Atheroregression via Enhanced Reverse Cholesterol Transport

描述（由申请人提供）：胆固醇是一种水不溶性化合物，在动脉粥样硬化的病因学中起着重要作用。胆固醇积聚在动脉壁上的斑块中，导致血液流动受阻，从而导致心脏病发作和中风。尽管降低血浆ldl -胆固醇的他汀类降胆固醇药物取得了成功，但对促进动脉粥样硬化病变中胆固醇的清除并将其转移到肝脏处理的补充疗法的需求仍未得到满足。我们发现了一种细菌蛋白，血清不透明因子（SOF），在低剂量（0.004 mg）下迅速（6分钟）并显著降低小鼠血浆胆固醇的一半。在肝细胞研究的基础上，我们了解到，SOF治疗促进了与血浆蛋白（载脂蛋白e）结合的多种受体对肝脏胆固醇的摄取。我们的计划是通过完成几个目标，使这些发现更接近于人类治疗。第一个是在原代人肝细胞中显示胆固醇去除的机制与在肝细胞系和小鼠肝细胞中一样有效。第二是确定每个相关的肝脏受体对胆固醇去除的贡献。这些信息将有助于选择最合适的辅助治疗，例如他汀类药物。第三，我们将证明，SOF增加了胆固醇从巨噬细胞（动脉粥样硬化所有阶段的重要细胞类型）转移到肝脏进行处理。最后，我们将证明软质动脉粥样硬化在小鼠中逆转。这些目标的完成将为未来在非人类灵长类动物以及最终在动脉粥样硬化高风险患者中的研究铺平道路。方法：肝细胞对放射性微量胆固醇的吸收和清除；使用色谱方法在细胞和小鼠中显示，SOF促进巨噬细胞胆固醇转化为进入肠道处理的水溶性胆汁盐；用化学分析和形态计量学方法观察小鼠动脉病变数量和质量的变化。

DESCRIPTION (provided by applicant): Cholesterol, a water insoluble compound, is a major player in the etiology of atherosclerosis. Cholesterol accumulates in plaques in the arterial wall causing obstructed blood flow leading to heart attacks and strokes. Despite the success of the statin class of cholesterol-lowering drugs, which reduce plasma LDL-cholesterol, there remains an unfulfilled need for complementary therapies that promote the removal of cholesterol from atherosclerotic lesions and its transfer to the liver for disposal. We identified a bacterial protein, serum opacity factor (SOF) that at low doses (0.004 mg) rapidly (6 min) and profoundly reduces by half the plasma cholesterol in mice. On the basis of studies with liver cells, we learned that SOF treatment promotes hepatic cholesterol uptake by multiple receptors that bind to a plasma protein, apolipoprotein E. Our plans are to move these discoveries closer to human therapy by completion of several objectives. The first is to show in primary human hepatocytes that the mechanisms for cholesterol removal are as efficient as they are in hepatic cell lines and in mouse liver cells. The second is to determine the contributions of each relevant liver receptor to cholesterol removal. This information would be useful in making choices about the most appropriate co therapy, e.g., a statin. Third, we will show that SOF increases the transfer of cholesterol from macrophages, an important cell type in all stages of atherosclerosis, to the liver for disposal. Lastly, we will show that SOF reverses atherosclerosis in mice. Completion of these objectives would pave the way to future studies in non human primates and ultimately in high risk patients with atherosclerosis. Methods: Radio trace cholesterol uptake and removal by liver cells in response to SOF; use chromatographic methods to show in cells and mice that SOF promotes conversion of macrophage-cholesterol to water-soluble bile salts that enter the intestine for disposal; characterize in mice the changes in response to SOF in the quantity and quality of arterial lesions by chemical analysis and morphometry.