic acid], is substantially potentiated by the RXR-selective agonists A GN 191701 [(E) 2-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)pr open-1-yl]-4-thiophene-carboxylic acid] and AGN 192849 [(3,5,5,8,8,-pentame thyl-5,6,7,8-tetrahydronaphthalen-2-yl) (5 carboxypyrid-2-yl) sulfide] in a dose-dependent manner. RXR-specific retinoids, as previously reported, had no independent effect on serum triglycerides when tested at 24 hr after fi nal dosing, but did elicit a reversible hypertriglyceridemia at 2.5 and 5 h r. This induction of serum trialycerides could not be blocked by the potent RAR-specific antagonist AGN 193109 {4-[(5,6-dihydro-5,5-dimethyl-8-(4-meth ylphenyl)-2-naphthalenyl)-ethynyl] benzoic acid}. The RXR ligand-induced hy pertriglyceridemia was independent of the effect of feeding or fasting. The relative potencies of RXR-specific retinoids for acute triglyceride elevat ion (AGN 194204 {3,7-dimethyl-6S,7S-methano-7-[1,1,4,4-tetramethyl-1,2,3,4- tetrahydronaphth-7-yl] 2(E),4(E) heptadienoic acid} > AGN 192849 similar to AGN 191701) approximately correlated with potencies in the activation of t he RXR receptors. The RAR/RXR pan-agonist effect included >50% inhibition o f total heparin-releasable lipase activity in serum, consistent with inhibi tion of lipase-mediated triglyceride disposal. These data also indicate tha t RAR and RXR ligands can act synergistically to induce hypertriglyceridemi a through distinct mechanisms of action. (C) 2001 Elsevier Science Inc. All rights reserved.