Pérez Efrén, Bourguet William, Gronemeyer Hinrich, de Lera Angel R
Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, Spain.
Biochim Biophys Acta. 2012 Jan;1821(1):57-69. doi: 10.1016/j.bbalip.2011.04.003. Epub 2011 Apr 16.
As the promiscuous partner of heterodimeric associations, retinoid X receptors (RXRs) play a key role within the Nuclear Receptor (NR) superfamily. Some of the heterodimers (PPAR/RXR, LXR/RXR, FXR/RXR) are "permissive" as they become transcriptionally active in the sole presence of either an RXR-selective ligand ("rexinoid") or a NR partner ligand. In contrast, "non-permissive" heterodimers (including RAR/RXR, VDR/RXR and TR/RXR) are unresponsive to rexinoids alone but these agonists superactivate transcription by synergizing with partner agonists. Despite their promiscuity in heterodimer formation and activation of multiple pathways, RXR is a target for drug discovery. Indeed, a rexinoid is used in the clinic for the treatment of cutaneous T-cell lymphoma. In addition to cancer RXR modulators hold therapeutical potential for the treatment of metabolic diseases. The modulation potential of the rexinoid (as agonist or antagonist ligand) is dictated by the precise conformation of the ligand-receptor complexes and the nature and extent of their interaction with co-regulators, which determine the specific physiological responses through transcription modulation of cognate gene networks. Notwithstanding the advances in this field, it is not yet possible to predict the correlation between ligand structure and physiological response. We will focus on this review on the modulation of PPARγ/RXR and LXR/RXR heterodimer activities by rexinoids. The genetic and pharmacological data from animal models of insulin resistance, diabetes and obesity demonstrate that RXR agonists and antagonists have promise as anti-obesity agents. However, the treatment with rexinoids raises triglycerides levels, suppresses the thyroid hormone axis, and induces hepatomegaly, which has complicated the development of these compounds as therapeutic agents for the treatment of type 2 diabetes and insulin resistance. The discovery of PPARγ/RXR and LXR/RXR heterodimer-selective rexinoids, which act differently than PPARγ or LXR agonists, might overcome some of these limitations.
作为异二聚体结合的“混杂”伙伴，维甲酸X受体（RXR）在核受体（NR）超家族中发挥关键作用。一些异二聚体（PPAR/RXR、LXR/RXR、FXR/RXR）是“允许性的”，因为它们在单独存在RXR选择性配体（“视黄酸类药物”）或NR伙伴配体时就会变得具有转录活性。相比之下，“非允许性”异二聚体（包括RAR/RXR、VDR/RXR和TR/RXR）对单独的视黄酸类药物无反应，但这些激动剂通过与伙伴激动剂协同作用来超激活转录。尽管RXR在异二聚体形成和多种途径激活方面具有混杂性，但它仍是药物研发的一个靶点。事实上，一种视黄酸类药物已在临床上用于治疗皮肤T细胞淋巴瘤。除了癌症，RXR调节剂在治疗代谢性疾病方面也具有治疗潜力。视黄酸类药物（作为激动剂或拮抗剂配体）的调节潜力取决于配体-受体复合物的精确构象以及它们与共调节因子相互作用的性质和程度，这些因素通过对同源基因网络的转录调节来决定特定的生理反应。尽管该领域取得了进展，但目前仍无法预测配体结构与生理反应之间的相关性。我们将在本综述中重点关注视黄酸类药物对PPARγ/RXR和LXR/RXR异二聚体活性的调节。来自胰岛素抵抗、糖尿病和肥胖动物模型的遗传和药理学数据表明，RXR激动剂和拮抗剂有望成为抗肥胖药物。然而，使用视黄酸类药物治疗会升高甘油三酯水平、抑制甲状腺激素轴并导致肝肿大，这使得这些化合物作为治疗2型糖尿病和胰岛素抵抗的治疗药物的开发变得复杂。PPARγ/RXR和LXR/RXR异二聚体选择性视黄酸类药物的发现，其作用方式不同于PPARγ或LXR激动剂，可能会克服其中一些局限性。
