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How good cholesterol turns bad
Date:2/21/2012

th in the United States and 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 clinical interest in CETP, little is known concerning 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 says. "We were successful because 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 and his colleagues used their 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 says. "This is an important step toward the rational design of next generation CETP inhibitors fo
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Contact: Lynn Yarris
lcyarris@lbl.gov
510-486-5375
DOE/Lawrence Berkeley National Laboratory
Source:Eurekalert  

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