Navigation Links
How good cholesterol turns bad

Researchers with the U.S. Department of Energy (DOE)'s Lawrence Berkeley National Laboratory (Berkeley Lab) have found new evidence to explain how cholesteryl ester transfer protein (CETP) mediates the transfer of cholesterol from "good" high density lipoproteins (HDLs) to "bad" low density lipoproteins (LDLs). These findings point the way to the design of safer, more effective next generation CETP inhibitors that could help prevent the development of heart disease.

Gang Ren, a materials physicist and electron microscopy expert with Berkeley Lab's Molecular Foundry, a DOE nanoscience research center, led a study in which the first structural images of CETP interacting with HDLs and LDLs were recorded. The images and structural analyses support the hypothesis that cholesterol is transferred from HDLs to LDLs via a tunnel running through the center 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," Ren says. "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."

Ren reports the results of this study in a paper in the journal Nature Chemical Biology titled "Structure basis of transfer between lipoproteins by cholesteryl ester transfer protein." Co-authoring this paper were Lei Zhang, Feng Yan, Shengli Zhang, Dongsheng Lei, M. Arthur Charles, Giorgio Cavigiolio, Michael Oda, Ronald Krauss, Karl Weisgraber, Kerry-Anne Rye, Henry Powna and Xiayang Qiu.

Cardiovascular or heart disease, mainly atherosclerosis, remains the leading cause of death 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 for treating cardiovascular disease."


Contact: Lynn Yarris
DOE/Lawrence Berkeley National Laboratory

Related biology news :

1. Cholesterol-lowering drugs and the effect on muscle repair and regeneration
2. Penn biophysicists create new model for protein-cholesterol interactions in brain and muscle tissue
3. MSU researcher studies ties between cholesterol drugs, muscle problems
4. A scientific breakthrough on the control of the bad cholesterol
5. Researchers learn that some good cholesterol isnt good enough
6. New genes present drug targets for managing cholesterol and glucose levels
7. Hypertension and cholesterol medications present in water released into the St. Lawrence River
8. Lowering your cholesterol may decrease your risk of cancer
9. Cholesterol-busting bug with a taste for waste
10. Cholesterol necessary for brain development
11. UCLA researchers reconstitute enzyme that synthesizes cholesterol drug lovastatin
Post Your Comments:
Related Image:
How good cholesterol turns bad
(Date:10/13/2015)... Research and Markets ( ) has announced the ... Market - Estimation & Forecast (2015-2020)" report to ... --> The biometric market value is anticipated to ... in 2020 at an estimated CAGR of 16.47% from ... . Growing digitization in the government sector is expected ...
(Date:10/12/2015)... -- NXTD ) ("NXT-ID" or the "Company"), a ... reports on the recent SNS Future in Review Conference in ... NXTD ) ("NXT-ID" or the "Company"), a biometric authentication company ... recent SNS Future in Review Conference in Park ... NXTD ) ("NXT-ID" or the "Company"), a biometric authentication ...
(Date:10/8/2015)... October 8, 2015 NXT-ID, ... "Company"), a biometric authentication company focused on the ... Wocket® smart wallet announces that revenues for the ... $410,000 compared with $113,00 for the three months ... months ended September 30, 2015 were approximately $520,000. ...
Breaking Biology News(10 mins):
(Date:10/13/2015)... ... ... Proove Biosciences, a commercial and research leader ... Medicine of the University of Southern California (USC) Pain Center to study ... Clinical Objectives Linking Genotypic and Phenotypic Association with Pain Outcomes) is one of ...
(Date:10/12/2015)... Calif. and BRUSSELS , Oct. ... (Euronext Brussels: UCB) today presented additional findings from an exploratory ... The findings were presented today in an oral plenary ... (ASBMR) 2015 Annual Meeting in Seattle . ... --> The small exploratory sub-study data showed ...
(Date:10/12/2015)... , Oct. 12, 2015 This report covers ... include cell type, products, applications, end-user markets and geographic ... HIGHLIGHTS The global cell expansion market generated revenue ... to reach revenues of $9.7 billion in 2015 and ... rate (CAGR) of 17.8% from 2015 to 2020. ...
(Date:10/12/2015)... octubre de 2015 El 8 de octubre, ... récord en el congreso con su declaración acerca del ... Plasma Awareness Week (IPAW), que se celebrará del 11 ... la Plasma Protein Therapeutics Association (PPTA) y ... , Aumentar la concienciación mundial acerca de la donación ...
Breaking Biology Technology: