Inhibition of cholesteryl ester transfer protein activity by monoclonal antibody. Effects on cholesteryl ester formation and neutral lipid mass transfer in human plasma

Abstract

We have employed a neutralizing monoclonal antibody, prepared against the Mr 74,000 cholesteryl ester transfer protein (CETP), to investigate the regulation of lecithin:cholesterol acyltransferase (LCAT) activity by cholesteryl ester (CE) transfer, and also to determine which lipoproteins are substrates for LCAT in human plasma. The incubation of normolipidemic plasma led to transfer of CE from HDL to VLDL, and of triglycerides from VLDL to LDL and HDL. This net mass transfer of neutral lipids between the lipoproteins was eliminated by the monoclonal antibody. However, CE transfer inhibition had no effect on the rate of plasma cholesterol esterification in plasma incubated from 10 min to 24 h at 37 degrees C. In the absence of CE transfer, HDL and LDL exhibited cholesterol esterification activity, whereas VLDL did not. The rate of CE formation in HDL was three to four times greater than in LDL during the first hour of incubation, but CE formation in HDL decreased after 6-8 h, while that in LDL continued. Thus, (a) the Mr 74,000 CETP is responsible for all neutral lipid mass transfer in incubated human plasma, (b) the rate of CE formation in plasma is not regulated by CE transfer from HDL to other lipoproteins, and (c) HDL is the major initial substrate for LCAT; LDL assumes a more significant role only after prolonged incubation of plasma.