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In a groundbreaking development, scientists at the U.S. National Institutes of Health (NIH) have uncovered critical new insights into how “bad” cholesterol—low-density lipoprotein cholesterol (LDL)—contributes to heart attacks and strokes. The discovery, which could lead to innovative treatments for cholesterol-related cardiovascular diseases, comes thanks to an advanced technology called cryo-electron microscopy (cryo-EM).
Cryo-EM, which won its inventors the Nobel Prize in 2017, allowed the researchers to capture a detailed, freeze-frame-like image of LDL molecules, revealing their structure for the first time. This unprecedented view has already begun to shed light on how LDL accumulates in the body, a key factor in heart disease, especially in those with a genetic condition called familial hypercholesterolemia (FH). FH causes abnormally high levels of LDL cholesterol from birth, increasing the risk of heart attacks and strokes at an early age.
The NIH scientists, led by Dr. Alan Remaley, senior investigator in lipoprotein metabolism, believe that understanding the precise structure of LDL could help develop new strategies to prevent its buildup in arteries. “Our findings provide a potential new strategy for increasing the ability of the LDL receptor for binding and removing LDL from the circulation,” Dr. Remaley explained.
Until now, while it was known that high LDL levels contribute to cardiovascular disease, researchers struggled to observe the exact process by which LDL accumulates and causes damage. The ability to visualize LDL in such fine detail using cryo-EM opens new possibilities for designing drugs that could prevent or reverse its harmful effects.
Cryo-EM works by freezing molecules at incredibly low temperatures, essentially capturing them in a “snapshot” form. These frozen images are then analyzed by a computer algorithm to create three-dimensional models. This technology has become an essential tool in biological and biomedical research, offering a revolutionary way to study the structures of biological molecules.
Dr. Aditi Das and Dr. MG Finn, both from Georgia Tech’s School of Chemistry and Biochemistry, emphasized the importance of this technology, describing it as a game-changer for understanding biological processes at the molecular level. “When we know the structure of molecules, we gain invaluable insight into how they function and how we can intervene when they malfunction,” Dr. Finn said.
LDL’s role in the body is not inherently harmful—it transports cholesterol to cells for energy, repair, and hormone production. However, when produced in excess, often due to unhealthy diets rich in saturated and trans fats, LDL can accumulate in the arteries, leading to plaque buildup. This process can cause inflammation, narrowing the blood vessels, and eventually lead to heart attacks or strokes.
The breakthrough also comes at a time when heart disease remains the leading cause of death in the United States. In individuals with FH, LDL levels can be extremely high, significantly increasing their risk of early coronary artery disease. Currently, most people with FH manage their condition with statins or other medications, but these treatments are not always fully effective.
As researchers continue to explore the implications of this discovery, the hope is that cryo-EM will unlock the key to developing more targeted and effective treatments for managing LDL cholesterol. Experts like Dr. Danny J. Eapen of Emory University School of Medicine stress the importance of dietary changes alongside medical interventions. Replacing harmful fats, such as those found in butter and margarine, with healthier options like olive oil, fish, and nuts can help lower LDL levels and reduce the risk of heart disease.
This breakthrough, made possible by cryo-EM technology, marks a significant step forward in the fight against heart disease, offering new hope for patients with genetically high cholesterol and potentially revolutionizing the way we approach cardiovascular health in the future.
