Synthetic LXR agonists increase LDL in CETP species
Synthetic LXR agonists increase LDL in CETP species
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DOI：
10.1194/jlr.m500116-jlr200
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发表时间：
2005-10-01
影响因子：
6.5
通讯作者：
Jaye, M
中科院分区：
文献类型：
--
作者：
Groot, PHE;Pearce, NJ;Jaye, M
肝X受体（LXR）核受体调节参与全身胆固醇运输的基因的表达，包括吸收、排泄、代谢和细胞外排，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标。合成的LXR激动剂在鼠遗传模型中显示出对动脉粥样硬化进展的抑制;然而，这些和其他研究表明，它们的主要不良副作用是血浆和肝脏甘油三酯的增加。将LXR激动剂的结果从小鼠外推到人的一个显著障碍是小鼠中缺乏胆固醇酯转移蛋白（一种已知的LXR靶基因），以及小鼠中胆固醇7 α-羟化酶上调，但人中没有。为了更好地预测人类对LXR激动剂的反应，在仓鼠和食蟹猴中检查了两种合成的LXR激动剂。与先前发表的小鼠结果相反，两种LXR激动剂均未增加仓鼠中的HDL-胆固醇，并且在食蟹猴中获得了类似的结果。重要的是，在这两个物种中，LXR激动剂增加LDL-胆固醇，这是一种在早期小鼠研究中不明显的不利作用。这些结果揭示了与当前合成的LXR激动剂相关的其他问题，并强调了在临床前物种中分析具有更像人类的LXR反应和脂蛋白代谢的化合物的重要性。
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 7 alpha-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.