Plasma cholesteryl ester transfer protein and high-density lipoproteins: new insights from molecular genetic studies

Recent studies in transgenic mice provide strong evidence for a direct anti-atherogenic role of high-density lipoproteins (HDL) and highlight the importance of multiple gene interactions in the regulation of HDL levels. Plasma lipid transfer processes mediated by cholesteryl ester transfer protein (CETP) have a major impact on HDL levels, as revealed in studies of human genetic CETP deficiency and CETP transgenic mice. Subsequent to the discovery of an intron 14 CETP gene splicing defect, several new CETP gene mutations have been discovered recently in Japanese and other populations. One of these is an exon 15 missense mutation, changing amino acid 442 of CETP from aspartate to glycine. Population studies in Japan indicate that CETP gene mutations are sufficiently common to have a significant influence on HDL levels in the general population. Studies in transgenic mice show that CETP expression results in decreased levels of HDL cholesterol, but that the effects of CETP on HDL apolipoprotein A-I (apoA-I) content and size show important modulation by co-expression with transgenes encoding human apoA-I, apoC-III and apoA-II. In addition to the apparent antiatherogenic phenotype of human genetic CETP deficiency, high level expression of CETP in transgenic mice leads to accelerated atherosclerosis, illustrating the pro-atherogenic potential of CETP expression.