The overall goal of the project during this period has been to understand, at a molecular level, how cholesterol from the diet is metabolized by the liver. To this end, three specific aims are proposed: 1) To further characterize the remnant removal pathway. Specifically, it appears that there are both LDL receptor-dependent and -independent pathways. We will use an antibody to the LDL receptor to eliminate its contribution to the process and then learn how remnant metabolism proceeds in the absence of the LDL receptor. We will attempt to visualize the process by electron microscopy and to purify the relevant binding site biochemically. The role of hepatic lipase in the removal process will be studied. 2) To study the consequences of LDL receptor-dependent and LDL receptor-independent remnant removal on hepatic lipid metabolism. Specifically, we will determine the amount and effects of non-LDL receptor-mediated remnant transport and attempt to explain the basis for the slower rate of degradation of remnants than beta-VLDL. 3) To characterize non-cholesterol mediated regulation of hepatic LDL receptors in liver and evaluate the consequence of this on remnant metabolism. Specifically, we will examine the mechanism whereby insulin and an as yet unidentified liver specific growth factor stimulate LDL receptors. We will conduct further studies of mechanisms of neoplasia-induced decrease in LDL receptors. The understanding achieved by these studies may eventually aid in the design of regimens that lead to the prevention of atherosclerosis and cholelithiasis.
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