News Release
Wednesday, December 11, 2024
Groundbreaking Discovery Could Revolutionize Cardiovascular Disease Treatments
Scientists at the National Institutes of Health (NIH) have made a monumental breakthrough in understanding the intricate workings of “bad” cholesterol – low-density lipoprotein-cholesterol, or LDL-C. For the first time, researchers have unlocked the secrets of how LDL binds to its receptor, a crucial step in clearing LDL from the bloodstream. This discovery sheds light on what happens when this process goes awry, paving the way for personalized treatments for cardiovascular disease, the world’s leading cause of death.
The findings, published in the prestigious journal Nature, deepen our understanding of how LDL contributes to heart disease, a global health crisis. This breakthrough could lead to more effective LDL-lowering drugs like statins by tailoring them to individual needs.
“LDL is a key driver of cardiovascular disease, which tragically claims one life every 33 seconds. To conquer this formidable foe, we must first understand its anatomy and behavior,” said Alan Remaley, M.D., Ph.D., co-senior author of the study and lead researcher at the Lipoprotein Metabolism Laboratory at NIH’s National Heart, Lung, and Blood Institute.
Until now, scientists had struggled to visualize the structure of LDL, particularly the critical moment when it connects with its receptor, known as LDLR. Typically, this binding initiates the removal of LDL from the blood. But genetic mutations can disrupt this process, leading to LDL buildup in the arteries as plaque, a precursor to atherosclerosis and heart disease.
In this groundbreaking study, researchers harnessed cutting-edge technology to observe the LDL-LDLR interaction in unprecedented detail. “LDL is a complex and massive molecule, varying widely in size, which made it extremely challenging to study,” explained Joseph Marcotrigiano, Ph.D., chief of the Structural Virology Section in the Laboratory of Infectious Diseases at NIH’s National Institute of Allergy and Infectious Diseases and co-senior author of the study. “Using cryo-electron microscopy, we achieved a level of resolution never seen before. We could witness intricate details of the binding process and begin to decipher its delicate mechanism.”
By combining this advanced imaging technique with AI-driven protein prediction software – technology recently recognized by the 2024 Nobel Prize in Chemistry – researchers were able to construct a complete 3D model of LDL bound to LDLR.
Remarkably, they discovered that many mutations associated with familial hypercholesterolemia (FH), a genetic disorder characterized by extremely high LDL levels, were concentrated in specific regions where LDL connects with LDLR. FH often leads to heart attacks at a young age.
These findings hold immense promise for developing targeted therapies to correct dysfunctional LDL-LDLR interactions caused by mutations.
Furthermore, this research could revolutionize treatments for individuals with high cholesterol who are taking statins. By precisely pinpointing where LDL and LDLR interact, researchers can design new drugs to enhance LDL clearance from the blood.
Funding: This work was supported by the Intramural Research Programs of the National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases, National Cancer Institute, and the High-Value Datasets program from the NIH Office of Data Science Strategy.
About the National Heart, Lung, and Blood Institute (NHLBI):
NHLBI is the world leader in advancing research and knowledge about heart, lung, and blood diseases and sleep disorders. We strive to improve public health and save lives. For more information, visit
www.nhlbi.nih.gov.
About the National Institutes of Health (NIH):
NIH, the nation’s medical research agency, comprises 27 Institutes and Centers and is a part of the U.S. Department of Health and Human Services. NIH is the leading federal agency conducting and supporting 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, visit www.nih.gov.
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Study
Reimund M, Dearborn AD, Graziano G, et al. Structure of Apolipoprotein B100 bound to low-density lipoprotein receptor. Nature. 2024. DOI: 10.1038/s41586-024-08223-0