Retinoids in clinical use today are known to induce
hypertriglyceridemia as one of their major side effects. The purpose of the present study was to determine, in an appropriate animal model, if
retinoid-induced
hypertriglyceridemia is mediated by
retinoic acid receptors (RARs) and/or by
retinoid X receptors (RXRs). Oral gavage of male Fischer rats with
13-cis-retinoic acid for 6 days caused a rapid and sustained increase in serum
triglycerides that was reversible within 4 days posttreatment. In subsequent experiments, rats were treated by gavage once daily for 3 days with various
retinoids, and serum
triglyceride levels were determined 24 hr after the last treatment without fasting. All-trans- and
13-cis-retinoic acid, which can be converted to both RAR and RXR agonists, and
9-cis-retinoic acid, an RAR/RXR pan-agonist, caused dose-dependent increases in serum
triglycerides at doses that did not cause
weight loss or mucocutaneous toxicity.
Ro 13-6298 and
AGN 190121, two RAR-specific agonists, caused dose-dependent increases in serum
triglycerides, although
Ro 13-6298 only induced
hypertriglyceridemia at weight-suppressive doses. Two RXR-selective agonists,
LG100268 and
AGN 191701, failed to induce
hypertriglyceridemia or
weight loss up to the highest doses tested. A structural isomer of
AGN 190121 that does not activate RARs or RXRs,
AGN 190727, did not induce
hypertriglyceridemia.
Hypertriglyceridemia induced by
AGN 190121 was significantly inhibited by cotreatment with an RAR-selective antagonist,
AGN 193109. Taken together, these data provide strong evidence that
retinoid-induced
hypertriglyceridemia is mediated, at least in part, by RARs. These data also suggest that RXR-specific agonists may have reduced potential to induce
hypertriglyceridemia relative to RAR-active
retinoids.