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 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 approximately 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.
Standeven
A M
AM
Department of Biology, Retinoid Research, Allergan, P.O. Box 19534, 2525 Dupont Drive, Irvine, CA 92623, USA.
Thacher
S M
SM
Yuan
Y D
YD
Escobar
M
M
Vuligonda
V
V
Beard
R L
RL
Chandraratna
R A
RA
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D002264:Carboxylic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005215:Fasting / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006493:Heparin / Q000378:metabolism; D015228:Hypertriglyceridemia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*; D014157:Transcription Factors / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D014280:Triglycerides / Q000097:blood*
C442301:(3,5,5,8,8,-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) (5 carboxypyrid-2-yl)sulfide; C104327:AGN 190121; C403783:AGN 191659; C430898:AGN 194204; D001565:Benzoates; D002264:Carboxylic Acids; D005231:Fatty Acids, Unsaturated; D007004:Hypoglycemic Agents; D009281:Naphthalenes; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; D014157:Transcription Factors; D014280:Triglycerides; D006493:Heparin; C096920:AGN 193109