The overall objective of this research is to determine the mechanism by which phospholipid infusions produce rapid, substantial regression of experimental atherosclerosis. This knowledge will allow rational modifications in the treatment and may eventually allow its application to the human disease. The present proposal will focus on the metabolism of infused phospholipid vesicles. Under the proper circumstances, these particles persist in the circulation for hours, acquire large amounts of endogenous cholesterol and apolipoprotein-E, and appear to be gradually taken up by the liver. Initial studies will be in three areas. First, to explore the mechanism by which vesicles may transport cholesterol from the periphery to the liver, the role of hepatic LDL receptors in hepatic uptake of vesicular particles will be determined. Hepatic clearance will be measured in rabbits with stimulated, suppressed, saturated, or absent hepatic LDL receptors. Second, because vesicles block the ability of B-VLDL, and atherogenic lipoprotein, to cholesterol-load cultured macrophages, blockage of B-VLDL uptake by aortic macrophages will be measured in vivo. Aortic uptake of 125 I-dilactitol tyramine-labeled B-VLDL will be compared in phospholipid-infused and saline-infused animals. Third, the abilities of infused vesicles of different size and composition to acquire endogenous cholesterol, to undergo hepatic clearance, and to block macrophage uptake of B-VLDL will be compared. Subsequent studies will depend on the results of these initial studies. If hepatic LDL receptors are found to be involved in hepatic uptake of vesicular particles, agents that stimulate hepatic LDL receptors will be examined for their ability to accelerate phospholipid-induced regression of atherosclerosis. Conversely, if substantial hepatic uptake of vesicles occurs in the absence of hepatic LDL receptors, the alternate pathways for uptake will be investigated in vitro. Also, the ability of phospholipid infusions to prevent or reverse atherosclerosis in receptor-deficient rabbits will be determined. This last study will be of particular interest, because atherosclerosis in receptor- deficient rabbits closely resembles the human disease in histology and anatomic distribution. The ultimate goal is a rational, non-invasive treatment that produces regression of atherosclerosis in humans.
| Williams, Kevin Jon; Tabas, Ira; Fisher, Edward A (2015) How an artery heals. Circ Res 117:909-13 |
| Williams, Kevin Jon; Chen, Keyang (2010) Recent insights into factors affecting remnant lipoprotein uptake. Curr Opin Lipidol 21:218-28 |
