Partial suppression of CETP activity beneficially modifies the lipid transfer profile of plasma.
Cholesteryl ester transfer protein (CETP) regulates human lipoprotein metabolism. Because reducing CETP increases plasma HDL, CETP inhibitors are currently being investigated for their pharmacologic value. However, complete CETP deficiency may have undesirable consequences. In contrast, based on previous studies with purified components, we hypothesized that partial CETP inhibition, which will still elevate HDL, may induce beneficial changes in plasma lipid metabolism. To address this, CETP activity in human plasma was variably inhibited with monoclonal antibody. In control plasma, VLDL to LDL lipid transfer was >2-fold higher than to HDL(3) with lipid transfer to HDL(2) intermediate. However, individual lipid transfer events were uniquely sensitive to CETP suppression such that when CETP activity was inhibited by 60%, lipid transfer from VLDL to LDL, HDL(2) and HDL(3) were equal. The ratio of lipid transfers to LDL versus HDL declined linearly with CETP inhibition. In mass lipid transfer experiments, 25-50% inhibition of CETP significantly reduced lipid flux between VLDL and LDL but minimally affected cholesteryl ester (CE) loss from HDL. Complete CETP inhibition did not reduce cholesterol esterification rates but completely blocked the delivery of new CE to VLDL, whereas, 50% inhibition of CETP reduced this CE flux to VLDL by <20%. Thus, inhibition of CETP by <or=50% preferentially blocks lipid transfers involving LDL while largely maintaining lipid flux through HDL. These results suggest that a more beneficial therapeutic outcome may be achieved with partial, rather than extensive, CETP suppression.
Morton
Richard E
RE
Department of Cell Biology, NC 10, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, United States. mortonr@ccf.org <mortonr@ccf.org>
Greene
Diane J
DJ
D019138:Antibodies, Blocking / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000187:drug effects*; D002460:Cell Line; D053480:Cholesterol Ester Transfer Proteins / Q000187:drug effects*; D004951:Esterification / Q000187:drug effects; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D053439:Lipoproteins, HDL2 / Q000187:drug effects / Q000378:metabolism*; D053440:Lipoproteins, HDL3 / Q000187:drug effects / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000187:drug effects / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D010949:Plasma / Q000201:enzymology
D019138:Antibodies, Blocking; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D053439:Lipoproteins, HDL2; D053440:Lipoproteins, HDL3; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D007862:Phosphatidylcholine-Sterol O-Acyltransferase