How good cholesterol turns bad
February 22, 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."
This research was supported in part by the DOE Office of Science, and in part by W. M. Keck foundations, the Chinese Ministry of Education, the National Institutes of Health, and the Tobacco Related Disease Research Program of California.
Lawrence Berkeley National Laboratory addresses the world's most urgent scientific challenges by advancing sustainable energy, protecting human health, creating new materials, and revealing the origin and fate of the universe. Founded in 1931, Berkeley Lab's scientific expertise has been recognized with 13 Nobel prizes. The University of California manages Berkeley Lab for the U.S. Department of Energy's Office of Science. For more, visit www.lbl.gov.
DOE's Office of Science is the single largest supporter of basic research in the physical sciences in the United States, and is working to address some of the most pressing challenges of our time. For more information, please visit science.energy.gov.
The Molecular Foundry is one of five DOE Nanoscale Science Research Centers (NSRCs), national user facilities for interdisciplinary research at the nanoscale, supported by the DOE Office of Science. Together the NSRCs comprise a suite of complementary facilities that provide researchers with state-of-the-art capabilities to fabricate, process, characterize and model nanoscale materials, and constitute the largest infrastructure investment of the National Nanotechnology Initiative. The NSRCs are located at DOE's Argonne, Brookhaven, Lawrence Berkeley, Oak Ridge and Sandia and Los Alamos National Laboratories. For more information about the DOE NSRCs, please visit http://science.energy.gov
DOE/Lawrence Berkeley National Laboratory
Related Cholesterol Current Events and Cholesterol News ArticlesCommunity-based weight loss program aids diabetes management
Weight loss and control of blood sugar can reduce the risk of complications in patients with diabetes but this is difficult for many to achieve.Scientists alter fat metabolism in animals to prevent most common type of heart disease
Working with mice and rabbits, Johns Hopkins scientists have found a way to block abnormal cholesterol production, transport and breakdown, successfully preventing the development of atherosclerosis, the main cause of heart attacks and strokes and the number-one cause of death among humans. Safer alternatives to nonsteroidal anti-inflammatory pain killers
Nonsteroidal antinflamatory drugs (NSAIDs) that block an enzyme called COX-2 relieve pain and inflammation but can cause heart attacks, stroke, heart failure, and even sudden cardiac death. Narrowing of neck artery without warning may signal memory and thinking decline
For the first time, researchers have demonstrated that narrowing of the carotid artery in the neck without any symptoms may be linked to problems in learning, memory, thinking and decision-making, compared to people with similar risk factors but no narrowing in the neck artery.Pharmacist-led interventions show high success rates for post-stroke care
A new study from the Faculty of Medicine & Dentistry is looking at nurse- and pharmacist-led interventions to improve the standard of care for patients who have suffered minor stroke or transient ischemic attack, also known as "mini stoke."Study links severe sleep apnea to increased risk of stroke, cancer and death
A new study shows that moderate to severe obstructive sleep apnea is independently associated with an increased risk of stroke, cancer and death.Eating rice boosts diet quality, reduces body weight and improves markers for health
New research, partially funded by the U.S. Department of Agriculture and the USA Rice Federation, shows that consumers can improve their diets simply by enjoying white or brown rice as part of their daily meals. Obeticholic acid produces meaningful biochemical and clinical improvements in PBC cirrhosis patients
Results from an international Phase III study presented today at the International Liver CongressTM 2014 have shown obeticholic acid (OCA) given to patients suffering from Primary Biliary Cirrhosis (PBC) who previously had an inadequate response to, or have been unable to tolerate ursodeoxycholic acid (UDCA), produced meaningful biochemical and clinical improvements.Vigilance for Kidney Problems Key for Rheumatoid Arthritis Patients
Rheumatoid arthritis patients are likelier than the average person to develop chronic kidney disease, and more severe inflammation in the first year of rheumatoid arthritis, corticosteroid use, high blood pressure and obesity are among the risk factors, new Mayo Clinic research shows.Montréal researchers explain how our immune system kills abnormal blood cells
A team of researchers at the IRCM, led by André Veillette, MD, explains how our immune system kills abnormal blood cells.
