Abstract
Two inhibitors of cynomolgus monkey cholesteryl ester transfer protein were evaluated. One, a monoclonal antibody made against purified cynomolgus monkey cholesteryl ester transfer protein, was capable of severely inhibiting triglyceride transfer, but had a variable effect on cholesteryl ester transfer. At low antibody to antigen ratios, there was what appeared to be a stoichiometric inhibition of cholesteryl ester transfer, but at high antibody to antigen ratios the inhibition of cholesteryl ester transfer was completely relieved, even though triglyceride transfer remained blocked. Fab fragments of the antibody had no effect whatsoever on cholesteryl ester transfer, but were capable of completely blocking triglyceride transfer. The other inhibitor, 6-chloromecuric cholesterol, severely inhibited cholesteryl ester transfer with minimal inhibition of triglyceride transfer. When both inhibitors were added to the assay, both cholesteryl ester and triglyceride transfer were inhibited; an indication that the inhibitors did not compete for the same binding site on cholesteryl ester transfer protein. When the antibody was given subcutaneously to cynomolgus monkeys at a dose which inhibited triglyceride transfer in the plasma by more than 90%, there was no detectable effect on the high density lipoprotein (HDL) cholesterol level, but the HDL triglyceride levels decreased from 13 +/- 2 to 1 +/- 0 mol/mol of HDL (mean +/- S.D.); an indication that the antibody uncoupled cholesteryl ester and triglyceride transfer in vivo. The 6-chloromecuric cholesterol could not be evaluated in vivo because it is a potent lecithin:cholesterol acyltransferase inhibitor. The fact that cholesteryl ester transfer can be inhibited without effect on triglyceride transfer and, conversely, that triglyceride transfer can be inhibited without effect on cholesteryl ester transfer indicates that these two lipids are not transferred by a single, non-discriminatory process.
Highlights
When the antibody was given subcutaneously to cynomolgus monkeys at a dose which inhibited triglyceride transfer in the plasma by more than 90%, there was no detectable effect on the high density lipoprotein (HDL) cholesterol level, but the HDL triglyceride levels decreased from 13 ؎ 2 to 1 ؎ 0 mol/mol of HDL; an indication that the antibody uncoupled cholesteryl ester and triglyceride transfer in vivo
The fact that cholesteryl ester transfer can be inhibited without effect on triglyceride transfer and, that triglyceride transfer can be inhibited without effect on cholesteryl ester transfer indicates that these two lipids are not transferred by a single, non-discriminatory process
The present paper addresses that question using cynomolgus monkey CETP as the transfer protein, and shows that, in vitro, can triglyceride transfer can be inhibited without effect on cholesteryl ester transfer, and that cholesteryl ester transfer can be inhibited without effect on triglyceride transfer
Summary
When the antibody was given subcutaneously to cynomolgus monkeys at a dose which inhibited triglyceride transfer in the plasma by more than 90%, there was no detectable effect on the high density lipoprotein (HDL) cholesterol level, but the HDL triglyceride levels decreased from 13 ؎ 2 to 1 ؎ 0 mol/mol of HDL (mean ؎ S.D.); an indication that the antibody uncoupled cholesteryl ester and triglyceride transfer in vivo. Most noteworthy is the observation that the carboxyl-terminal 38 amino acids of the two proteins are identical, for that is the region of CETP thought to be essential for lipid transfer [11,12,13,14,15]. This high degree of homology between the human and cynomolgus monkey proteins implies that observations made using the monkey protein are germane to our understanding of human CETP structure and function. We present evidence that cholesteryl ester transfer can be uncoupled from triglyceride transfer in vivo
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