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© 1996 Oxford University Press

research-article

Retinoid-Induced Hypertriglyceridemia in Rats Is Mediated by Retinoic Acid Receptors

ANDREW M. STANDEVEN*,1, RICHARD L. BEARD{dagger}, ALAN T. JOHNSON{dagger}, MARCUS F. BOEHM{ddagger}, MARIA ESCOBAR*, RICHARD A. HEYMAN§ and ROSHANTHA A. S. CHANDRARATNA*,{dagger},1

*Retinoid Research, Departments of Biology, Allergan Inc. Irvine, California 92713-9534 {dagger}Retinoid Research, Departments of Retinoid Research, Departments of Chemistry, Allergan Inc. Irvine, California 92713-9534 {ddagger}Retinoid Research, Departments of Medicinal Chemistry, Ligand Pharmaceuticals San Diego, California §Retinoid Research, Departments of Cell Biology, Ligand Pharmaceuticals San Diego, California

Received May 24, 1996; accepted August 13, 1996

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 co-treatment 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.


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