Cholesteryl ester transfer protein and its inhibition

Abstract

Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that facilitates the transfer of cholesteryl esters from the atheroprotective high density lipoprotein (HDL) to the proatherogenic low density lipoprotein cholesterol (LDL) and very low density lipoprotein cholesterol (VLDL) leading to lower levels of HDL but raising the levels of proatherogenic LDL and VLDL. Inhibition of CETP is considered a potential approach to treat dyslipidemia. However, discussions regarding the role of CETP-mediated lipid transfer in the development of atherosclerosis and CETP inhibition as a potential strategy for prevention of atherosclerosis have been controversial. Although many animal studies support the hypothesis that inhibition of CETP activity may be beneficial, negative phase III studies on clinical endpoints with the CETP inhibitor torcetrapib challenged the future perspectives of CETP inhibitors as potential therapeutic agents. The review provides an update on current understanding of the molecular mechanisms involved in CETP activity and its inhibition.

Fig. 1

CETP facilitates bi-directional transfer of cholesteryl esters and triglycerides between plasma lipoproteins. The overall effect of the heteroexchange is the transfer of cholesteryl ester from HDL to triglyceride-rich lipoprotein (TRL like VLDL) and LDL and a transfer of triglycerides from TRL to LDL and HDL. CE cholesterylester; VLDL very low density lipoproteins, triglyceride-rich; TG triglycerides; SRB1 scavenger receptor B1; FC free cholesterol; LCAT lecithin:cholesterol acetyltransferase