Ligand activation of LXRβ reverses atherosclerosis and cellular cholesterol overload in mice lacking LXRα and apoE
Ligand activation of LXRβ reverses atherosclerosis and cellular cholesterol overload in mice lacking LXRα and apoE
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DOI：
10.1172/jci31909
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发表时间：
2007-08-01
影响因子：
15.9
通讯作者：
Tontonoz, Peter
中科院分区：
文献类型：
--
作者：
Bradley, Michelle N.;Hong, Cynthia;Tontonoz, Peter
肝脏X受体（LXRs）α和β是胆固醇稳态的转录调节因子，也是开发抗动脉粥样硬化药物的潜在靶点。然而，个别LXR同种型在动脉粥样硬化中的具体作用和合成激动剂的药理学作用仍不清楚。先前的研究表明，缺乏LXR α的小鼠在肝脏中积累胆固醇，但不在外周组织中。与此形成鲜明对比的是，我们在此证明LXR alpha（-）/（-）apoE（-）/（-）小鼠在外周组织中表现出极端的胆固醇积聚，全身胆固醇负荷急剧增加，并加速动脉粥样硬化。这些小鼠的表型表明，通过LXR和内源性配体实现的巨噬细胞中的LXR途径活化水平不能在高胆固醇血症的情况下维持稳态。然而，令人惊讶的是，一种高效的合成激动剂能够补偿LXR α的损失。用合成LXR配体治疗LXR alpha（-）/（-）apoE（-）/（-）小鼠可改善胆固醇超载表型并减少动脉粥样硬化。这些观察结果表明，LXR α在维持高胆固醇血症背景下的外周胆固醇稳态方面具有重要作用，并为靶向LXR β的药物开发策略提供体内支持。
Liver X receptors (LXRs) alpha and beta are transcriptional regulators of cholesterol homeostasis and potential targets for the development of antiatherosclerosis drugs. However, the specific roles of individual LXR isotypes in atherosclerosis and the pharmacological effects of synthetic agonists remain unclear. Previous work has shown that mice lacking LXR alpha accumulate cholesterol in the liver but not in peripheral tissues. In striking contrast, we demonstrate here that LXR alpha(-)/(-)apoE(-)/(-) mice exhibit extreme cholesterol accumulation in peripheral tissues, a dramatic increase in whole-body cholesterol burden, and accelerated atherosclerosis. The phenotype of these mice suggests that the level of LXR pathway activation in macrophages achieved by LXR and endogenous ligand is unable to maintain homeostasis in the setting of hypercholesterolemia. Surprisingly, however, a highly efficacious synthetic agonist was able to compensate for the loss of LXR alpha. Treatment of LXR alpha(-)/(-)apoE(-)/(-) mice with synthetic LXR ligand ameliorates the cholesterol overload phenotype and reduces atherosclerosis. These observations indicate that LXR alpha has an essential role in maintaining peripheral cholesterol homeostasis in the context of hypercholesterolemia and provide in vivo support for drug development strategies targeting LXR beta.