Synthetic LXR ligand inhibits the development of atherosclerosis in mice
Synthetic LXR ligand inhibits the development of atherosclerosis in mice
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DOI：
10.1073/pnas.112059299
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发表时间：
2002-05-28
影响因子：
11.1
通讯作者：
Tontonoz, P
中科院分区：
文献类型：
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作者：
Joseph, SB;McKilligin, E;Tontonoz, P
核受体LXR α和LXR β参与多种细胞类型中胆固醇和脂肪酸代谢的控制。这些受体的激活刺激巨噬细胞中的胆固醇流出，促进肝脏中胆汁酸的合成，并抑制肠胆固醇吸收，这些作用共同预期会降低动脉粥样硬化的风险。然而，合成的LXR配体也已显示在小鼠中诱导脂肪生成和高脂血症，这引起了关于这些化合物对心血管疾病发展的净效应的问题。我们在这里证明，非甾体类LXR激动剂GW 3965在两种不同的小鼠模型中具有有效的抗动脉粥样硬化活性。在LDLR-/-小鼠中，GW 3965使雄性和雌性的病变面积分别减少了53%和34%。在雄性apoE（-/-）小鼠中观察到类似的47%的降低。LXR激动剂长期（12周）给药对LDLR-/-和apoE（-/-）小鼠的血脂谱具有不同的影响。GW 3965诱导的ATP结合盒A1和G1在体外修饰的低密度脂蛋白负载的巨噬细胞，以及在高脂血症小鼠的动脉粥样硬化的表达，这表明直接作用的LXR配体血管基因表达可能有助于其抗动脉粥样硬化的效果。这些观察结果为LXR激动剂的动脉粥样硬化保护作用提供了直接证据，并支持其作为人类心血管疾病潜在调节剂的进一步评价。
The nuclear receptors LXRalpha and LXRbeta have been implicated in the control of cholesterol and fatty acid metabolism in multiple cell types. Activation of these receptors stimulates cholesterol efflux in macrophages, promotes bile acid synthesis in liver, and inhibits intestinal cholesterol absorption, actions that would collectively be expected to reduce atherosclerotic risk. However, synthetic LXR ligands have also been shown to induce lipogenesis and hypertriglyceridemia in mice, raising questions as to the net effects of these compounds on the development of cardiovascular disease. We demonstrate here that the nonsteroidal LXR agonist GW3965 has potent antiatherogenic activity in two different murine models. In LDLR-/- mice, GW3965 reduced lesion area by 53% in males and 34% in females. A similar reduction of 47% was observed in male apoE(-/-) mice. Long-term (12-week) treatment with LXR agonist had differential effects on plasma lipid profiles in LDLR-/- and apoE(-/-) mice. GW3965 induced expression of ATP-binding cassettes A1 and G1 in modified low-density lipoprotein-loaded macrophages in vitro as well as in the aortas of hyperlipidemic mice, suggesting that direct actions of LXR ligands on vascular gene expression are likely to contribute to their antiatherogenic effects. These observations provide direct evidence for an atheroprotective effect of LXR agonists and support their further evaluation as potential modulators of human cardiovascular disease.