Retinoid X receptor agonist elevation of serum triglycerides in rats by potentiation of retinoic acid receptor agonist induction or by action as single agents
Por:
Standeven A.M., Thacher S.M., Yuan Y.-D., Escobar M., Vuligonda V., Beard R.L., Chandraratna R.A.S.
Publicada:
1 ene 2001
Resumen:
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 male Fischer rats, and that, surprisingly, the RAR/RXR pan-agonists 9-cis-retinoic acid and AGN 191659 {(E)-5-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-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 agonist, 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 AGN 191701 [(E) 2-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)propen-1-yl]-4- thiophene-carboxylic acid] and AGN 192849 [(3,5,5,8,8,-pentamethyl-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 final dosing, but did elicit a reversible hypertriglyceridemia at 2.5 and 5 hr. This induction of serum triglycerides could not be blocked by the potent RAR-specific antagonist AGN 193109 {4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)-ethynyl] benzoic acid}. The RXR ligand-induced hypertriglyceridemia was independent of the effect of feeding or fasting. The relative potencies of RXR-specific retinoids for acute triglyceride elevation (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 ? AGN 191701) approximately correlated with potencies in the activation of the RXR receptors. The RAR/RXR pan-agonist effect included >50% inhibition of total heparin-releasable lipase activity in serum, consistent with inhibition of lipase-mediated triglyceride disposal. These data also indicate that RAR and RXR ligands can act synergistically to induce hypertriglyceridemia through distinct mechanisms of action. © 2001 Elsevier Science Inc. All rights reserved.
Filiaciones:
Standeven A.M.:
Department of Biology, Retinoid Research, P.O. Box 19534, 2525 Dupont Drive, Allergan, Irvine, CA 92623, United States
Thacher S.M.:
Department of Biology, Retinoid Research, P.O. Box 19534, 2525 Dupont Drive, Allergan, Irvine, CA 92623, United States
Yuan Y.-D.:
Department of Biology, Retinoid Research, P.O. Box 19534, 2525 Dupont Drive, Allergan, Irvine, CA 92623, United States
Escobar M.:
Department of Biology, Retinoid Research, P.O. Box 19534, 2525 Dupont Drive, Allergan, Irvine, CA 92623, United States
Vuligonda V.:
Department of Chemistry, Retinoid Research, Allergan, Irvine, CA 92623, United States
Beard R.L.:
Department of Chemistry, Retinoid Research, Allergan, Irvine, CA 92623, United States
Chandraratna R.A.S.:
Department of Biology, Retinoid Research, P.O. Box 19534, 2525 Dupont Drive, Allergan, Irvine, CA 92623, United States
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