news release
Wednesday, December 11, 2024
This discovery could pave the way for more personalized treatments for cardiovascular disease.
Scientists at the National Institutes of Health (NIH) have made significant advances in understanding how “bad” cholesterol, known as low-density lipoprotein cholesterol, or LDL-C, accumulates in the body. Researchers are now able to show for the first time how LDL’s main structural protein binds to its receptor, the process that initiates its removal from the blood, and what happens when that process is impaired. I was able to do it.
of findingswas published in nature, This could lead to a better understanding of how LDL contributes to heart disease, the world’s leading cause of death, and open the door to personalizing LDL-lowering treatments like statins to make them even more effective. There is.
“LDL is one of the leading causes of cardiovascular disease, killing one person every 33 seconds. So if you want to understand your enemy, you need to know what it looks like.” said co-investigator Alain Lemarie, MD. -Senior author of this study who runs the Lipoprotein Metabolism Laboratory at the National Heart, Lung, and Blood Institute at NIH.
Until now, scientists have not been able to visualize the structure of LDL, specifically what happens when it binds to a protein receptor known as LDLR. Normally, when LDL binds to the LDLR, the process of removing LDL from the blood begins. But genetic mutations can prevent it from working, causing LDL to build up in the blood and deposit in the arteries as plaque, causing atherosclerosis, a precursor to heart disease.
In a new study, researchers used high-end technology to understand what’s happening at a key step in that process, allowing them to look at LDL in a new light.
“LDL is large, varies in size, and is extremely complex,” explains co-senior author Joseph Marcotorigiano, Ph.D., chief of the Section on Structural Viruses, Institute of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH. About research. “No one has come to a solution like we have. We have seen so many details that we were able to begin to figure out how it works in the body. ”
Using an advanced imaging technique called cryo-electron microscopy, the researchers were able to see the entire structural protein structure of LDL as it binds to the LDLR. Using artificial intelligence-powered protein prediction software, they were then able to model the structure and identify known genetic mutations that cause increased LDL. The software’s developer, who was not involved in the research, was recently awarded the 2024 Nobel Prize in Chemistry.
Researchers found that many of the mutations mapped to the location where LDL and LDLR bind are associated with an inherited disease called familial hypercholesterolemia (FH). FH is characterized by a defect in the way the body takes LDL into cells, and people with FH have very high LDL levels and can suffer from heart attacks at a very young age. They found that FH-related mutations tend to cluster in specific regions on LDL.
The findings could open new avenues for the development of targeted therapies aimed at correcting these types of dysfunctional interactions caused by mutations. But importantly, researchers said it could also help people who don’t have the genetic mutation but have high cholesterol and are taking statins, which lower LDL by increasing LDLR in their cells. Researchers say that by knowing exactly where and how the LDLR binds to LDL, they may be able to design new drugs that target those binding points to lower LDL in the blood.
Funding: This research was supported by the National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious Diseases, the National Cancer Institute’s Intramural Research Program, and the NIH Data Science Strategy Office’s High-Value Datasets Program.
About the National Heart, Lung, and Blood Institute (NHLBI): NHLBI is a world leader in conducting and supporting research in heart, lung, and blood diseases and sleep disorders that advances scientific knowledge, improves public health, and saves lives. For more information, please visit: www.nhlbi.nih.gov.
About the National Institutes of Health (NIH):The nation’s medical research agency, NIH, has 27 institutes and centers and is part of the U.S. Department of Health and Human Services. NIH is the primary federal agency that conducts and supports basic, clinical, and translational medical research, investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, please visit www.nih.gov.
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study
Reimund M, Dearborn AD, Graziano G, et al. Structure of apolipoprotein B100 bound to the low-density lipoprotein receptor. Nature. 2024.DOI: 10.1038/s41586-024-08223-0
