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

描述(申请人提供)：高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，降低胆固醇水平可以促进巨噬细胞迁移和动脉粥样硬化的消退。这在体内是通过LXR�诱导趋化因子受体CCR7介导的。此外，糖尿病小鼠动脉粥样硬化的消退和CCR7的表达受到损害。我们最近发现，在动脉粥样硬化斑块的进展中，LXRCCR7S198的磷酸化水平很高，并且在体外降低了�的转录。因此，我们认为血浆胆固醇和血糖水平的变化是LxR�基因表达的重要调节因素，它通过S198上LxR�磷酸化的变化来实现。为了验证这一点，我们将采用一种综合的系统生物学方法，结合强大的动脉粥样硬化消退小鼠模型和复杂的基因组学方法来阐明LXR�介导的动脉粥样硬化和糖尿病的基因调控机制。这些基础研究的见解将为治疗动脉粥样硬化提供新的方法，特别是在糖尿病患者中。

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.