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首页> 外文期刊>Cell metabolism >Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils
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Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils

机译:LXR激动剂对人体脂质和脂蛋白代谢及中性粒细胞循环的有益和不良影响

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摘要

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.
机译:在动物模型中,LXR激动剂用于治疗冠状动脉疾病的开发受到了不良特性的挑战。在这里,我们显示了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是一种新型的LXRb选择性化合物,在食蟹猴和小鼠的动物模型中具有良好的治疗效果,并且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,胆固醇逆向转运途径的诱导与动物模型相似。但是,血浆和肝TG,血浆LDL-C,apoB,apoE和CETP升高,循环中性粒细胞减少也很明显。此外,在正常胆固醇血症的受试者和他汀类药物治疗的患者中观察到了类似的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,并且不能预测人类的嗜中性粒细胞作用。这些研究证明了LXR激动剂的有益和不良临床反应,并强调了在这一领域进行进一步翻译研究的重要性。

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