Berkeley Lab Discover New Evidence On How ‘Good’ Cholesterol Turns ‘Bad’

Researchers with the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) have discovered new proof to clarify how cholesteryl ester transfer protein (CETP) mediates the move of cholesterol from “good” high density lipoproteins (HDLs) to “bad” low density lipoproteins (LDLs).

The outcomes of the research study were conveyed in the journal Nature Chemical Biology, titled ‘Structure basis of transfer between lipoproteins by cholesteryl ester transfer protein’.  The results offer insights into the design of safer, more effective next generation CETP inhibitors that could assist in preventing the development of heart disease.

Gang Ren, a materials physicist and electron microscopy expert with Berkeley Lab’s Molecular Foundry, led a study in which the first structural images of CETP interacting with HDLs and LDLs were recorded.

The images and structural analyses back the theory that cholesterol is transferred from HDLs to LDLs via a tunnel running through the centre of the CETP molecule.

“Our images show that CETP is a small (53 kilodaltons) banana-shaped asymmetric molecule with a tapered N-terminal domain and a globular C-terminal domain,” Gang Ren commented.

“We discovered that the CETP’s N-terminal penetrates HDL and its C-terminal interacts with LDL forming a ternary complex.  Structure analyses lead us to hypothesize that the interaction may generate molecular forces that twist the terminals, creating pores at both ends of the CETP.  These pores connect with central cavities in the CETP to form a tunnel that serves as a conduit for the movement of cholesterol from the HDL,” he added.

Cardiovascular or heart disease, mainly atherosclerosis, continues to be the leading cause of death throughout the world.  Elevated levels of LDL cholesterol and/or reduced levels of HDL cholesterol in human plasma are major risk factors for heart disease.

Since CETP activity can reduce HDL-cholesterol concentrations and CETP deficiency is associated with elevated HDL-cholesterol levels, CETP inhibitors have become a highly sought-after pharmacological target for the treatment of heart disease.

However, despite this intense interest, not much is known about the molecular mechanisms of CETP-mediated cholesterol transfers among lipoproteins, or even how CETP interacts with and binds to lipoproteins.

“It has been very difficult to investigate CETP mechanisms using conventional structural imaging methods because interaction with CETP can alter the size, shape and composition of lipoproteins, especially HDL,” Ren observed.

As a result, “we used our optimized negative-staining electron microscopy protocol that allows us to flash-fix the structure and efficiently screen more than 300 samples prepared under different conditions,” Ren added.

The study used the optimized negative-staining electron microscopy protocol to image CETP as it interacted with spherical HDL and LDL particles.

Image processing techniques yielded three-dimensional reconstructions of CETP and CETP-bound HDL.  Molecular dynamic simulations were used to assess CETP molecular mobility and predict the changes that would be associated with cholesterol transfer.  CETP antibodies were used to identify the CEPT interaction domains and validate the cholesterol transfer model by inhibiting CETP.  This model presents inviting new targets for future CETP inhibitors.

“Our model identifies new interfaces of CETP that interact with HDL and LDL and delineates the mechanism by which the transfer of cholesterol takes place,” Ren commented.  “This is an important step toward the rational design of next generation CETP inhibitors for treating cardiovascular disease.”

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