TY - JOUR
T1 - A widely used retinoic acid receptor antagonist induces peroxisome proliferator-activated receptor-γ activity
AU - Schupp, Michael
AU - Curtin, Joshua C.
AU - Kim, Roy J.
AU - Billin, Andrew N.
AU - Lazar, Mitchell A.
PY - 2007/5
Y1 - 2007/5
N2 - Nuclear receptors (NRs) are transcription factors whose activity is regulated by the binding of small lipophilic ligands, including hormones, vitamins, and metabolites. Pharmacological NR ligands serve as important therapeutic agents; for example, all-trans retinoic acid, an activating ligand for retinoic acid receptor α (RARα), is used to treat leukemia. Another RARα ligand, (E)-S,S-dioxide-4-(2-(7-(heptyloxy)-3,4-dihydro-4,4- dimethyl-2H-1-benzothiopyran-6-yl)-1-propenyl)-benzoic acid (Ro 41-5253), is a potent antagonist that has been a useful and purportedly specific probe of RARα function. Here, we report that Ro 41-5253 also activates the peroxisome proliferatoractivated receptor γ (PPARγ), a master regulator of adipocyte differentiation and target of widely prescribed antidiabetic thiazolidinediones (TZDs). Ro 41-5253 enhanced differentiation of mouse and human preadipocytes and activated PPARγ target genes in mature adipocytes. Like the TZDs, Ro 41-5253 also down-regulated PPARγ protein expression in adipocytes. In addition, Ro 41-5253 activated the PPARγ-ligand binding domain in transiently transfected HEK293T cells. These effects were not prevented by a potent RARα agonist or by depleting cells of RARα, indicating that PPARγ activation was not related to RARα antagonism. Indeed, Ro 41-5253 was able to compete with TZD ligands for binding to PPARγ, suggesting that Ro 41-5253 directly affects PPAR activity. These results vividly demonstrate that pharmacological NR ligands may have "off-target" effects on other NRs. Ro 41-5253 is a PPARγ agonist as well as an RARα antagonist whose pleiotropic effects on NRs may signify a unique spectrum of biological responses.
AB - Nuclear receptors (NRs) are transcription factors whose activity is regulated by the binding of small lipophilic ligands, including hormones, vitamins, and metabolites. Pharmacological NR ligands serve as important therapeutic agents; for example, all-trans retinoic acid, an activating ligand for retinoic acid receptor α (RARα), is used to treat leukemia. Another RARα ligand, (E)-S,S-dioxide-4-(2-(7-(heptyloxy)-3,4-dihydro-4,4- dimethyl-2H-1-benzothiopyran-6-yl)-1-propenyl)-benzoic acid (Ro 41-5253), is a potent antagonist that has been a useful and purportedly specific probe of RARα function. Here, we report that Ro 41-5253 also activates the peroxisome proliferatoractivated receptor γ (PPARγ), a master regulator of adipocyte differentiation and target of widely prescribed antidiabetic thiazolidinediones (TZDs). Ro 41-5253 enhanced differentiation of mouse and human preadipocytes and activated PPARγ target genes in mature adipocytes. Like the TZDs, Ro 41-5253 also down-regulated PPARγ protein expression in adipocytes. In addition, Ro 41-5253 activated the PPARγ-ligand binding domain in transiently transfected HEK293T cells. These effects were not prevented by a potent RARα agonist or by depleting cells of RARα, indicating that PPARγ activation was not related to RARα antagonism. Indeed, Ro 41-5253 was able to compete with TZD ligands for binding to PPARγ, suggesting that Ro 41-5253 directly affects PPAR activity. These results vividly demonstrate that pharmacological NR ligands may have "off-target" effects on other NRs. Ro 41-5253 is a PPARγ agonist as well as an RARα antagonist whose pleiotropic effects on NRs may signify a unique spectrum of biological responses.
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U2 - 10.1124/mol.106.033662
DO - 10.1124/mol.106.033662
M3 - Article
C2 - 17290005
AN - SCOPUS:34247546618
SN - 0026-895X
VL - 71
SP - 1251
EP - 1257
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 5
ER -