Groot Pieter H E, Pearce Nigel J, Yates John W, Stocker Claire, Sauermelch Charles, Doe Christopher P, Willette Robert N, Olzinski Alan, Peters Tambra, d'Epagnier Denise, Morasco Kathleen O, Krawiec John A, Webb Christine L, Aravindhan Karpagam, Jucker Beat, Burgert Mark, Ma Chun, Marino Joseph P, Collins Jon L, Macphee Colin H, Thompson Scott K, Jaye Michael
Cardiovascular Center for Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, PA 19406-0939, USA.
J Lipid Res. 2005 Oct;46(10):2182-91. doi: 10.1194/jlr.M500116-JLR200. Epub 2005 Jul 16.
Liver X receptor (LXR) nuclear receptors regulate the expression of genes involved in whole body cholesterol trafficking, including absorption, excretion, catabolism, and cellular efflux, and possess both anti-inflammatory and antidiabetic actions. Accordingly, LXR is considered an appealing drug target for multiple indications. Synthetic LXR agonists demonstrated inhibition of atherosclerosis progression in murine genetic models; however, these and other studies indicated that their major undesired side effect is an increase of plasma and hepatic triglycerides. A significant impediment to extrapolating results with LXR agonists from mouse to humans is the absence in mice of cholesteryl ester transfer protein, a known LXR target gene, and the upregulation in mice but not humans of cholesterol 7alpha-hydroxylase. To better predict the human response to LXR agonism, two synthetic LXR agonists were examined in hamsters and cynomolgus monkeys. In contrast to previously published results in mice, neither LXR agonist increased HDL-cholesterol in hamsters, and similar results were obtained in cynomolgus monkeys. Importantly, in both species, LXR agonists increased LDL-cholesterol, an unfavorable effect not apparent from earlier murine studies. These results reveal additional problems associated with current synthetic LXR agonists and emphasize the importance of profiling compounds in preclinical species with a more human-like LXR response and lipoprotein metabolism.
肝脏X受体（LXR）核受体调节参与全身胆固醇转运的基因表达，包括吸收、排泄、分解代谢和细胞流出，并且具有抗炎和抗糖尿病作用。因此，LXR被认为是多种适应症的有吸引力的药物靶点。合成LXR激动剂在小鼠遗传模型中显示出抑制动脉粥样硬化进展的作用；然而，这些研究和其他研究表明，它们的主要不良副作用是血浆和肝脏甘油三酯升高。将LXR激动剂的研究结果从小鼠外推至人类的一个重大障碍是，小鼠缺乏胆固醇酯转移蛋白（一种已知的LXR靶基因），且胆固醇7α-羟化酶在小鼠中上调而在人类中未上调。为了更好地预测人类对LXR激动作用的反应，在仓鼠和食蟹猴中检测了两种合成LXR激动剂。与先前在小鼠中发表的结果相反，两种LXR激动剂均未增加仓鼠的高密度脂蛋白胆固醇，在食蟹猴中也得到了类似结果。重要的是，在这两个物种中，LXR激动剂均增加了低密度脂蛋白胆固醇，这一不良效应在早期小鼠研究中并不明显。这些结果揭示了与当前合成LXR激动剂相关的其他问题，并强调了在具有更类似人类LXR反应和脂蛋白代谢的临床前物种中对化合物进行分析的重要性。
