Researchers at the National Institute of Health (NIH) have unveiled groundbreaking insights into the mechanism by which low-density lipoprotein cholesterol (LDL-C), commonly referred to as “bad” cholesterol, accumulates in the body. For the first time, scientists demonstrated how the structural protein of LDL attaches to its receptor, initiating the process of clearing LDL from the bloodstream—a process that is disrupted when impaired, leading to cholesterol accumulation.
Published in the journal Nature, this research enhances our understanding of LDL’s role in cardiovascular diseases, a predominant cause of mortality globally. It holds potential for personalizing cholesterol-reducing therapies such as statins, optimizing their efficacy.
“Understanding LDL is crucial as it’s a major contributor to cardiovascular disease, which claims a life every 33 seconds,” remarked Dr. Alan Remaley, MD, PhD, co-senior author and head of the Lipoprotein Metabolism Laboratory at NIH’s National Heart, Lung, and Blood Institute.
Previously, visualizing the specific structure of LDL during its interaction with its receptor, LDLR, had been out of reach. Typically, this binding sets off the removal of LDL from the bloodstream. However, genetic mutations can hinder this process, triggering cholesterol accumulation in the blood, leading to arterial plaques and eventually atherosclerosis, a precursor to heart disease.
In this study, researchers applied cutting-edge technology to gain critical insights into this process, viewing LDL from a fresh perspective.
“LDL’s considerable size and variability add complexity,” stated Dr. Joseph Marcotrigiano, PhD, chief of the Structural Virology Section at NIH’s National Institute of Allergy and Infectious Diseases and co-senior study author. “Our resolution level is unprecedented, allowing us to see intricate details and understand its bodily functions.”
Through advanced cryo-electron microscopy, the team visualized the complete structural protein of LDL while it engaged with LDLR. Assisted by artificial intelligence-driven protein modeling software, they constructed a detailed structure and identified mutations leading to elevated LDL levels. The software developers recently received the 2024 Nobel Prize in Chemistry for their contributions.
The study identified mutations at the connectivity points of LDL and LDLR, often linked to familial hypercholesterolemia (FH). FH disrupts the body’s ability to uptake LDL into cells, resulting in extremely elevated LDL levels and early-onset heart attacks. The study found FH-related variants concentrated in specific LDL regions.
These revelations could pave the way for tailored therapies addressing dysfunctional interactions caused by these mutations. Moreover, the research has implications for individuals without genetic mutations but with high cholesterol levels on statins, increasing cellular LDLR to reduce LDL levels. By understanding precisely how LDLR binds to LDL, researchers can potentially design novel drugs targeting these interaction sites.
Funding: The study was funded by the Intramural Research Programs across 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.
About NIH: The National Institutes of Health (NIH) stands as a leader in health research and support, comprising 27 Institutes and Centers as part of the US Department of Health and Human Services. NIH plays a pivotal role in advancing medical understanding and investigating causes, treatments, and cures for both prevalent and uncommon diseases.