Regulation of LXR alpha by glucose & cholesterol in diabetes & atherosclerosis

高胆固醇和糖尿病是动脉粥样硬化的主要危险因素。我们有 在小鼠模型中显示，降低胆固醇水平促进巨噬细胞 动脉粥样硬化的移居和消退。这是在体内通过诱导 趋化因子受体CCR7通过LXR？此外，动脉粥样硬化的消退和 糖尿病小鼠CCR7表达受损。我们最近发现， LXR？S198的磷酸化在动脉粥样硬化斑块的进展中和在 体外降低CCR7转录。因此，我们认为血浆中的变化 胆固醇和葡萄糖水平是LXR基因表达的重要调节因素 通过S198位LXR？磷酸化的变化。为了测试这一点，我们将采取一个 综合系统生物学方法结合功能强大的小鼠模型 用复杂的基因组学方法阐明动脉粥样硬化的消退 LXR？在动脉粥样硬化和糖尿病中的基因调控机制。真知灼见 这些基础研究将为治疗动脉粥样硬化提供新的方法， 尤其是在糖尿病患者中。

High plasma cholesterol and diabetes are major risk factors for atherosclerosis. We have shown in mouse models that lowering cholesterol levels promotes macrophage emigration and regression of atherosclerosis. This is mediated in vivo by the induction of the chemokine receptor CCR7 via LXR¿. Moreover, regression of atherosclerosis and expression of CCR7 are impaired in diabetic mice. We have recently found that phosphorylation of S198 of LXR¿ is high in progressing atherosclerotic plaques and in vitro decreases CCR7 transcription.Therefore, we propose that changes in plasma cholesterol and glucose levels are important modulators of LXR¿ gene expression through changes in LXR¿ phosphorylation at S198. To test this will we take an integrated systems biology approach combining powerful mouse models of atherosclerosis regression with sophisticated genomics approaches to elucidate mechanisms of LXR¿-mediated gene regulation in atherosclerosis and diabetes. Insights from these basic studies will inform new approaches to treating atherosclerosis, particularly in diabetics.