Critical role of cholesterol transfer protein in atherosclerosis development

D A Dorovsky,A L Zagayko

doi:10.24959/ubphj.16.78

Abstract

Cholesterol ester transfer protein (CETP) is a plasma protein that facilitates the transport of cholesterol esters and triglicerides between the lipoproteins. CETP collects triglycerides from very-low-density lipoproteins (VLDL) or low-density lipoproteins (LDL) and exchanges them for cholesterol esters from high-density lipoproteins (HDL). Mutations wich lead to the cholesterol ester transfer protein function reduction have been involved in atherosclerosis development. This mutations also increase the prevalence of coronary heart disease in patients with hypertriglyceridemia. There is a wide variety of HDL-C increase therapies that have been tested during the last ten years. Among them is the modification of cholesterol ester transfer protein function. A novel pharmacologic strategy was proposed where drugs are designed to modify the lipid substrate preference of cholesterol ester transfer protein instead of simply blocking its activity. This approach provides an opportunity to improve the lipid transfer properties of cholesterol ester transfer protein and to harness its capacity to alter lipid metabolism to achieve specific beneficial outcomes.

Highlights

Interaction of discoidal nascent high-density lipoproteins (HDL) with Cholesterol ester transfer protein (CETP) The associations between the HDL metabolism, plasma level of HDL-cholesterol (HDL-C), and the atheroprotective functions of HDL have been the main forces to make HDL a potential therapeutic target [9, 14]
Negative-stain electron microscopy (EM) experiments have demonstrated that CETP binds to the edge of nascent HDL since CETP curvature proved to match the edge of nascent HDL perfectly, while barely attaching at the narrow top side [6]
Lipid transfer mechanism mediated by CETP upon penetration into HDL CETP faciliates the transfer of cholesterol oleate (ChOE) from HDL to apoB-100-containing lipoproteins, primarily to low-density lipoproteins [34]

Summary

CRITICAL ROLE OF CHOLESTEROL TRANSFER PROTEIN IN ATHEROSCLEROSIS DEVELOPMENT

Cholesterol ester transfer protein (CETP) is a plasma protein that facilitates the transport of cholesterol esters and triglicerides between the lipoproteins. Cholesterol ester transfer protein induced a change in the nascent HDL particle structure The mechanism behind this interaction is the strong ionic interaction with POPC located at the surface of the discoidal high-density lipoprotein particles , as well as interactions with apoA-I. Close contacts were established between the molecules of estradiol oleate and amino acids of Ω5 (with the Trps located at the beginning of the interaction) These contribute to the immobilization of cholesterol ester transfer protein on high-density lipoprotein particles, allowing further penetration of HDL by CETP, wich induces the opening formation at the N barrel domain end of cholesterol ester transfer protein molucule. The number of apoA-I per high-density lipoprotein particle contributes to the interaction of cholesterol ester transfer protein with HDL and accelerates the process of penetration by immobilization of CETP molecule. The highest level of cholesterol ester transfer protein expression can be observed in tissues that store lipids [8]

Cellular TG synthesis and movement

Effect of CETP mutations on lipid transfer between various lipoproteins