Phenex Pharmaceuticals AG, Heidelberg, Germany.
J Pharmacol Exp Ther. 2012 Dec;343(3):556-67. doi: 10.1124/jpet.112.196519. Epub 2012 Aug 23.
Farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor, plays an important role in the regulation of cholesterol and more specifically high-density lipoprotein (HDL) homeostasis. Activation of FXR is reported to lead to both pro- and anti-atherosclerotic effects. In the present study we analyzed the impact of different FXR agonists on cholesterol homeostasis, plasma lipoprotein profiles, and transhepatic cholesterol efflux in C57BL/6J mice and cynomolgus monkeys and atherosclerosis development in cholesteryl ester transfer protein transgenic (CETPtg) low-density lipoprotein receptor (LDLR) (-/-) mice. In C57BL/6J mice on a high-fat diet the synthetic FXR agonists isopropyl 3-(3,4-difluorobenzoyl)-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (FXR-450) and 4-[2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]phenyl]cyclopropyl]benzoic acid (PX20606) demonstrated potent plasma cholesterol-lowering activity that affected all lipoprotein species, whereas 3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl]benzoic acid (GW4064) and 6-ethyl chenodeoxycholic acid (6-ECDCA) showed only limited effects. In FXR wild-type mice, but not FXR(-/-) mice, the more efficacious FXR agonists increased fecal cholesterol excretion and reduced intestinal cholesterol (re)uptake. In CETPtg-LDLR(-/-) mice PX20606 potently lowered total cholesterol and, despite the observed HDL cholesterol (HDLc) reduction, caused a highly significant decrease in atherosclerotic plaque size. In normolipidemic cynomolgus monkeys PX20606 and 6-ECDCA both reduced total cholesterol, and PX20606 specifically lowered HDL(2c) but not HDL(3c) or apolipoprotein A1. That pharmacological FXR activation specifically affects this cholesterol-rich HDL(2) subclass is a new and highly interesting finding and sheds new light on FXR-dependent HDLc lowering, which has been perceived as a major limitation for the clinical development of FXR agonists.
法尼醇 X 受体（FXR）是一种胆汁酸激活的核激素受体，在胆固醇的调节中发挥着重要作用，尤其是在高密度脂蛋白（HDL）的稳态调节中。研究表明，FXR 的激活既具有抗动脉粥样硬化作用，也具有促动脉粥样硬化作用。在本研究中，我们分析了不同 FXR 激动剂对胆固醇稳态、血浆脂蛋白谱以及 C57BL/6J 小鼠和食蟹猴肝内胆固醇流出的影响，并研究了 FXR 激动剂在胆固醇酯转移蛋白转基因（CETPtg）低密度脂蛋白受体（LDLR）（-/-）小鼠中的动脉粥样硬化发展中的作用。在高脂肪饮食的 C57BL/6J 小鼠中，合成的 FXR 激动剂异丙基 3-(3,4-二氟苯甲酰基)-1,1-二甲基-1,2,3,6-四氢氮杂环庚并[4,5-b]吲哚-5-羧酸（FXR-450）和 4-[2-[2-氯-4-[[5-环丙基-3-(2,6-二氯苯基)-4-异噁唑基]甲氧基]苯基]环丙基]苯甲酸（PX20606）表现出很强的降低血浆胆固醇的活性，影响所有脂蛋白种类，而 3-[2-[2-氯-4-[[3-(2,6-二氯苯基)-5-（1-甲基乙基）-4-异噁唑基]甲氧基]苯基]乙烯基]苯甲酸（GW4064）和 6-乙基鹅去氧胆酸（6-ECDCA）则仅有有限的作用。在 FXR 野生型小鼠中，但在 FXR（-/-）小鼠中，更有效的 FXR 激动剂增加了粪便胆固醇排泄并减少了肠道胆固醇（再）摄取。在 CETPtg-LDLR（-/-）小鼠中，PX20606 可显著降低总胆固醇，尽管观察到高密度脂蛋白胆固醇（HDLc）降低，但显著降低了动脉粥样硬化斑块的大小。在正常血脂的食蟹猴中，PX20606 和 6-ECDCA 均降低了总胆固醇，而 PX20606 特异性降低了富含胆固醇的 HDL（2c），但不降低 HDL（3c）或载脂蛋白 A1。药理 FXR 激活特异性影响这种富含胆固醇的 HDL（2）亚类，这是一个新的、非常有趣的发现，为 FXR 依赖性 HDLc 降低提供了新的视角，这一直被认为是 FXR 激动剂临床开发的主要限制。