More Cholesterol Current Events and Cholesterol News Articles
The Great Cholesterol Myth: Why Lowering Your Cholesterol Won't Prevent Heart Disease-and the Statin-Free Plan That Will|
by Jonny Bowden (Author), Stephen Sinatra (Author)
Heart disease is the #1 killer. However, traditional heart disease protocols--with their emphasis on lowering cholesterol--have it all wrong. Emerging science is showing that cholesterol levels are a poor predictor of heart disease and that standard prescriptions for lowering it, such as ineffective low-fat/high-carb diets and serious, side-effect-causing statin drugs, obscure the real causes of heart disease. Even doctors at leading institutions have been misled for years based on creative reporting of research results from pharmaceutical companies intent on supporting the $31-billion-a-year cholesterol-lowering drug industry.The Great Cholesterol Myth reveals the real culprits of heart disease, including:
Cholesterol Down: Ten Simple Steps to Lower Your Cholesterol in Four Weeks--Without Prescription Drugs|
by Janet Brill (Author)
Take Control of Your Cholesterol— Without Drugs
If you are one of the nearly 100 million Americans struggling with high cholesterol, then Dr. Janet Brill offers you a revolutionary new plan for taking control of your health—without the risks of statin drugs. With Dr. Brill’s breakthrough Cholesterol Down Plan, you simply add nine “miracle foods” to your regular diet and thirty minutes of walking to your daily routine. That’s all. This straightforward and easy-to-follow program can lower your LDL (“bad”) cholesterol by as much as 47 percent in just four weeks.
Cholesterol Down explains Dr. Brill’s ten-point plan as well as the science behind it. You’ll learn how each miracle food affects LDL cholesterol and how the foods work together for maximum effect,...
The Cholesterol Solution Guide: Lower Your Cholesterol in 30 Days Without Drugs|
Discover How Easy It Is To Lower Your Cholesterol in 30 DAYS
This book will tell you what cholesterol is, its signs, symptoms, causes, and types, so that you will be aware of the need to reduce your LDL or bad cholesterol levels and increase the HDL or good cholesterol levels.
This book contains proven steps and strategies on how to lower your cholesterol the natural way in just 30 days.
Here Is A Preview Of What You'll Learn...
What is Cholesterol? Symptoms and Effects of High Cholesterol What Causes High Cholesterol? Cholesterol-Lowering Foods Home Remedies to Lower Cholesterol Lowering Cholesterol with FiberOatmeal for Cholesterol Barley and Cholesterol Red Yeast Rice for Cholesterol Reduction Eggplant and Cholesterol Cinnamon and...
Heart Health: 101 Best Foods To Lower Cholesterol and Prevent Heart Disease|
by Millwood Media
Don’t be the next statistic!
Heart disease is the leading cause of death in the United States and is a major cause of disability!
While it’s important to always be paying attention to your calorie intake in order to achieve a healthy body weight, one cannot overlook where these calories are coming from. If you eat a diet that is full of fatty meats, highly refined carbohydrates, and other fast and processed foods, you’re setting yourself up for numerous health problems.
Some of the main health conditions that you could be at risk for include cancer, diabetes, stroke, as well as heart disease. If you let your cholesterol levels get out of check and are experiencing high blood pressure or other factors due to that, you could be at risk for one...
Cholesterol Clarity: What The HDL Is Wrong With My Numbers?|
by Jimmy Moore (Author), Eric C. Westman (Author)
Are you confused by what your cholesterol levels really say about your health?
Don't you wish someone could just spell it out in simple, easy-to-understand language and tell you what, if anything, you need to do about your cholesterol? Good news! That's precisely what Cholesterol Clarity is designed to do. Jimmy Moore, a prominent and highly respected health blogger and podcaster, has teamed up with Dr. Eric Westman, a practicing internist and nutrition researcher, to bring you one of the most unique books you'll ever read on this subject, featuring exclusive interviews with twenty-nine of the world's top experts from various fields to give you the complete lowdown on cholesterol. If you're worried about any confusing medical jargon in this book, don't be—this critical...
