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

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
lcyarris@lbl.gov
510-486-5375
DOE/Lawrence Berkeley National Laboratory
Source:Eurekalert  

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:
*Name:
*Comment:
*Email:
Related Image:
How good cholesterol turns bad
(Date:2/3/2016)... 2016 http://www.researchandmarkets.com/research/d8zjcd/emotion_detection ... "Emotion Detection and Recognition Market by ... Software Tools (Facial Expression, Voice Recognition and ... - Global forecast to 2020" report ... http://www.researchandmarkets.com/research/d8zjcd/emotion_detection ) has announced the addition of ...
(Date:2/2/2016)... YORK , Feb. 2, 2016 ... of that Rising Market Are you interested ... analysis forecasts revenues for checkpoint inhibitors. Visiongain,s report ... market, submarket, product and national level. Avoid ... discover what progress, opportunities and revenues those emerging ...
(Date:2/2/2016)... Calif. , Feb. 2, 2016  Based ... market, Frost & Sullivan recognizes US-based Intelligent Retinal ... Frost & Sullivan Award for New Product Innovation. ... in North America , is ... the rapidly growing diabetic retinopathy market. The IRIS ...
Breaking Biology News(10 mins):
(Date:2/4/2016)... ... February 04, 2016 , ... ... of Semantic Graph Database technology has been recognized As “ Best in Semantic ... America Magazine. , “At Corporate America, it’s our priority to showcase prominent professionals ...
(Date:2/3/2016)... 2016  Discovery Laboratories, Inc. (NASDAQ: DSCO ... KL4 surfactant therapies for respiratory diseases, today announced ... inducement award as a component of employment compensation ... President and Chief Executive Officer.  The award was ... 1, 2016 and granted as an inducement material ...
(Date:2/3/2016)... 2016 New Jersey Health Foundation (NJHF) has ... for researchers in New Jersey ... demonstrates exciting potential.   James M. ... New Jersey Health Foundation Research Grant Program ... institutions— Princeton University, Rutgers University, Rowan University and ...
(Date:2/3/2016)... ... February 03, 2016 , ... ... which summarizes and analyzes nearly 750 unique supply chain notifications and alerts ... service. , Supply chain risk management practitioners subscribe to the EventWatch service ...
Breaking Biology Technology: