All iLive content is medically reviewed or fact checked to ensure as much factual accuracy as possible.
We have strict sourcing guidelines and only link to reputable media sites, academic research institutions and, whenever possible, medically peer reviewed studies. Note that the numbers in parentheses ([1], [2], etc.) are clickable links to these studies.
If you feel that any of our content is inaccurate, out-of-date, or otherwise questionable, please select it and press Ctrl + Enter.
The mechanism of conversion of "good" lipoprotein to "bad" lipoprotein has been elucidated
Last reviewed: 01.07.2025
American scientists from the Lawrence Berkeley National Laboratory have finally figured out how the cholesterol ester transfer protein (CETP) ensures the transfer of cholesterol from "good" high-density lipoproteins (HDLs ) to "bad" low-density lipoproteins (LDLs). This opens up new ways to design safer and more effective next-generation CETP inhibitors that could prevent the development of cardiovascular diseases.
(1) CETP penetrates HDL. (2) Formation of pores at both ends of CETP. (3) The pores mate with a cavity in CETP, forming a channel for cholesterol transfer, (4) resulting in a decrease in HDL size. (Illustration by Gang Ren/Berkeley Lab.)
The team that first recorded a structural representation of CETP's interactions with HDLs and LDLs is led by Gan Ren, an electron microscopy specialist and materials physicist at Lawrence Berkeley National Laboratory. Her structural mappings and structural analysis support the hypothesis that cholesterol is transferred from HDLs to LDLs via a tunnel through the center of the CETP molecule.
According to the researchers, CETP is a small (53 kDa), asymmetric molecule resembling a banana with a wedge-shaped N-terminal domain and a spherical C-terminal domain. The scientists found that the N-terminal penetrates HDL, while the C-terminal interacts with LDL. Structural analysis allowed them to hypothesize that this triple interaction is capable of generating a force that twists the terminals, forming pores at both ends of CETP. The pores, in turn, mate with a central cavity in the CETP molecule, forming a tunnel that serves as a kind of aqueduct for the movement of cholesterol from HDL.
The results of the work were published in the journal Nature Chemical Biology.
Cardiovascular diseases (mainly atherosclerosis) remain the leading cause of early death in the United States and worldwide. Elevated LDL-cholesterol and/or decreased HDL-cholesterol levels in blood plasma, for their part, are the main risk factors for the development of heart failure. That is why the development of effective CETP inhibitors has become a very popular pharmacological approach to the treatment of cardiovascular diseases. However, despite the highest clinical interest in CETP, little was known about the mechanism of cholesterol transfer between lipoproteins until now. Even how exactly CETP binds to these lipoproteins remained unclear.
Mr Ren explains that it is very difficult to study the mechanisms of CETP using standard structural imaging methods, since interactions with CETP change the size, shape and even the composition of lipoproteins, especially HDL. His group was able to achieve this using a method called negative contrast electron microscopy, an optimized protocol for which he and his colleagues developed to image how CETP interacts with spherical particles of HDL and LDL. A special technique for processing the resulting images made it possible to create a three-dimensional reconstruction of the CETP molecule and the CETP-HDL adduct. Modeling the dynamics of the system made it possible to calculate the molecular mobility of CETP and predict changes associated with cholesterol transfer.
According to Gan Ren, the model created outlines the mechanism by which cholesterol transfer occurs. This is indeed an important step towards the rational design of next-generation CETP inhibitors for the treatment of cardiovascular diseases.