A widely used retinoic acid receptor antagonist induces peroxisome proliferator-activated receptor-γ activity
A widely used retinoic acid receptor antagonist induces peroxisome proliferator-activated receptor-γ activity
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DOI：
10.1124/mol.106.033662
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发表时间：
2007-05-01
影响因子：
3.6
通讯作者：
Lazar, Mitchell A.
中科院分区：
文献类型：
--
作者：
Schupp, Michael;Curtin, Joshua C.;Lazar, Mitchell A.
核受体（NRs）是转录因子，其活性受小亲脂配体（包括激素、维生素和代谢物）结合的调节。药理NR配体是重要的治疗药物；例如，全反式维甲酸是维甲酸受体α (RAR α)的激活配体，用于治疗白血病。另一种RAR α配体(E)- s, s -2 -（2-（7-（庚氧基）-3,4-二氢-4,4-二甲基- 2h -1-苯并噻吩吡喃-6-基）-1-丙烯基）-苯甲酸（Ro 41- 5253）是一种有效的拮抗剂，据称是一种有用的RAR α功能特异性探针。在这里，我们报道Ro 41- 5253还激活过氧化物酶体增殖物激活受体γ (PPAR γ)， PPAR γ是脂肪细胞分化的主要调节剂，也是广泛使用的抗糖尿病噻唑烷二酮（TZDs）的靶标。Ro 41- 5253增强小鼠和人前脂肪细胞的分化，激活成熟脂肪细胞中的PPAR γ靶基因。与TZDs一样，Ro 41-5253也下调了脂肪细胞中PPAR γ蛋白的表达。此外，Ro 41-5253在瞬时转染的HEK293T细胞中激活PPAR γ -配体结合域。这些作用不能被有效的RAR α激动剂或通过消耗RAR α细胞来阻止，这表明PPAR γ激活与RAR α拮抗剂无关。事实上，Ro 41-5253能够与TZD配体竞争PPAR γ的结合，这表明Ro 41-5253直接影响PPAR活性。这些结果生动地表明，药理学NR配体可能对其他NR具有“脱靶”作用。Ro 41-5253是一种PPAR γ激动剂和RAR α拮抗剂，其对NRs的多效作用可能意味着一种独特的生物反应谱。
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.