Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils
Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils
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DOI：
10.1016/j.cmet.2016.07.016
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发表时间：
2016-08-09
期刊：
影响因子：
29
通讯作者：
Frost, Robert J. A.
中科院分区：
文献类型：
--
作者：
Kirchgessner, Todd G.;Sleph, Paul;Frost, Robert J. A.
用于治疗冠状动脉疾病的LXR激动剂的开发受到动物模型中不期望的性质的挑战。在这里，我们展示了LXR激动剂对人类受试者的脂质和脂蛋白代谢以及中性粒细胞的影响。BMS-852927是一种新型LXR b选择性化合物，在食蟹猴和小鼠的动物模型中具有良好的特征，具有广泛的治疗指数。在健康受试者和高胆固醇血症患者中，诱导的胆固醇逆向转运途径与动物模型相似。然而，血浆和肝脏TG、血浆LDL-C、apoB、apoE和CETP升高以及循环中性粒细胞减少也很明显。此外，在正常胆固醇血症受试者和他汀类药物治疗患者中观察到相似的LDL-C升高。灵长类动物模型明显低估了人类的脂肪生成反应，并没有预测人类中性粒细胞的影响。这些研究证明了有益和不利的LXR激动剂临床反应，并强调了在这一领域进一步转化研究的重要性。
The development of LXR agonists for the treatment of coronary artery disease has been challenged by undesirable properties in animal models. Here we show the effects of an LXR agonist on lipid and lipoprotein metabolism and neutrophils in human subjects. BMS-852927, a novel LXRb-selective compound, had favorable profiles in animal models with a wide therapeutic index in cynomolgus monkeys and mice. In healthy subjects and hypercholesterolemic patients, reverse cholesterol transport pathways were induced similarly to that in animal models. However, increased plasma and hepatic TG, plasma LDL-C, apoB, apoE, and CETP and decreased circulating neutrophils were also evident. Furthermore, similar increases in LDL-C were observed in normocholesterolemic subjects and statin-treated patients. The primate model markedly underestimated human lipogenic responses and did not predict human neutrophil effects. These studies demonstrate both beneficial and adverse LXR agonist clinical responses and emphasize the importance of further translational research in this area.