Scientists at the National Institute of Health (NIH) have made an important discovery about how “bad” cholesterol, also known as low-density lipoprotein cholesterol (LDL-C), builds up in the body.
For the first time, researchers have visualized how LDL’s main structural protein binds to its receptor, LDLR, a key process that helps remove LDL from the bloodstream.
The breakthrough, published in Nature, sheds light on how disruptions in this process contribute to heart disease, the leading cause of death worldwide.
LDL is often called “bad” cholesterol because when it accumulates in the blood, it can form plaque in the arteries, a condition known as atherosclerosis. This is a major risk factor for heart disease.
Normally, LDL binds to LDLR, allowing the body to clear it from the bloodstream. However, genetic mutations can impair this process, leading to dangerously high LDL levels.
Dr. Alan Remaley, a senior researcher at NIH, explained the importance of understanding LDL at a deeper level. “LDL is a major driver of cardiovascular disease, which kills one person every 33 seconds. If you want to fight it, you need to understand how it works,” he said.
Until now, the complex structure of LDL and its interaction with LDLR had been a mystery. The LDL particle is enormous and varies in size, making it difficult to study.
Using advanced cryo-electron microscopy (a powerful imaging technique), NIH scientists were able to observe the entire structural protein of LDL when it binds to LDLR.
Artificial intelligence-powered protein modeling further helped researchers understand the structure and pinpoint genetic mutations that increase LDL levels.
These findings have significant implications for people with familial hypercholesterolemia (FH), a genetic condition that prevents the body from properly absorbing LDL into cells. Individuals with FH often have extremely high cholesterol levels and are at risk of heart attacks, even at a young age.
The study revealed that many genetic mutations linked to FH occur at the connection points between LDL and LDLR. These findings provide insights into why LDL builds up in people with FH and highlight potential areas for therapeutic intervention.
The implications of this study go beyond genetic conditions. Many people with high cholesterol do not have genetic mutations but rely on medications like statins to manage their LDL levels.
Statins work by increasing the number of LDLR proteins in cells, which enhances the body’s ability to remove LDL from the bloodstream. Understanding exactly how LDLR binds to LDL could lead to the development of more targeted treatments that improve the effectiveness of current therapies.
“This is a huge step forward,” said Dr. Joseph Marcotrigiano, another senior author of the study. “No one has ever seen LDL in such detail before. Now we can start to unravel how it works and why it goes wrong.”
The study not only opens up possibilities for designing better cholesterol-lowering drugs but also provides hope for more personalized treatments.
By targeting specific connection points between LDL and LDLR, researchers may be able to create therapies that address the root causes of high cholesterol in different individuals.
While the work is still in its early stages, this discovery marks a critical step in the fight against heart disease. By uncovering the intricate mechanics of LDL and its receptor, scientists are paving the way for new solutions to a global health crisis.
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The research findings can be found in Nature.
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