The long term objective of this study is to investigate the role of cholesteryl ester transfer (CET) reaction in the regulation of lecithin- cholesterol acyltrasferase (LCAT) activity and the phospholipid composition of lipoproteins. In this pilot project we propose to address this question by employing the recently identified families of high HDL1 baboons which have an inhibitor of CET reaction in their plasma, and which accumulate high concentration of HDL1 in response to high cholesterol high saturated fat (HCSF) diet. The LCAT activity will be assayed in the whole plasma of high and low HDL1 baboons before and after HCSF diet to determine whether CET inhibition in vivo results in feed-back inhibition of the LCAT reaction also. It is postulated that the paradoxical elevation of LDL in these baboons, despite the lack of CE transfer from HDL to LDL and the lack of increased apo B synthesis by liver, is due to the direct action of LCAT on LDL, as a result of LCAT inhibition in HDL. To test this hypothesis, various lipoprotein fractions will be prepared from the low and high HDL1 baboons and evaluated as substrates for purified baboon LCAT. The relative contributions of LDL and HDL for CE formation in intact plasma of low and high HDL1 animals will be studied in order to determine whether more LCAT reaction takes place on LDL in high HDL1 baboons compared to low HDL1 animals. The phospholipid composition of apo E-containing and apo E-free HDL1 particles will be studied in order to determine whether the surface lipid composition influences the binding of apo E to HDL1 and thus regulate the clearance of HDL1. The possibility that the CET inhibitor protein also inhibits the redistribution of phospholipids between the lipoproteins will be investigated by determining the phospholipid transfer activity in low and high HDL1 baboons. These studies are expected to provide valuable novel information on the possible roles of CETP and its inhibitor protein in the regulation of LCAT activity, as well as in the re-distribution of phospholipids among the lipoproteins.
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