Scientists have discovered how bad cholesterol, known as low-density lipoprotein cholesterol or LDL-C, accumulates and acts in the body.
A research team from the National Institutes of Health (NIH), United States Department of Health, has shown for the first time how the main structural protein of LDL binds to its receptor and what happens when this process deteriorates.
The results, on Wednesday at Natureshed light on LDL’s contribution to heart disease – the world’s leading cause of death – and could open the door to more effective personalized treatments to lower LDL.
“LDL is one of the main causes of cardiovascular disease, which kills one person every 33 secondsbut if we want to understand the enemy, we have to know what it is like”, highlighted Alan Remaley, co-main author of the study and director of the Lipoprotein Metabolism Laboratory at the National Heart, Lung and Blood Institute of the NIH, cited by the Lusa agency.
Until now it was not possible to visualize the structure of LDLnor what happens when it binds to its receptor, a protein known as LDLR.
Here’s what happens in our body
Normally, when LDL and LDLR come together, the process of removing LDL from the blood begins.
However, genetic mutations can impede this work, causing the LDL accumulates in the blood and is deposited in the arteries as plaquesleading to atherosclerosis that causes heart disease.
In this research, for the first time and with cutting-edge technology, researchers were able to see what happens at a critical stage of this process and observe LDL in a new light.
“No one has ever reached the resolution we have. We can see it in so much detail and begin to unravel how it works in the body,” explained Joseph Marcotrigiano, of the National Institute of Allergy and Infectious Diseases at the NIH and co-lead author of the study.
The researchers used an advanced imaging technique – called cryo-electron microscopy – to see the entire structural protein of LDL as it binds to LDLR.
Then, using ‘software’ based on artificial intelligence, they modeled the structure and located the genetic mutations that lead to increased LDL (The software developers, who were not involved in the study, were recently awarded the 2024 Nobel Prize in Chemistry).
Thus, they discovered that many of the mutations located at the point of connection between LDL and LDLR were associated with a hereditary disease called Familial hypercholesterolemia (FH).
FH is characterized by defects in the way the body absorbs LDL into its cells, and patients have extremely high levels of LDL and can suffer heart attacks at a very young age. It turned out that the variants associated with FH tended to cluster in certain regions of LDL.
The results of the study could open new avenues for developing therapies designed to correct these types of dysfunctional interactions caused by mutations and, equally important, could help people who do not have genetic mutations but who have high cholesterol and take statins, which reduce the LDL in increasing LDLR in cells.
By knowing precisely where and how LDLR binds to LDL, the authors argued that they can now target these binding points to engineer new drugs to reduce LDL in the blood.