The Cholesterol Myth: The Biggest Medical Conspiracy of The Last 50 Years|
With all the hype about cholesterol one would think that heart disease would be all but wiped out. Sadly this is not the case, heart disease is still the number one killer. The cholesterol theory of heart disease has been shown to be invalid time after time. Homocystine and CRP are far more accurate predictors of heart disease. Inflamation causes the oxidation of LDL which contributes to cholesterol buildup in the blood vessels. Read on to find out what you can do to restor your LDL?/HDL balance.
You need cholesterol; You need it desperately. Every Cell in your body cries out for it. Life without cholesterol is miserable. You will be weak, slow, frail, and impotent.
Controlling Cholesterol For Dummies|
by Carol Ann Rinzler (Author), Martin W. Graf MD (Contributor)
Need to get your cholesterol in check? You’ll find the latest information about cholesterol, including treatments, drug information, and dietary advice, in Controlling Cholesterol For Dummies, 2nd Edition, an easy-to-understand guide to cholesterol control. You’ll learn how to lower your numbers and maintain healthy cholesterol levels. You’ll also find out how to eat and exercise properly, use vitamins and supplements, and quit unhealthy habits.You’ll find out cholesterol’s positive functions and why too much can be a bad thing. You can also assess your cholesterol risk by taking your age, sex, ethnicity, and family history into consideration. Find out what you need to ask your doctor about stress tests, ECBT, and angiograms to check for plaque buildup. Design a...
The Everything Low-Cholesterol Cookbook: Keep you heart healthy with 300 delicious low-fat, low-carb recipes (Everything: Cooking)|
by Linda Larsen (Author)
Good fats, bad fats, trans fats . . . eating right may sound complicated but it doesn't have to be. You can eat well and keep your cholesterol levels in check. In The Everything Low-Cholesterol Cookbook you'll find 300 mouth-watering recipes that are low fat and low sodium including: Chocolate Pancakes Cinnamon Hazelnut Scones Stuffed Jalapeño Peppers Creamy Grilled Cheese Sandwiches Chunky Irish Potato Leek Soup Texas BBQ Chicken Thighs Corned Beef Hash Mango Walnut Upside-Down Cake Lite Creamy Cheesecake If you are one of the millions of people living with high cholesterol, this cookbook will give you healthy and scrumptious options that you-and your family-will love!
American Heart Association Low-Fat, Low-Cholesterol Cookbook, 4th edition: Delicious Recipes to Help Lower Your Cholesterol|
by American Heart Association (Author)
Eat wisely, eat well.
The nation’s most trusted authority on heart-healthy living presents the fourth edition of this classic cookbook, with the most up-to-date information on heart health and nutrition—including the effects of saturated and trans fats and cholesterol—and 50 exciting new recipes.
American Heart Association Low-Fat, Low-Cholesterol Cookbook offers more than 200 delicious, easy-to-prepare dishes, including:
•Fresh Basil and Kalamata Hummus
•Elegant Beef Tenderloin
•Tilapia Tacos with Fresh Salsa
•Garlic Chicken Fillets in Balsamic Vinegar
•Peppery Beef with Blue Cheese Sauce
•Thai Coconut Curry with Vegetables
•Sweet Potatoes in Creamy Cinnamon Sauce
A Cholesterol Solution : Lower Cholesterol Levels Naturally In Less Than 4 weeks (Cholesterol, Cholesterol Diet, Cholesterol Solution, reduce cholesterol)|
by Brian Rogers
LOWER CHOLESTEROL LEVELS NATURALLY FAST AND KEEP THEM THAT WAY
Today only, get this Amazon bestseller for just $0.99. Regularly priced
at $4.99. Read on your PC, Mac, smart phone, tablet or Kindle device.
Many people suffer from cholesterol problems, but only few know how to treat it naturally. In this book, you will learn how to lower your cholesterol levels naturally and keep them low in less than 4 weeks. This book also provides symptoms and signs of low cholesterol. High Cholesterol can be fatal to anyone's health, that's why it is good to lower it naturally.
Here Is A Preview Of What You'll Learn...
Cholesterol and its usesCholesterol and HealthFoods that Lower CholesterolExercising for Health to lower cholesterolFactors Affecting CholesterolGood...