The inhibition of cholesteryl ester transfer protein: a long and winding road.

Journal of Lipid Research Volume 53, 2012 1039 Copyright © 2012 by the American Society for Biochemistry and Molecular Biology, Inc. The presence in human plasma of a protein that promotes bidirectional transfers of neutral lipids (cholesteryl esters and triglycerides) between all lipoprotein particles was fi rst reported in 1978 ( 1 , 2 ). This protein was identifi ed as cholesteryl ester transfer protein (CETP) and subsequently cloned in 1987 by Drayna et al. ( 3 ). CETP promotes the equilibration of cholesteryl esters and triglycerides between HDL, LDL, and triglyceride-rich lipoproteins (TRL), which include VLDL that are produced in the liver, intestinally-derived chylomicrons, and chylomicron remnants. As most of the cholesteryl esters in plasma originate in HDL in the reaction catalyzed by lecithin:cholesterol acyltransferase, and triglycerides mostly enter the plasma compartment as a component of TRL, this process of equilibration results in a net mass transfer of cholesteryl esters from potentially anti-atherogenic HDL particles to LDL and TRL, which are known to be atherogenic. Subsequent studies of Taq1 B polymorphisms of the CETP gene provided the fi rst indication of an inverse relationship between CETP gene expression and activity and plasma HDL-cholesterol levels ( 4 ). This raised the possibility that inhibition of CETP activity may increase the concentration of HDL, thereby reducing cardiovascular risk, This relationship is supported by a recent meta-analysis of 92 studies involving 113,833 participants, which concluded that people carrying CETP gene polymorphisms that are associated with decreased CETP activity and mass have elevated HDL-cholesterol levels and are at decreased risk of having a coronary event ( 5 ). A similar conclusion was drawn from an analysis of a cohort of 18,245 healthy Americans in the Women ’ s Genome Health Study ( 6 ). A major advance in the CETP story came in 1990 with the identifi cation of several unrelated families in Japan with CETP defi ciency and high plasma HDL levels ( 7 , 8 ). These individuals also had reduced apoB and LDL levels, which was attributed to increased catabolism of apoBcontaining lipoproteins ( 9 ). It was also noteworthy that these people did not have atherosclerosis or other cardiovascular diseases. These observations agree with the results from a recent meta-analysis of several human population studies The inhibition of cholesteryl ester transfer protein: a long and winding road 1