PMID- 11728386
OWN - NLM
STAT- MEDLINE
DCOM- 20020102
LR  - 20190623
IS  - 0006-2952 (Print)
IS  - 0006-2952 (Linking)
VI  - 62
IP  - 11
DP  - 2001 Dec 1
TI  - Retinoid X receptor agonist elevation of serum triglycerides in rats by 
      potentiation of retinoic acid receptor agonist induction or by action as single 
      agents.
PG  - 1501-9
AB  - 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.
FAU - Standeven, A M
AU  - Standeven AM
AD  - Department of Biology, Retinoid Research, Allergan, P.O. Box 19534, 2525 Dupont 
      Drive, Irvine, CA 92623, USA.
FAU - Thacher, S M
AU  - Thacher SM
FAU - Yuan, Y D
AU  - Yuan YD
FAU - Escobar, M
AU  - Escobar M
FAU - Vuligonda, V
AU  - Vuligonda V
FAU - Beard, R L
AU  - Beard RL
FAU - Chandraratna, R A
AU  - Chandraratna RA
LA  - eng
PT  - Journal Article
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 ((3,5,5,8,8,-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) (5 
      carboxypyrid-2-yl)sulfide)
RN  - 0 (AGN 190121)
RN  - 0 (AGN 191659)
RN  - 0 (AGN 194204)
RN  - 0 (Benzoates)
RN  - 0 (Carboxylic Acids)
RN  - 0 (Fatty Acids, Unsaturated)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Naphthalenes)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (Tetrahydronaphthalenes)
RN  - 0 (Thiophenes)
RN  - 0 (Transcription Factors)
RN  - 0 (Triglycerides)
RN  - 9005-49-6 (Heparin)
RN  - ZC6062V1O9 (AGN 193109)
SB  - IM
MH  - Animals
MH  - Benzoates/pharmacology
MH  - Carboxylic Acids/*pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - Fasting/metabolism
MH  - Fatty Acids, Unsaturated/pharmacology
MH  - Heparin/metabolism
MH  - Hypertriglyceridemia/chemically induced
MH  - Hypoglycemic Agents/pharmacology
MH  - Male
MH  - Naphthalenes/pharmacology
MH  - Rats
MH  - Rats, Inbred F344
MH  - Receptors, Retinoic Acid/*agonists/antagonists & inhibitors/metabolism
MH  - Retinoid X Receptors
MH  - Tetrahydronaphthalenes/pharmacology
MH  - Thiophenes/*pharmacology
MH  - Transcription Factors/*agonists/antagonists & inhibitors/metabolism
MH  - Triglycerides/*blood
EDAT- 2001/12/01 10:00
MHDA- 2002/01/05 10:01
CRDT- 2001/12/01 10:00
PHST- 2001/12/01 10:00 [pubmed]
PHST- 2002/01/05 10:01 [medline]
PHST- 2001/12/01 10:00 [entrez]
AID - S0006-2952(01)00803-6 [pii]
AID - 10.1016/s0006-2952(01)00803-6 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2001 Dec 1;62(11):1501-9. doi: 10.1016/s0006-2952(01)00803-6.