Photo credit: www.sciencedaily.com
NIH Researchers Unravel LDL-C Binding Mechanism: A Step Towards Personalized Heart Disease Treatments
Scientists at the National Institutes of Health (NIH) have achieved an important milestone in deciphering the mechanism behind the accumulation of low-density lipoprotein cholesterol (LDL-C), commonly referred to as “bad” cholesterol, in the body. This groundbreaking research illustrates how the primary structural protein of LDL interacts with its receptor, a process pivotal for the removal of LDL from the bloodstream, and examines the implications when this interaction is disrupted.
The results of this study, featured in Nature, enhance the understanding of LDL’s role in heart disease, which continues to be the predominant cause of mortality globally. This research could potentially pave the way for more tailored LDL-lowering therapies, such as statins, increasing their effectiveness for individuals.
“Understanding the intricacies of LDL is crucial, as it is one of the key contributors to cardiovascular disease, which claims a life every 33 seconds,” remarked Alan Remaley, M.D., Ph.D., one of the study’s co-senior authors and head of the Lipoprotein Metabolism Laboratory at NIH’s National Heart, Lung, and Blood Institute.
Historically, researchers faced challenges in visualizing the specific structure of LDL and its binding interactions with its receptor, known as LDLR. Normally, the binding of LDL to LDLR triggers the process of removing LDL from circulation. Yet, certain genetic mutations can hinder this process, leading to elevated LDL levels in the bloodstream and subsequent plaque formation in arteries, a key factor in atherosclerosis and heart disease.
In the current study, investigators utilized advanced imaging techniques to observe the LDL binding process in unprecedented detail.
“The LDL particle is large and exhibits considerable complexity due to its size variations,” explained Joseph Marcotrigiano, Ph.D., chief of the Structural Virology Section at NIH’s National Institute of Allergy and Infectious Diseases and co-senior author of the research. “Our study achieved a resolution that has never been attained before, providing a clear picture and enabling us to discern the functional aspects of LDL within the body.”
Employing cryo-electron microscopy, researchers captured detailed images of the entire LDL structural protein as it interacted with LDLR. They then utilized artificial intelligence-based protein prediction software to model this structure, highlighting known genetic mutations linked to heightened LDL levels. Notably, the developers of this software were recognized with the 2024 Nobel Prize in Chemistry for their groundbreaking work, though they were not directly involved in this study.
The analysis revealed that numerous mutations correlated with the site of LDL and LDLR binding were associated with familial hypercholesterolemia (FH), a hereditary condition characterized by the body’s impaired ability to process LDL, resulting in significantly elevated LDL levels and an increased risk of early heart attacks. The research identified that variants associated with FH frequently concentrated in specific areas of the LDL molecule.
The implications of these findings are promising, opening up possibilities for targeted therapies designed to rectify dysfunctional interactions caused by these genetic mutations. Additionally, for individuals without these mutations but suffering from high cholesterol, insights into the exact binding mechanisms of LDLR and LDL could lead to the development of new pharmacological strategies aimed at enhancing the efficacy of existing LDL-lowering treatments.
Source
www.sciencedaily.com