Retinoid X receptor agonist elevation of serum triglycerides in rats by potentiation of retinoic acid receptor agonist induction or by action as single agents
Am. Standeven et al., Retinoid X receptor agonist elevation of serum triglycerides in rats by potentiation of retinoic acid receptor agonist induction or by action as single agents, BIOCH PHARM, 62(11), 2001, pp. 1501-1509
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.