The Liver X Receptors (LXRs) are oxysterol-activated transcription factors that upregulate a suite of genes that together promote coordinated mobilization of excess cholesterol from cells and from the body. The LXRs, like other nuclear receptors, are anti-inflammatory, inhibiting signal-dependent induction of pro-inflammatory genes by nuclear factor-κB, activating protein-1, and other transcription factors. Synthetic LXR agonists have been shown to ameliorate atherosclerosis and a wide range of inflammatory disorders in preclinical animal models. Although this has suggested potential for application to human disease, systemic LXR activation is complicated by hepatic steatosis and hypertriglyceridemia, consequences of lipogenic gene induction in the liver by LXRα. The past several years have seen the development of multiple advanced LXR therapeutics aiming to avoid hepatic lipogenesis, including LXRβ-selective agonists, tissue-selective agonists, and transrepression-selective agonists. Although several synthetic LXR agonists have made it to phase I clinical trials, none have progressed due to unforeseen adverse reactions or undisclosed reasons. Nonetheless, several sophisticated pharmacologic strategies, including structure-guided drug design, cell-specific drug targeting, as well as non-systemic drug routes have been initiated and remain to be comprehensively explored. In addition, recent studies have identified potential utility for targeting the LXRs during therapy with other agents, such as glucocorticoids and rexinoids. Despite the pitfalls encountered to date in translation of LXR agonists to human disease, it appears likely that this accelerating field will ultimately yield effective and safe applications for LXR targeting in humans.

中文翻译：

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靶向肝脏 X 受体治疗炎症性疾病的挑战和前景。

肝脏 X 受体 (LXR) 是氧甾醇激活的转录因子，可上调一组基因，这些基因共同促进细胞和体内过量胆固醇的协调动员。与其他核受体一样，LXR 具有抗炎作用，可抑制核因子-κB 对促炎基因的信号依赖性诱导，激活蛋白-1 和其他转录因子。在临床前动物模型中，合成的 LXR 激动剂已被证明可以改善动脉粥样硬化和多种炎症性疾病。尽管这表明了应用于人类疾病的潜力，但全身性 LXR 激活因肝脏脂肪变性和高甘油三酯血症而复杂化，这是 LXRα 在肝脏中诱导脂肪生成基因的后果。在过去的几年里，已经出现了多种旨在避免肝脏脂肪生成的先进 LXR 疗法，包括 LXRβ 选择性激动剂、组织选择性激动剂和反式抑制选择性激动剂。尽管几种合成的 LXR 激动剂已进入 I 期临床试验，但由于不可预见的不良反应或未公开的原因，均未取得进展。尽管如此，一些复杂的药理学策略，包括结构指导的药物设计、细胞特异性药物靶向以及非全身药物途径已经启动，仍有待全面探索。此外，最近的研究已经确定了在使用其他药物（如糖皮质激素和 rexinoids）治疗期间靶向 LXR 的潜在效用。