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

高血浆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 动脉粥样硬化的迁移和消退。这在体内通过诱导 趋化因子受体CCR7通过LXR？此外，动脉粥样硬化的消退和 CCR7的表达在糖尿病小鼠中受损。我们最近发现， LXR的S198磷酸化水平在进展性动脉粥样硬化斑块中较高， 因此，我们认为，血浆中CCR7的变化可能是由于CCR7基因的转录水平降低而导致的。 胆固醇和葡萄糖水平是LXR基因表达的重要调节因子 通过改变LXR在S198的磷酸化。为了验证这一点， 综合系统生物学方法结合强大的小鼠模型， 用复杂的基因组学方法阐明动脉粥样硬化消退 动脉粥样硬化和糖尿病中LXR介导的基因调控机制。见解 从这些基础研究将告知治疗动脉粥样硬化的新方法， 尤其是糖尿病患者。

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.