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The findings could lead to more tailored treatments for cardiovascular disease.
Scientists at the National Institutes of Health (NIH) have achieved a groundbreaking breakthrough in understanding how “bad” cholesterol, or low-density lipoprotein cholesterol (LDL-C), accumulates in the body. For the first time, researchers have unveiled how LDL’s primary structural protein interacts with its receptor, triggering the process of LDL clearance from the bloodstream. The study, published in Nature, could significantly enhance our understanding of heart disease—the leading cause of death globally—and pave the way for personalized treatments to lower LDL levels, potentially improving the efficacy of existing therapies.
The Link Between LDL and Cardiovascular Disease
“LDL is one of the main drivers of cardiovascular disease, which kills one person every 33 seconds,” said Dr. Alan Remaley, co-senior author of the study and head of the Lipoprotein Metabolism Laboratory at the NIH’s National Heart, Lung, and Blood Institute. “If you want to understand your enemy, you need to know what it looks like.”
Until now, scientists have struggled to visualize the structure of LDL, particularly the crucial moment when it binds with its receptor, LDLR. Normally, this binding process triggers LDL’s removal from the bloodstream. However, genetic mutations can disrupt this mechanism, leading to LDL buildup in the blood, where it forms plaque in the arteries—a precursor to atherosclerosis and cardiovascular disease.
In this new study, researchers employed cutting-edge technology to examine LDL at a pivotal moment in the process, revealing unprecedented details about its structure and function.
Advanced Techniques Uncover New Insights
Using cryo-electron microscopy, a highly advanced imaging technique, the researchers captured the full structure of LDL as it binds to LDLR. In collaboration with artificial intelligence-driven protein prediction software, they were able to model the interaction and pinpoint genetic mutations known to cause elevated LDL levels. The creators of this AI software were recently awarded the 2024 Nobel Prize in Chemistry.
The study revealed that many of the genetic mutations associated with familial hypercholesterolemia (FH)—a condition marked by defective LDL uptake—occur at the very point where LDL and LDLR interact. People with FH often have dangerously high LDL levels and may experience heart attacks at a young age. These mutations were found to cluster in specific regions of LDL, offering critical insights into the mechanisms at play.
The research opens new possibilities for developing therapies that target these dysfunctional interactions. In addition to benefiting individuals with genetic conditions, the findings could also help those without genetic mutations who are taking statins to lower LDL levels. By precisely understanding how LDLR binds to LDL, researchers may now be able to design new drugs that more effectively reduce LDL in the blood.
Looking Ahead
This study represents a crucial step toward tailoring treatments for cardiovascular disease. With better insight into the structure of LDL and its receptor, the door is now open for developing more effective and targeted therapies, potentially reducing the global burden of heart disease.
Reference: “Structure of apolipoprotein B100 bound to the low-density lipoprotein receptor” by Mart Reimund, Altaira D. Dearborn, Giorgio Graziano, Haotian Lei, Anthony M. Ciancone, Ashish Kumar, Ronald Holewinski, Edward B. Neufeld, Francis J. O’Reilly, Alan T. Remaley, and Joseph Marcotrigiano, published on December 11, 2024, in Nature. DOI: 10.1038/s41586-024-08223-0
This research was supported by the Intramural Research Programs of the National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, and the NIH Office of Data Science Strategy’s High-Value Datasets program.
