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.
Low plasma high density lipoproteins (HDL)-cholesterol, due to impaired reverse cholesterol transport (RCT), is a serious disorder and public health problem for which current treatments are inadequate. We discovered that streptococal serum opacity factor enhances multiple RCT steps in vitro and in vivo. We plan to move this discovery toward a new therapy by determining whether this process improves RCT and inhibits and/or reverses atherosclerosis in cell and mouse models of lipid disorders and atherosclerosis.
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|Rodriguez, Perla J; Gillard, Baiba K; Barosh, Rachel et al. (2016) Neo High-Density Lipoprotein Produced by the Streptococcal Serum Opacity Factor Activity against Human High-Density Lipoproteins Is Hepatically Removed via Dual Mechanisms. Biochemistry 55:5845-5853|
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|Murray, Stephen C; Gillard, Baiba K; Ludtke, Steven J et al. (2016) Direct Measurement of the Structure of Reconstituted High-Density Lipoproteins by Cryo-EM. Biophys J 110:810-6|
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