科研之友
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摘要
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 alpha (RAR alpha), is used to treat leukemia. Another RAR alpha 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 RAR alpha function. Here, we report that Ro 41- 5253 also activates the peroxisome proliferator-activated receptor gamma (PPAR gamma), 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 PPAR gamma target genes in mature adipocytes. Like the TZDs, Ro 41-5253 also down-regulated PPAR gamma protein expression in adipocytes. In addition, Ro 41-5253 activated the PPAR gamma-ligand binding domain in transiently transfected HEK293T cells. These effects were not prevented by a potent RAR alpha agonist or by depleting cells of RAR alpha, indicating that PPAR gamma activation was not related to RAR alpha antagonism. Indeed, Ro 41-5253 was able to compete with TZD ligands for binding to PPAR gamma, 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 PPAR gamma agonist as well as an RAR alpha antagonist whose pleiotropic effects on NRs may signify a unique spectrum of biological responses.
- 出版日期2007-5
