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

描述（由申请人提供）：高血浆胆固醇和糖尿病是动脉粥样硬化的主要危险因素。我们已经在小鼠模型中表明，降低胆固醇水平促进巨噬细胞迁移和动脉粥样硬化消退。这在体内通过LXR？诱导趋化因子受体CCR 7介导。此外，在糖尿病小鼠中，动脉粥样硬化的消退和CCR 7的表达受损。我们最近发现LXR的S198磷酸化在进展性动脉粥样硬化斑块中是高的，并且在体外降低CCR 7转录。因此，我们认为血浆胆固醇和葡萄糖水平的变化是LXR <$基因表达的重要调节剂，通过改变LXR <$在S198的磷酸化。为了验证这一点，我们将采取一种综合的系统生物学方法，将强大的动脉粥样硬化消退小鼠模型与复杂的基因组学方法相结合，以阐明LXR介导的动脉粥样硬化和糖尿病基因调控机制。从这些基础研究中获得的见解将为治疗动脉粥样硬化，特别是糖尿病患者提供新的方法。

DESCRIPTION (provided by applicant): 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, we will 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.