Cholesteryl ester transfer protein (CETP) inhibition beyond raising high-density lipoprotein cholesterol levels: pathways by which modulation of CETP activity may alter atherogenesis.
Raising high-density lipoprotein cholesterol (HDL-C) is a promising strategy in the struggle to prevent cardiovascular disease, and cholesteryl ester transfer protein (CETP) inhibitors have been developed to accomplish this. The first results are encouraging, and, in fact, in rabbits, inhibition of CETP reduces atherosclerosis. Because human data regarding the reduction of atheroma burden require more time, the biochemical mechanisms underlying the putative atheroprotection of CETP inhibitors are currently dissected, and several pathways have emerged. First, CETP inhibition increases HDL-C and reduces low-density lipoprotein cholesterol (LDL-C) levels consistent with CETP lipid transfer activity and its role in reverse cholesterol transport (RCT). This coincides with putative beneficial increases in both HDL and LDL size. However, many aspects regarding the impact of CETP inhibition on the RCT pathway remain elusive, in particular whether the first step concerning cholesterol efflux from peripheral tissues to HDL is influenced. Moreover, the relevance of scavenger receptor BI and consequently the central role of HDL in human RCT is still unclear. Second, CETP inhibition was shown recently to increase antioxidant enzymes associated with HDL, in turn associated with decreased oxidation of LDL. Atheroprotection in man is currently anticipated based on the improvement of these biochemical parameters known to influence atherosclerosis, but final confirmation regarding the impact of CETP inhibition on cardiovascular outcome will have to come from trials evaluating clinical end points.
Klerkx
Anke H E M
AH
Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
El Harchaoui
Karim
K
van der Steeg
Wim A
WA
Boekholdt
S Matthijs
SM
Stroes
Erik S G
ES
Kastelein
John J P
JJ
Kuivenhoven
Jan Albert
JA
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D001692:Biological Transport; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D011817:Rabbits; D051122:Scavenger Receptors, Class B / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D006023:Glycoproteins; D051122:Scavenger Receptors, Class B