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.
Patients with diabetes have a number of complications including cardiovascular disease (CVD). In fact, high cholesterol and high glucose are recognized risk factors for CVD. Using powerful mouse and cell culture models, coupled with state of the art genomic approaches, we will examine the effects of high cholesterol and high glucose on the action in macrophages, the building blocks of atherosclerotic plaques, of the nuclear receptor LXR?, which protects these cells against adverse effects of high cholesterol and glucose. Understanding the mechanisms whereby cholesterol and glucose impact LXR? gene regulatory functions will inform new approaches for treating diabetes and atherosclerosis.
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